Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits.

PubMed

Odening, Katja E; Jung, Bernd A; Lang, Corinna N; Cabrera Lozoya, Rocio; Ziupa, David; Menza, Marius; Relan, Jatin; Franke, Gerlind; Perez Feliz, Stefanie; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Brunner, Michael; Sermesant, Maxime; Föll, Daniela

2013-10-01

Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias. To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS. Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments. In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data. The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an

Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs

PubMed Central

Herrera, José A.; Ward, Christopher S.; Pitcher, Meagan R.; Percy, Alan K.; Skinner, Steven; Kaufmann, Walter E.; Glaze, Daniel G.; Wehrens, Xander H. T.; Neul, Jeffrey L.

2015-01-01

One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na+ channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na+ channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na+ channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na+ channel blocker antiepileptic therapies. Thus, Na+ channel blockers should be considered for the clinical management of LQT in individuals with RTT. PMID:25713300

Visualizing Mutation-Specific Differences in the Trafficking-Deficient Phenotype of Kv11.1 Proteins Linked to Long QT Syndrome Type 2.

PubMed

Hall, Allison R; Anderson, Corey L; Smith, Jennifer L; Mirshahi, Tooraj; Elayi, Claude S; January, Craig T; Delisle, Brian P

2018-01-01

KCNH2 encodes the Kv11.1 α-subunit that underlies the rapidly activating delayed-rectifier K + current in the heart. Loss-of-function KCNH2 mutations cause long QT syndrome type 2 (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channel protein to the cell surface membrane. Several trafficking-deficient LQT2 mutations (e.g., G601S) generate Kv11.1 proteins that are sequestered in a microtubule-dependent quality control (QC) compartment in the transitional endoplasmic reticulum (ER). We tested the hypothesis that the QC mechanisms that regulate LQT2-linked Kv11.1 protein trafficking are mutation-specific. Confocal imaging analyses of HEK293 cells stably expressing the trafficking-deficient LQT2 mutation F805C showed that, unlike G601S-Kv11.1 protein, F805C-Kv11.1 protein was concentrated in several transitional ER subcompartments. The microtubule depolymerizing drug nocodazole differentially affected G601S- and F805C-Kv11.1 protein immunostaining. Nocodazole caused G601S-Kv11.1 protein to distribute into peripheral reticular structures, and it increased the diffuse immunostaining of F805C-Kv11.1 protein around the transitional ER subcompartments. Proteasome inhibition also affected the immunostaining of G601S- and F805C-Kv11.1 protein differently. Incubating cells in MG132 minimally impacted G601S-Kv11.1 immunostaining, but it dramatically increased the diffuse immunostaining of F805C-Kv11.1 protein in the transitional ER. Similar results were seen after incubating cells in the proteasome inhibitor lactacystin. Differences in the cellular distribution of G601S-Kv11.1 and F805C-Kv11.1 protein persisted in transfected human inducible pluripotent stem cell derived cardiomyocytes. These are the first data to visually demonstrate mutation-specific differences in the trafficking-deficient LQT2 phenotype, and this study has identified a novel way to categorize trafficking-deficient LQT2 mutations based on differences in intracellular

Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes.

PubMed

Matsa, Elena; Dixon, James E; Medway, Christopher; Georgiou, Orestis; Patel, Minal J; Morgan, Kevin; Kemp, Paul J; Staniforth, Andrew; Mellor, Ian; Denning, Chris

2014-04-01

Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K(+) currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart.

Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

PubMed Central

Matsa, Elena; Dixon, James E.; Medway, Christopher; Georgiou, Orestis; Patel, Minal J.; Morgan, Kevin; Kemp, Paul J.; Staniforth, Andrew; Mellor, Ian; Denning, Chris

2014-01-01

Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart. PMID:23470493

Maternal and neonatal outcomes in labor and at delivery when long QT syndrome is present.

PubMed

Tanaka, Hiroaki; Katsuragi, Shinji; Tanaka, Kayo; Sawada, Masami; Iwanaga, Naoko; Yoshimatsu, Jun; Ikeda, Tomoaki

2016-01-01

Women during labor may be susceptible to torsades de pointes (TdP), which may cause the fetal condition to deteriorate. The aim of the present investigation was to analyze maternal and fetal outcomes during labor when long QT syndrome (LQTS) was present. We examined the maternal and neonatal outcomes of 25 pregnancies (18 women) with LQT between 1995 and 2012 at the Department of Perinatology, National Cardiovascular Center, Japan. Maternal and neonatal outcomes including cardiovascular events, cardiovascular events within a week after delivery, caesarean delivery rate, still births, preterm births, and non-reassuring fetal heart rate pattern (NRFHR) during labor were investigated. All the mothers survived, and no cardiovascular events occurred in labor or postpartum due to LQTS in either vaginal delivery or caesarean delivery. A total of 23 women (92%) had used beta blockers in this study. Caesarean delivery was performed due to NRFHR during labor in 5 pregnancies (20%). Delivery when LQTS is present has a low likelihood of cardiovascular events, but pregnancy with LQTS had a higher caesarean delivery rate due to NRFHR in labor. Most women used beta blockers in this study, and it is possible that beta blocker use prevents cardiovascular events during labor. NRFHR during labor may be related with inherited LQT through the mother.

Prevalence and Spectrum of Large Deletions or Duplications in the Major Long QT Syndrome-Susceptibility Genes and Implications for Long QT Syndrome Genetic Testing

PubMed Central

Tester, David J.; Benton, Amber J.; Train, Laura; Deal, Barbara; Baudhuin, Linnea M.; Ackerman, Michael J.

2010-01-01

Long QT Syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for three cardiac ion channel alpha-subunits (LQT1-3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. Here, we set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes among unrelated patients who were mutation-negative following point mutation analysis of LQT1-12-susceptibility genes. Forty-two unrelated clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification (MLPA), a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA-MLPA LQTS Kit from MRC-Holland was used to analyze the three major LQTS-associated genes: KCNQ1, KCNH2, and SCN5A and the two minor genes: KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2/42 (4.8%, CI, 1.7–11%) unrelated patients. A deletion of KCNQ1 exon 3 was identified in a 10 year-old Caucasian boy with a QTc of 660 milliseconds (ms), a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17 year-old Caucasian girl with a QTc of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, since nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value. PMID:20920651

Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3

PubMed Central

Tsurugi, Takuo; Nagatomo, Toshihisa; Abe, Haruhiko; Oginosawa, Yasushi; Takemasa, Hiroko; Kohno, Ritsuko; Makita, Naomasa; Makielski, Jonathan C.; Otsuji, Yutaka

2009-01-01

Aims In the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by β-adrenergic agents produces similar effects on the late sodium current (INa) to those by overdrive pacing therapy. We analyzed the β-adrenergic-like effects of protein kinase A and fluoride on INa in R1623Q mutant channels. Main methods cDNA encoding either wild-type (WT) or R1623Q mutant of hNav1.5 was stably transfected into HEK293 cells. INa was recorded using a whole-cell patch-clamp technique at 23 °C. Key findings In R1623Q channels, 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late INa in a time-dependent manner. Modulations of peak INa gating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of β-adrenergic stimulation by analyzing the frequency-dependence of the late INa. Fluoride augmented frequency-dependent reduction of the late INa, which was due to preferential delay of recovery of late INa. However, the increase in late INa by fluoride at steady-state was more potent than the frequency-dependent reduction of late INa. Significance Different basic mechanisms participate in the QT interval shortening by pacing and β-adrenergic stimulation in the LQT3. PMID:19167409

Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residue in the Voltage Sensor

PubMed Central

McBride, Christie M.; Smith, Ashley M.; Smith, Jennifer L.; Reloj, Allison R.; Velasco, Ellyn J.; Powell, Jonathan; Elayi, Claude S.; Bartos, Daniel C.; Burgess, Don E.

2013-01-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing IKr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (IKv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients’ genotypes) mostly corrected the changes in IKv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing IKr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease IKr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient. PMID:23546015

Trafficking-deficient hERG K+ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER

PubMed Central

Smith, Jennifer L.; McBride, Christie M.; Nataraj, Parvathi S.; Bartos, Daniel C.; January, Craig T.

2011-01-01

The human ether-a-go-go related gene (hERG) encodes the voltage-gated K+ channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an “immature” N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2. PMID:21490315

Stressful life events and depressive symptoms among symptomatic long QT syndrome patients.

PubMed

Hintsa, Taina; Jokela, Markus; Elovainio, Marko; Määttänen, Ilmari; Swan, Heikki; Hintsanen, Mirka; Toivonen, Lauri; Kontula, Kimmo; Keltikangas-Järvinen, Liisa

2016-04-01

We examined whether long QT syndrome status moderates the association between stressful life events and depressive symptoms. Participants were 562 (n= 246 symptomatic) long QT syndrome mutation carriers. Depressive symptoms were measured with a modified version of the Beck's Depression Inventory. There was an interaction between long QT syndrome status and stressful life events on depressive symptoms. In the symptomatic long QT syndrome patients, stressful life events were associated with depressive symptoms (B= 0.24, p< 0.001). In the asymptomatic long QT syndrome mutation carriers, this association was 62.5 percent weaker (B= 0.09, p= 0.057). Compared to asymptomatic long QT syndrome mutation carriers, symptomatic long QT syndrome patients are more sensitive to the depressive effects of stressful life events. © The Author(s) 2014.

Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome.

PubMed

Mazzanti, Andrea; Maragna, Riccardo; Vacanti, Gaetano; Monteforte, Nicola; Bloise, Raffaella; Marino, Maira; Braghieri, Lorenzo; Gambelli, Patrick; Memmi, Mirella; Pagan, Eleonora; Morini, Massimo; Malovini, Alberto; Ortiz, Martin; Sacilotto, Luciana; Bellazzi, Riccardo; Monserrat, Lorenzo; Napolitano, Carlo; Bagnardi, Vincenzo; Priori, Silvia G

2018-04-17

Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Transient Outward K+ Current (Ito) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1.

PubMed

Choi, Bum-Rak; Li, Weiyan; Terentyev, Dmitry; Kabakov, Anatoli Y; Zhong, Mingwang; Rees, Colin M; Terentyeva, Radmila; Kim, Tae Yun; Qu, Zhilin; Peng, Xuwen; Karma, Alain; Koren, Gideon

2018-06-01

Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1. Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits. The results showed that shorter action potential duration in the right ventricle (RV) was associated with focal activity during pVT initiation. RV cardiomyocytes demonstrated higher incidence of EADs under 50 nmol/L isoproterenol. Voltage-clamp studies revealed that the transient outward potassium current (I to ) magnitude was 28% greater in RV associated with KChiP2 but with no differences in terms of calcium-cycling kinetics and other sarcolemmal currents. Perfusing with the I to blocker 4-aminopyridine changed the initial focal sites of pVT from the RV to the left ventricle, corroborating the role of I to in pVT initiation. Computer modeling showed that EADs occur preferentially in the RV because of the larger conductance of the slow-inactivating component of I to , which repolarizes the membrane potential sufficiently rapidly to allow reactivation of I Ca,L before I Kr has had sufficient time to activate. I to heterogeneity creates both triggers and an arrhythmogenic substrate in LQT1. In the absence of I Ks , I to interactions with I Ca,L and I Kr promote EADs in the RV while prolonging action potential duration in the left ventricle. This heterogeneity of action potential enhances dispersion of refractoriness and facilitates conduction blocks that initiate pVTs. © 2018 American Heart Association, Inc.

Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.

PubMed

McBride, Christie M; Smith, Ashley M; Smith, Jennifer L; Reloj, Allison R; Velasco, Ellyn J; Powell, Jonathan; Elayi, Claude S; Bartos, Daniel C; Burgess, Don E; Delisle, Brian P

2013-05-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

Third trimester fetal heart rate predicts phenotype and mutation burden in the type 1 long QT syndrome.

PubMed

Winbo, Annika; Fosdal, Inger; Lindh, Maria; Diamant, Ulla-Britt; Persson, Johan; Wettrell, Göran; Rydberg, Annika

2015-08-01

Early diagnosis and risk stratification is of clinical importance in the long QT syndrome (LQTS), however, little genotype-specific data are available regarding fetal LQTS. We investigate third trimester fetal heart rate, routinely recorded within public maternal health care, as a possible marker for LQT1 genotype and phenotype. This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110 KCNQ1 mutation carriers, whereof 13 double mutation carriers). Pedigree-based measured genotype analysis revealed significant associations between fetal heart rate, genotype, and phenotype; mean third trimester prelabor fetal heart rates obtained from obstetric records (gestational week 29-41) were lower per added mutation (no mutation, 143±5 beats per minute; single mutation, 134±8 beats per minute; double mutations, 111±6 beats per minute; P<0.0001), and lower in symptomatic versus asymptomatic mutation carriers (122±10 versus 137±9 beats per minute; P<0.0001). Strong correlations between fetal heart rate and neonatal heart rate (r=0.700; P<0.001), and postnatal QTc (r=-0.762; P<0.001) were found. In a multivariable model, fetal genotype explained the majority of variance in fetal heart rate (-10 beats per minute per added mutation; P<1.0×10(-23)). Arrhythmia symptoms and intrauterine β-blocker exposure each predicted -7 beats per minute, P<0.0001. In this study including 184 fetuses from 2 LQT1 founder populations, third trimester fetal heart rate discriminated between fetal genotypes and correlated with severity of postnatal cardiac phenotype. This finding strengthens the role of fetal heart rate in the early detection and risk stratification of LQTS, particularly for fetuses with double mutations, at high risk of early life-threatening arrhythmias. © 2015 American Heart Association, Inc.

Development of a High-Throughput Flow Cytometry Assay to Monitor Defective Trafficking and Rescue of Long QT2 Mutant hERG Channels

PubMed Central

Kanner, Scott A.; Jain, Ananya; Colecraft, Henry M.

2018-01-01

Long QT Syndrome (LQTS) is an acquired or inherited disorder characterized by prolonged QT interval, exertion-triggered arrhythmias, and sudden cardiac death. One of the most prevalent hereditary LQTS subtypes, LQT2, results from loss-of-function mutations in the hERG channel, which conducts IKr, the rapid component of the delayed rectifier K+ current, critical for cardiac repolarization. The majority of LQT2 mutations result in Class 2 deficits characterized by impaired maturation and trafficking of hERG channels. Here, we have developed a high-throughput flow cytometric assay to analyze the surface and total expression of wild-type (WT) and mutant hERG channels with single-cell resolution. To test our method, we focused on 16 LQT2 mutations in the hERG Per-Arnt-Sim (PAS) domain that were previously studied via a widely used biochemical approach that compares levels of 135-kDa immature and 155-kDa fully glycosylated hERG protein to infer surface expression. We confirmed that LQT2 mutants expressed in HEK293 cells displayed a decreased surface density compared to WT hERG, and were differentially rescued by low temperature. However, we also uncovered some notable differences from the findings obtained via the biochemical approach. In particular, three mutations (N33T, R56Q, and A57P) with apparent WT-like hERG glycosylation patterns displayed up to 50% decreased surface expression. Furthermore, despite WT-like levels of complex glycosylation, these mutants have impaired forward trafficking, and exhibit varying half-lives at the cell surface. The results highlight utility of the surface labeling/flow cytometry approach to quantitatively assess trafficking deficiencies associated with LQT2 mutations, to discern underlying mechanisms, and to report on interventions that rescue deficits in hERG surface expression. PMID:29725305

Not all Beta-Blockers are Equal in the Management of Long QT Syndrome Types 1 and 2: Higher Recurrence of Events under Metoprolol

PubMed Central

Chockalingam, Priya; Crotti, Lia; Girardengo, Giulia; Johnson, Jonathan N.; Harris, Katy M.; van der Heijden, Jeroen F.; Hauer, Richard N.W.; Beckmann, Britt M.; Spazzolini, Carla; Rordorf, Roberto; Rydberg, Annika; Clur, Sally-Ann B.; Fischer, Markus; van den Heuvel, Freek; Kääb, Stefan; Blom, Nico A.; Ackerman, Michael J.; Schwartz, Peter J.; Wilde, Arthur A.M.

2012-01-01

Objectives To compare the efficacy of beta-blockers (BB) in congenital long QT syndrome (LQTS). Background BB are the mainstay in managing LQTS. Studies comparing the efficacy of commonly-used BB are lacking and clinicians generally assume they are equally effective. Methods ECG and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n=134), metoprolol (n=147), and nadolol (n=101) were analyzed, excluding patients aged <1 year at BB initiation. Symptoms prior to therapy and the first breakthrough cardiac events (BCEs) were documented. Results Patients (56% females, 27% symptomatic, HR 76±16 bpm, QTc 472±46 ms) were started on BB therapy at a median age of 14 years (IQR 8–32 years). QTc-shortening with propranolol was significantly greater than with other BB 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). 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 other two BB combined, after adjustment for genotype (OR 3.95, 95% CI 1.2–13.1, p=0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients on 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 in symptomatic LQT1 and LQT2 patients. PMID:23083782

A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation.

PubMed

Bartos, Daniel C; Giudicessi, John R; Tester, David J; Ackerman, Michael J; Ohno, Seiko; Horie, Minoru; Gollob, Michael H; Burgess, Don E; Delisle, Brian P

2014-03-01

Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1-encoded Kv7.1 channel that conducts the slowly activating component of the delayed rectifier K(+) current (IKs). Clinically, the diagnosis of LQT1 is complicated by variable phenotypic expressivity, whereby approximately 25% of genotype-positive individuals present with concealed LQT1 (resting corrected QT [QTc] interval ≤460 ms). To determine whether a specific molecular mechanism contributes to concealed LQT1. We identified a multigenerational LQT1 family whereby 79% of the patients genotype-positive for p.Ile235Asn-KCNQ1 (I235N-Kv7.1) have concealed LQT1. We assessed the effect I235N-Kv7.1 has on IKs and the ventricular action potential (AP) by using in vitro analysis and computational simulations. Clinical data showed that all 10 patients with I235N-Kv7.1 have normal resting QTc intervals but abnormal QTc interval prolongation during the recovery phase of an electrocardiographic treadmill stress test. Voltage-clamping HEK293 cells coexpressing wild-type Kv7.1 and I235N-Kv7.1 (to mimic the patients' genotypes) showed that I235N-Kv7.1 generated relatively normal functioning Kv7.1 channels but were insensitive to protein kinase A (PKA) activation. Phosphomimetic and quinidine sensitivity studies suggest that I235N-Kv7.1 limits the conformational changes in Kv7.1 channels, which are necessary to upregulate IKs after PKA phosphorylation. Computational ventricular AP simulations predicted that the PKA insensitivity of I235N-Kv7.1 is primarily responsible for prolonging the AP with β-adrenergic stimulation, especially at slower cycle lengths. KCNQ1 mutations that generate relatively normal Kv7.1 channels, but limit the upregulation of IKs by PKA activation, likely contribute to concealed LQT1. Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

The genetic architecture of long QT syndrome: A critical reappraisal.

PubMed

Giudicessi, John R; Wilde, Arthur A M; Ackerman, Michael J

2018-03-30

Collectively, the completion of the Human Genome Project and subsequent development of high-throughput next-generation sequencing methodologies have revolutionized genomic research. However, the rapid sequencing and analysis of thousands upon thousands of human exomes and genomes has taught us that most genes, including those known to cause heritable cardiovascular disorders such as long QT syndrome, harbor an unexpected background rate of rare, and presumably innocuous, non-synonymous genetic variation. In this Review, we aim to reappraise the genetic architecture underlying both the acquired and congenital forms of long QT syndrome by examining how the clinical phenotype associated with and background genetic variation in long QT syndrome-susceptibility genes impacts the clinical validity of existing gene-disease associations and the variant classification and reporting strategies that serve as the foundation for diagnostic long QT syndrome genetic testing. Copyright © 2018 Elsevier Inc. All rights reserved.

A model of cardiac ryanodine receptor gating predicts experimental Ca2+-dynamics and Ca2+-triggered arrhythmia in the long QT syndrome

NASA Astrophysics Data System (ADS)

Wilson, Dan; Ermentrout, Bard; Němec, Jan; Salama, Guy

2017-09-01

Abnormal Ca2+ handling is well-established as the trigger of cardiac arrhythmia in catecholaminergic polymorphic ventricular tachycardia and digoxin toxicity, but its role remains controversial in Torsade de Pointes (TdP), the arrhythmia associated with the long QT syndrome (LQTS). Recent experimental results show that early afterdepolarizations (EADs) that initiate TdP are caused by spontaneous (non-voltage-triggered) Ca2+ release from Ca2+-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca2+-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca2+ elevation increases gradually in amplitude, occurs before overt voltage instability, and then precedes the rise of EADs. Here, we used a modified Shannon-Puglisi-Bers model of rabbit ventricular myocytes to reproduce experimental Ca2+ dynamics in bradycardia and LQT2. Abnormal systolic Ca2+-oscillations and EADs caused by SR Ca2+-release are reproduced in a modified 0-dimensional model, where 3 gates in series control the ryanodine receptor (RyR2) conductance. Two gates control RyR2 activation and inactivation and sense cytosolic Ca2+ while a third gate senses luminal junctional SR Ca2+. The model predicts EADs in bradycardia and low extracellular [K+] and cessation of SR Ca2+-release terminate salvos of EADs. Ca2+-waves, systolic cell-synchronous Ca2+-release, and multifocal diastolic Ca2+ release seen in subcellular Ca2+-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca2+-overload, abnormal SR Ca2+-release, and the subsequent activation of the electrogenic Na+/Ca2+-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.

Long QT syndrome unmasked in an adult subject presenting with excited delirium.

PubMed

Bozeman, William P; Ali, Karim; Winslow, James E

2013-02-01

Excited delirium is increasingly recognized as a risk factor for sudden death, though the specific pathophysiology of these deaths is typically unclear. We describe a survivor of excited delirium that displayed a transient severe prolongation of the QT interval, suggesting unmasking of long QT syndrome as a possible mechanism of sudden death. A 30-year-old man was arrested by police for violent assaultive behavior. Officers at the scene noted confusion, nonsensical speech, sweating, and bizarre agitated behavior; he was transported to the Emergency Department for medical evaluation of possible excited delirium. His initial electrocardiogram revealed a markedly prolonged corrected QT interval of over 600 ms. Intravenous hydration and sodium bicarbonate were administered, with normalization of the QT; he was admitted and recovered uneventfully. We discuss the possible association between long QT syndrome and unexplained sudden deaths seen with excited delirium. Sodium bicarbonate may be considered when long QT syndrome is identified during or after agitated delirium, though its routine use cannot be recommended based on a case report. Copyright © 2013 Elsevier Inc. All rights reserved.

BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome.

PubMed

Kostera-Pruszczyk, Anna; Suszek, Małgorzata; Płoski, Rafał; Franaszczyk, Maria; Potulska-Chromik, Anna; Pruszczyk, Piotr; Sadurska, Elżbieta; Karolczak, Justyna; Kamińska, Anna M; Rędowicz, Maria Jolanta

2015-12-01

BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.

Complex aberrant splicing in the induced pluripotent stem cell-derived cardiomyocytes from a patient with long-QT syndrome carrying KCNQ1-A344Aspl mutation.

PubMed

Wuriyanghai, Yimin; Makiyama, Takeru; Sasaki, Kenichi; Kamakura, Tsukasa; Yamamoto, Yuta; Hayano, Mamoru; Harita, Takeshi; Nishiuchi, Suguru; Chen, Jiarong; Kohjitani, Hirohiko; Hirose, Sayako; Yokoi, Fumika; Gao, Jingshan; Chonabayashi, Kazuhisa; Watanabe, Ken; Ohno, Seiko; Yoshida, Yoshinori; Kimura, Takeshi; Horie, Minoru

2018-05-29

Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α-subunit of the slow delayed rectifier potassium current (I Ks ) channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl in KCNQ1 is most commonly identified in the genotyped LQT1 Japanese patients, and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remains unclear. To establish and analyze patient-specific human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl. We generated hiPSCs from the peripheral blood mononuclear cells obtained from an LQT1 patient carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiological studies. We identified seven aberrant RNA variants in A344Aspl-hiPSC-CMs, more complex compared with those in the peripheral lymphocytes. Multi-electrode array analysis revealed that 1 μM isoproterenol significantly prolonged the duration of corrected field potential in A344Aspl-hiPSC-CMs, compared with that in the controls. Additionally, 100 nM E-4031, I Kr blocker, was shown to induce early afterdepolarization-like waveforms in A344Aspl-hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administrating 500 nM isoproterenol, APDs of A344Aspl-hiPSC-CMs were significantly longer than those of the controls. ML277 and phenylboronic acid, I Ks activators, ameliorated the APDs of hiPSC-CMs. We identified complex aberrant mRNA variants in the A344Aspl-hiPSC-CM model, and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies. Copyright © 2018. Published by Elsevier Inc.

Competition of calcified calmodulin N lobe and PIP2 to an LQT mutation site in Kv7.1 channel

PubMed Central

Tobelaim, William Sam; Dvir, Meidan; Lebel, Guy; Cui, Meng; Buki, Tal; Peretz, Asher; Marom, Milit; Haitin, Yoni; Logothetis, Diomedes E.; Hirsch, Joel Alan; Attali, Bernard

2017-01-01

Voltage-gated potassium 7.1 (Kv7.1) channel and KCNE1 protein coassembly forms the slow potassium current IKS that repolarizes the cardiac action potential. The physiological importance of the IKS channel is underscored by the existence of mutations in human Kv7.1 and KCNE1 genes, which cause cardiac arrhythmias, such as the long-QT syndrome (LQT) and atrial fibrillation. The proximal Kv7.1 C terminus (CT) binds calmodulin (CaM) and phosphatidylinositol-4,5-bisphosphate (PIP2), but the role of CaM in channel function is still unclear, and its possible interaction with PIP2 is unknown. Our recent crystallographic study showed that CaM embraces helices A and B with the apo C lobe and calcified N lobe, respectively. Here, we reveal the competition of PIP2 and the calcified CaM N lobe to a previously unidentified site in Kv7.1 helix B, also known to harbor an LQT mutation. Protein pulldown, molecular docking, molecular dynamics simulations, and patch-clamp recordings indicate that residues K526 and K527 in Kv7.1 helix B form a critical site where CaM competes with PIP2 to stabilize the channel open state. Data indicate that both PIP2 and Ca2+-CaM perform the same function on IKS channel gating by producing a left shift in the voltage dependence of activation. The LQT mutant K526E revealed a severely impaired channel function with a right shift in the voltage dependence of activation, a reduced current density, and insensitivity to gating modulation by Ca2+-CaM. The results suggest that, after receptor-mediated PIP2 depletion and increased cytosolic Ca2+, calcified CaM N lobe interacts with helix B in place of PIP2 to limit excessive IKS current inhibition. PMID:28096388

Competition of calcified calmodulin N lobe and PIP2 to an LQT mutation site in Kv7.1 channel.

PubMed

Tobelaim, William Sam; Dvir, Meidan; Lebel, Guy; Cui, Meng; Buki, Tal; Peretz, Asher; Marom, Milit; Haitin, Yoni; Logothetis, Diomedes E; Hirsch, Joel Alan; Attali, Bernard

2017-01-31

Voltage-gated potassium 7.1 (Kv7.1) channel and KCNE1 protein coassembly forms the slow potassium current I KS that repolarizes the cardiac action potential. The physiological importance of the I KS channel is underscored by the existence of mutations in human Kv7.1 and KCNE1 genes, which cause cardiac arrhythmias, such as the long-QT syndrome (LQT) and atrial fibrillation. The proximal Kv7.1 C terminus (CT) binds calmodulin (CaM) and phosphatidylinositol-4,5-bisphosphate (PIP 2 ), but the role of CaM in channel function is still unclear, and its possible interaction with PIP 2 is unknown. Our recent crystallographic study showed that CaM embraces helices A and B with the apo C lobe and calcified N lobe, respectively. Here, we reveal the competition of PIP 2 and the calcified CaM N lobe to a previously unidentified site in Kv7.1 helix B, also known to harbor an LQT mutation. Protein pulldown, molecular docking, molecular dynamics simulations, and patch-clamp recordings indicate that residues K526 and K527 in Kv7.1 helix B form a critical site where CaM competes with PIP 2 to stabilize the channel open state. Data indicate that both PIP 2 and Ca 2+ -CaM perform the same function on I KS channel gating by producing a left shift in the voltage dependence of activation. The LQT mutant K526E revealed a severely impaired channel function with a right shift in the voltage dependence of activation, a reduced current density, and insensitivity to gating modulation by Ca 2+ -CaM. The results suggest that, after receptor-mediated PIP 2 depletion and increased cytosolic Ca 2+ , calcified CaM N lobe interacts with helix B in place of PIP 2 to limit excessive I KS current inhibition.

Long QT interval in Turner syndrome--a high prevalence of LQTS gene mutations.

PubMed

Trolle, Christian; Mortensen, Kristian H; Pedersen, Lisbeth N; Berglund, Agnethe; Jensen, Henrik K; Andersen, Niels H; Gravholt, Claus H

2013-01-01

QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc) over time and relate the findings to the Turner syndrome phenotype. Adult women with Turner syndrome (n = 88) were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%), and adjusted for influence of heart rate by Bazett's (bQTc) and Hodges's formula (hQTc). The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms). Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done. The mean hQTc in women with Turner syndrome (414.0 ± 25.5 ms) compared to controls (390.4 ± 17.8 ms) was prolonged (p<0.001) and did not change over time (416.9 ± 22.6 vs. 415.6 ± 25.5 ms; p =0.4). 45,X karyotype was associated with increased hQTc prolongation compared to other Turner syndrome karyotypes (418.2 ± 24.8 vs. 407.6 ± 25.5 ms; p = 0.055). In women with Turner syndrome and a bQTc >432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2) and one in a minor Long QT syndrome gene (KCNE2). There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women. NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/selectaction/View/ts/3/uid/U000099E.

Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum.

PubMed

Smith, Jennifer L; Reloj, Allison R; Nataraj, Parvathi S; Bartos, Daniel C; Schroder, Elizabeth A; Moss, Arthur J; Ohno, Seiko; Horie, Minoru; Anderson, Corey L; January, Craig T; Delisle, Brian P

2013-11-01

KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K(+) current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4-5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential.

Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum

PubMed Central

Smith, Jennifer L.; Reloj, Allison R.; Nataraj, Parvathi S.; Bartos, Daniel C.; Schroder, Elizabeth A.; Moss, Arthur J.; Ohno, Seiko; Horie, Minoru; Anderson, Corey L.; January, Craig T.

2013-01-01

KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K+ current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4–5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential. PMID:23864605

Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant.

PubMed

Lane, Conor; Giudicessi, John R; Ye, Dan; Tester, David J; Rohatgi, Ram K; Bos, J Martijn; Ackerman, Michael J

2018-04-03

Long QT syndrome (LQTS) genetic test reports commonly exclude potentially proarrhythmic common variants such as p.Asp85Asn-KCNE1. The purpose of this study was to determine whether a discernible phenotype is associated with p.Asp85Asn-KCNE1 and whether relatively common KCNE1 variants underlie transient QT prolongation pedigrees with negative commercial LQTS genetic tests. Retrospective review was used to compare demographics, symptomatology, and QT parameters of individuals with p.Asp85Asn-KCNE1 in the absence of other rare/ultra-rare variants in LQTS-susceptibility genes and those who underwent comprehensive LQTS genetic testing. Compared to the Genome Aggregation Database, p.Asp85Asn-KCNE1 was more prevalent in individuals undergoing LQTS genetic testing (33/1248 [2.6%] vs 1552/126,652 [1.2%]; P = .0001). In 19 of 33 patients (58%), only p.Asp85Asn-KCNE1 was observed. These patients were predominantly female (90% vs 62%; P = .02) and were less likely to experience syncope (0% vs 34%; P = .0007), receive β-blockers (53% vs 85%; P = .001), or require an implantable cardioverter-defibrillator (5.3% vs 33%; P = .01). However, they exhibited a similar degree of QT prolongation (QTc 460 ms vs 467 ms; P = NS). Whole exome sequencing of 2 commercially genotype-negative pedigrees revealed that p.Asp85Asn-KCNE1 and p.Arg36His-KCNE1 traced with a transient QT prolongation phenotype. Functional characterization of p.Arg36His-KCNE1 demonstrated loss of function, with a 47% reduction in peak I Ks current density in the heterozygous state. We provide further evidence that relatively common variants in KCNE1 may result in a mild QT phenotype designated as "LQT5-Lite" to distinguish such potentially proarrhythmic common variants (ie, functional risk alleles) from rare pathogenic variants that truly confer monogenic disease susceptibility, albeit with incomplete penetrance. Copyright © 2018. Published by Elsevier Inc.

Brief report: Emotional distress and recent stressful life events in long QT syndrome mutation carriers.

PubMed

Määttänen, Ilmari; Jokela, Markus; Pulkki-Råback, Laura; Keltikangas-Järvinen, Liisa; Swan, Heikki; Toivonen, Lauri; Merjonen, Päivi; Hintsa, Taina

2015-11-01

To study emotional distress in symptomatic and asymptomatic long QT syndrome mutation carriers who had experienced a recent stressful life event. The participants were 209 symptomatic and 279 asymptomatic long QT syndrome mutation carriers. Emotional distress was assessed with the Cope questionnaire and stressful life events with the Social Readjustment Rating Scale. Symptomatic long QT syndrome mutation carriers with burdening recent stressful life events reported a higher emotional distress (β = 0.35, p < 0.001), while the asymptomatic did not show such difference (β = 0.13, p = 0.393). Symptomatic long QT syndrome mutation carriers who have experienced stressful life events recently report an increased emotional distress. © The Author(s) 2013.

Trafficking Defect and Proteasomal Degradation Contribute to the Phenotype of a Novel KCNH2 Long QT Syndrome Mutation

PubMed Central

Mihic, Anton; Chauhan, Vijay S.; Gao, Xiaodong; Oudit, Gavin Y.; Tsushima, Robert G.

2011-01-01

The Kv11.1 (hERG) K+ channel plays a fundamental role in cardiac repolarization. Missense mutations in KCNH2, the gene encoding Kv11.1, cause long QT syndrome (LQTS) and frequently cause channel trafficking-deficiencies. This study characterized the properties of a novel KCNH2 mutation discovered in a LQT2 patient resuscitated from a ventricular fibrillation arrest. Proband genotyping was performed by SSCP and DNA sequencing. The electrophysiological and biochemical properties of the mutant channel were investigated after expression in HEK293 cells. The proband manifested a QTc of 554 ms prior to electrolyte normalization. Mutation analysis revealed an autosomal dominant frameshift mutation at proline 1086 (P1086fs+32X; 3256InsG). Co-immunoprecipitation demonstrated that wild-type Kv11.1 and mutant channels coassemble. Western blot showed that the mutation did not produce mature complex-glycosylated Kv11.1 channels and coexpression resulted in reduced channel maturation. Electrophysiological recordings revealed mutant channel peak currents to be similar to untransfected cells. Co-expression of channels in a 1∶1 ratio demonstrated dominant negative suppression of peak Kv11.1 currents. Immunocytochemistry confirmed that mutant channels were not present at the plasma membrane. Mutant channel trafficking rescue was attempted by incubation at reduced temperature or with the pharmacological agents E-4031. These treatments did not significantly increase peak mutant currents or induce the formation of mature complex-glycosylated channels. The proteasomal inhibitor lactacystin increased the protein levels of the mutant channels demonstrating proteasomal degradation, but failed to induce mutant Kv11.1 protein trafficking. Our study demonstrates a novel dominant-negative Kv11.1 mutation, which results in degraded non-functional channels leading to a LQT2 phenotype. PMID:21483829

Genetics Home Reference: short QT syndrome

MedlinePlus

... on PubMed Central Gaita F, Giustetto C, Bianchi F, Wolpert C, Schimpf R, Riccardi R, Grossi S, Richiardi E, Borggrefe M. Short QT Syndrome: a familial cause of sudden death. Circulation. 2003 Aug 26;108(8):965-70. Epub 2003 ... P, Dalmasso P, Borggrefe M, Gaita F. Long-term follow-up of patients with short ...

Long QT syndrome and sudden unexpected infant death.

PubMed

Van Niekerk, Chantal; Van Deventer, Barbara Ströh; du Toit-Prinsloo, Lorraine

2017-09-01

Long QT syndrome (LQTS) is an inheritable primary electric disease of the heart characterised by abnormally long QT intervals and a propensity to develop atrial and ventricular tachyarrhythmias. It is caused by an inherited channelopathy responsible for sudden cardiac death in individuals with structurally normal hearts. Long QT syndrome can present early in life, and some studies suggest that it may be associated with up to 20% of sudden unexplained infant death (SUID), particularly when associated with external stressors such as asphyxia, which is commonly seen in many infant death scenes. With an understanding of the genetic defects, it has now been possible to retrospectively analyse samples from infants who have presented to forensic pathology services with a history of unexplained sudden death, which may, in turn, enable the implementation of preventative treatment for siblings previously not known to have pathogenic genetic variations. In this viewpoint article, we will discuss SUID, LQTS and postmortem genetic analysis. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A case of long QT syndrome: challenges on a bumpy road.

PubMed

Magnusson, Peter; Gustafsson, Per-Erik

2017-06-01

Beta-agonist treatment during pregnancy may unmask the diagnosis of long QT syndrome. The QT prolongation can result in functional AV block. A history of seizure and/or sudden death in a family member should raise suspicion of ventricular tachycardia. More than one mutation may coexist. Refusal of beta-blocker therapy complicates risk stratification.

Using the genome aggregation database, computational pathogenicity prediction tools, and patch clamp heterologous expression studies to demote previously published long QT syndrome type 1 mutations from pathogenic to benign.

PubMed

Clemens, Daniel J; Lentino, Anne R; Kapplinger, Jamie D; Ye, Dan; Zhou, Wei; Tester, David J; Ackerman, Michael J

2018-04-01

Mutations in the KCNQ1-encoded Kv7.1 potassium channel cause long QT syndrome (LQTS) type 1 (LQT1). It has been suggested that ∼10%-20% of rare LQTS case-derived variants in the literature may have been published erroneously as LQT1-causative mutations and may be "false positives." The purpose of this study was to determine which previously published KCNQ1 case variants are likely false positives. A list of all published, case-derived KCNQ1 missense variants (MVs) was compiled. The occurrence of each MV within the Genome Aggregation Database (gnomAD) was assessed. Eight in silico tools were used to predict each variant's pathogenicity. Case-derived variants that were either (1) too frequently found in gnomAD or (2) absent in gnomAD but predicted to be pathogenic by ≤2 tools were considered potential false positives. Three of these variants were characterized functionally using whole-cell patch clamp technique. Overall, there were 244 KCNQ1 case-derived MVs. Of these, 29 (12%) were seen in ≥10 individuals in gnomAD and are demotable. However, 157 of 244 MVs (64%) were absent in gnomAD. Of these, 7 (4%) were predicted to be pathogenic by ≤2 tools, 3 of which we characterized functionally. There was no significant difference in current density between heterozygous KCNQ1-F127L, -P477L, or -L619M variant-containing channels compared to KCNQ1-WT. This study offers preliminary evidence for the demotion of 32 (13%) previously published LQT1 MVs. Of these, 29 were demoted because of their frequent sighting in gnomAD. Additionally, in silico analysis and in vitro functional studies have facilitated the demotion of 3 ultra-rare MVs (F127L, P477L, L619M). Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Drug-induced life-threatening arrhythmias and sudden cardiac death: A clinical perspective of long QT, short QT and Brugada syndromes.

PubMed

Ramalho, Diogo; Freitas, João

2018-05-01

Sudden cardiac death is a major public health challenge, which can be caused by genetic or acquired structural or electrophysiological abnormalities. These abnormalities include hereditary channelopathies: long QT, short QT and Brugada syndromes. These syndromes are a notable concern, particularly in young people, due to their high propensity for severe ventricular arrhythmias and sudden cardiac death. Current evidence suggests the involvement of an increasing number of drugs in acquired forms of long QT and Brugada syndromes. However, drug-induced short QT syndrome is still a rarely reported condition. Therefore, there has been speculation on its clinical significance, since few fatal arrhythmias and sudden cardiac death cases have been described so far. Drug-induced proarrhythmia is a growing challenge for physicians, regulatory agencies and the pharmaceutical industry. Physicians should weigh the risks of potentially fatal outcomes against the therapeutic benefits, when making decisions about drug prescriptions. Growing concerns about its safety and the need for more accurate predictive models for drug-induced fatal outcomes justify further research in these fields. The aim of this article is to comprehensively and critically review the recently published evidence with regard to drug-induced life-threatening arrhythmias and sudden cardiac death. This article will take into account the provision of data to physicians that are useful in the identification of the culprit drugs, and thus, contribute to the prompt recognition and management of these serious clinical conditions. Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

QT correction formulas and laboratory analysis on patients with metabolic syndrome and diabetes

NASA Astrophysics Data System (ADS)

Wong, Sara; Rivera, Pedro; Rodríguez, María. G.; Severeyn, Érika; Altuve, Miguel

2013-11-01

This article presents a study of ventricular repolarization in diabetic and metabolic syndrome subjects. The corrected QT interval (QTc) was estimated using four correction formulas commonly employed in the literature: Bazett, Fridericia, Framingham and Hodges. After extracting the Q, R and T waves from the electrocardiogram of 52 subjects (19 diabetic, 15 with metabolic syndrome and 18 control), using a wavelet-based approach, the RR interval and QT interval were determined. Then, QTc interval was computed using the formulas previously mentioned. Additionally, laboratory test (fasting glucose, cholesterol, triglycerides) were also evaluated. Results show that metabolic syndrome subjects have normal QTc. However, a longer QTc in this population may be a sign of future complication. The corrected QT interval by Fridericia's formula seems to be the most appropriated for metabolic syndrome subjects (low correlation coefficient between RR and QTc). Significant differences were obtained in the blood glucose and triglyceride levels, principally due to the abnormal sugar metabolization of metabolic syndrome and diabetic subjects. Further studies are focused on the acquisition of a larger database of metabolic syndrome and diabetics subjects and the repetition of this study using other populations, like high performance athletes.

Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.

PubMed

Giudicessi, John R; Roden, Dan M; Wilde, Arthur A M; Ackerman, Michael J

2018-02-06

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues. © 2018 American Heart Association, Inc.

Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval.

PubMed

Kosaki, Rika; Ono, Hiroshi; Terashima, Hiroshi; Kosaki, Kenjiro

2018-05-07

Timothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension. Exome analysis showed a previously undescribed de novo heterozygous mutation in the CACNA1C gene, p.Arg1024Gly. To our knowledge, this patient is the first to exhibit syndactyly and to carry a CACNA1C mutation but to not have QT prolongation, which has long been considered an obligatory feature of Timothy syndrome. © 2018 Wiley Periodicals, Inc.

Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome.

PubMed

Mathias, Andrew; Moss, Arthur J; Lopes, Coeli M; Barsheshet, Alon; McNitt, Scott; Zareba, Wojciech; Robinson, Jennifer L; Locati, Emanuela H; Ackerman, Michael J; Benhorin, Jesaia; Kaufman, Elizabeth S; Platonov, Pyotr G; Qi, Ming; Shimizu, Wataru; Towbin, Jeffrey A; Michael Vincent, G; Wilde, Arthur A M; Zhang, Li; Goldenberg, Ilan

2013-05-01

Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. To hypothesize that the assessment of QTc variance in patients with congenital LQTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. The study population comprised 1206 patients with LQTS with 95 different mutations and ≥ 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P = .002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P = .95; P value for QTcSD-by-genotype interaction = .002). Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype. Copyright © 2013. Published by Elsevier Inc.

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity

PubMed Central

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127

Low extracellular potassium prolongs repolarization and evokes early afterdepolarization in human induced pluripotent stem cell-derived cardiomyocytes.

PubMed

Kuusela, Jukka; Larsson, Kim; Shah, Disheet; Prajapati, Chandra; Aalto-Setälä, Katriina

2017-06-15

Long QT syndrome (LQTS) is characterized by a prolonged QT-interval on electrocardiogram and by increased risk of sudden death. One of the most common and potentially life-threatening electrolyte disturbances is hypokalemia, characterized by low concentrations of K + Using a multielectrode array platform and current clamp technique, we investigated the effect of low extracellular K + concentration ([K + ] Ex ) on the electrophysiological properties of hiPSC-derived cardiomyocytes (CMs) generated from a healthy control subject (WT) and from two symptomatic patients with type 1 of LQTS carrying G589D (LQT1A) or IVS7-2A>G mutation (LQT1B) in KCNQ1 The baseline prolongations of field potential durations (FPDs) and action potential durations (APDs) were longer in LQT1-CMs than in WT-CMs. Exposure to low [K + ] Ex prolonged FPDs and APDs in a concentration-dependent fashion. LQT1-CMs were found to be more sensitive to low [K + ] Ex compared to WT-CMs. At baseline, LQT1A-CMs had more prolonged APDs than LQT1B-CMs, but low [K + ] Ex caused more pronounced APD prolongation in LQT1B-CMs. Early afterdepolarizations in the action potentials were observed in a subset of LQT1A-CMs with further prolonged baseline APDs and triangular phase 2 profiles. This work demonstrates that the hiPSC-derived CMs are sensitive to low [K + ] Ex and provide a platform to study acquired LQTS. © 2017. Published by The Company of Biologists Ltd.

[Long QT syndrome. History, genetics, clinical symptoms, causes and therapy].

PubMed

Krönauer, T; Friederich, P

2015-08-01

The long QT syndrome is caused by a change in cardiac repolarization due to functional ion channel defects. A differentiation is made between a congenital (cLQTS) and an acquired (aLQTS) form of the disease. The disease results in the name-giving prolongation of the QT interval in the electrocardiogram and represents a predisposition for cardiac arrhythmia and sudden cardiac death. This article summarizes the current knowledge on the history, pathophysiology, clinical symptoms and therapy of cLQTS and aLQTS. This knowledge of pathophysiological features of the symptoms allows the underlying anesthesiological approach for individualized perioperative concepts for patients suffering from LQTS to be derived.

Sports participation in long QT syndrome.

PubMed

Aziz, Peter F; Saarel, Elizabeth V

2017-01-01

Untreated congenital long QT syndrome may result in potentially lethal ventricular tachycardia. In the most common type, risk of such an event has been linked to exercise. This originally resulted in very restrictive guidelines for sports participation in affected individuals. Although the complex interactions of a specific genotype, modifying cofactors, and risk are only now being explored, scientific evidence based on clinical experience now suggests that in many instances such restrictive guidelines are unwarranted. In particular, patients with this condition who are compliant with β-blocker therapy and who have never had symptoms during exertion are now enjoying the benefits of athletic activity.

Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1.

PubMed

Hoppe, U C; Marbán, E; Johns, D C

2001-04-24

The long QT syndrome (LQTS) is a heritable disorder that predisposes to sudden cardiac death. LQTS is caused by mutations in ion channel genes including HERG and KCNE1, but the precise mechanisms remain unclear. To clarify this situation we injected adenoviral vectors expressing wild-type or LQT mutants of HERG and KCNE1 into guinea pig myocardium. End points at 48-72 h included electrophysiology in isolated myocytes and electrocardiography in vivo. HERG increased the rapid component, I(Kr), of the delayed rectifier current, thereby accelerating repolarization, increasing refractoriness, and diminishing beat-to-beat action potential variability. Conversely, HERG-G628S suppressed I(Kr) without significantly delaying repolarization. Nevertheless, HERG-G628S abbreviated refractoriness and increased beat-to-beat variability, leading to early afterdepolarizations (EADs). KCNE1 increased the slow component of the delayed rectifier, I(Ks), without clear phenotypic sequelae. In contrast, KCNE1-D76N suppressed I(Ks) and markedly slowed repolarization, leading to frequent EADs and electrocardiographic QT prolongation. Thus, the two genes predispose to sudden death by distinct mechanisms: the KCNE1 mutant flagrantly undermines cardiac repolarization, and HERG-G628S subtly facilitates the genesis and propagation of premature beats. Our ability to produce electrocardiographic long QT in vivo with a clinical KCNE1 mutation demonstrates the utility of somatic gene transfer in creating genotype-specific disease models.

Emerging therapeutic targets in the short QT syndrome.

PubMed

Hancox, Jules C; Whittaker, Dominic G; Du, Chunyun; Stuart, A Graham; Zhang, Henggui

2018-05-01

Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K + channel inhibitors. A combination of K + current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K + channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.

A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

PubMed Central

Chung, Wendy; Spyres, Meghan; Pass, Robert H.; Silver, Eric; Sampson, Kevin J.; Kass, Robert S.

2007-01-01

Background SCN5A encodes the α-subunit (Nav1.5) of the principle Na+ channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Nav1.5 channel. Pharmacological targeting of mutation-altered Na+ channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults. Methods and Results Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na+ channel blockers flecainide and mexiletine. Our goal was to determine the Na+ channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na+ channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na+ channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically. Significance The results of our study provide further evidence of the grave vulnerability of newborns to Na+ channel defects and suggest that both genetic background

Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis.

PubMed

Winbo, Annika; Stattin, Eva-Lena; Westin, Ida Maria; Norberg, Anna; Persson, Johan; Jensen, Steen M; Rydberg, Annika

2017-07-18

Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1AP sequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations. This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs. A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with

Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome.

PubMed

Etienne, Pauline; Huchet, François; Gaborit, Nathalie; Barc, Julien; Thollet, Aurélie; Kyndt, Florence; Guyomarch, Béatrice; Le Marec, Hervé; Charpentier, Flavien; Schott, Jean-Jacques; Redon, Richard; Probst, Vincent; Gourraud, Jean-Baptiste

2018-04-20

QT prolongation during mental stress test (MST) has been associated with familial idiopathic ventricular fibrillation. In long QT syndrome (LQTS), up to 30% of mutation carriers have normal QT duration. Our aim was to assess the QT response during MST, and its accuracy in the diagnosis of concealed LQTS. All patients who are carrier of a KCNQ1 or KCNH2 mutations without QT prolongation were enrolled. A control group was constituted of patients with negative exercise and epinephrine tests. Electrocardiogram were recorded at rest and at the maximum heart rate during MST and reviewed by two physicians. Among the 70 patients enrolled (median age 41±2.1 years, 46% male), 36 were mutation carrier for LQTS (20 KCNQ1 and 16 KCNH2), and 34 were controls. KCNQ1 and KCNH2 mutation carriers presented a longer QT interval at baseline [405(389; 416) and 421 (394; 434) ms, respectively] compared with the controls [361(338; 375)ms; P < 0.0001]. QT duration during MST varied by 9 (4; 18) ms in KCNQ1, 3 (-6; 16) ms in KCNH2, and by -22 (-29; -17) ms in controls (P < 0.0001). These QT variations were independent of heart rate (P < 0.3751). Receiver operating characteristic curve analysis identified a cut-off value of QT variation superior to -11 ms as best predictor of LQTS. It provided 97% sensitivity and 97% specificity of QT prolongation in the diagnosis of LQTS. We identified a paradoxical response of the QT interval during MST in LQTS. Easy to assess, MST may be efficient to unmask concealed LQTS in patients at risk of this pathology.

Perioperative considerations in a newly described subtype of congenital long QT syndrome.

PubMed

Joseph-Reynolds, A M; Auden, S M; Sobczyzk, W L

1997-01-01

An infant with a newly-described subtype of congenital long QT syndrome is presented, along with her perioperative management on three separate occasions. During each anaesthetic characteristic arrhythmias occurred. The available literature and rational approaches to these high risk patients are reviewed.

Recent advances in understanding sex differences in cardiac repolarization.

PubMed

James, Andrew F; Choisy, Stéphanie C M; Hancox, Jules C

2007-07-01

A number of gender differences exist in the human electrocardiogram (ECG): the P-wave and P-R intervals are slightly longer in men than in women, whilst women have higher resting heart rates than do men, but a longer rate-corrected QT (QT(C)) interval. Women with the LQT1 and LQT2 variants of congenital long-QT syndrome (LQTS) are at greater risk of adverse cardiac events. Similarly, many drugs associated with acquired LQTS have a greater risk of inducing torsades de pointes (TdP) arrhythmia in women than in men. There are also male:female differences in Brugada syndrome, early repolarisation syndrome and sudden cardiac death. The differences in the ECG between men and women, and in particular those relating to the QT interval, have been explored experimentally and provide evidence of differences in the processes underlying ventricular repolarization. The data available from rabbit, canine, rat, mouse and guinea pig models are reviewed and highlight involvement of male:female differences in Ca and K currents, although the possible involvement of rapid and persistent Na current and Na-Ca exchange currents cannot yet be excluded. The mechanisms underlying observed differences remain to be elucidated fully, but are likely to involve the influence of gonadal steroids. With respect to the QT interval and risk of TdP, a range of evidence implicates a protective role of testosterone in male hearts, possibly by both genomic and non-genomic pathways. Evidence regarding oestrogen and progesterone is less unequivocal, although the interplay between these two hormones may influence both repolarization and pro-arrhythmic risk.

Perioperative considerations in a newly described subtype of congenital long QT syndrome.

PubMed

Joseph-Reynolds, Ann; Auden, Steve; Sobczyzk, Walter

1997-05-01

An infant with a newly-described subtype of congenital long QT syndrome is presented, along with her perioperative management on three separate occasions. During each anaesthetic characteristic arrhythmias occurred. The available literature and rational approaches to these high risk patients are reviewed. 1997 Blackwell Science Ltd.

Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel

PubMed Central

Zhang, Hongkang; Zou, Beiyan; Yu, Haibo; Moretti, Alessandra; Wang, Xiaoying; Yan, Wei; Babcock, Joseph J.; Bellin, Milena; McManus, Owen B.; Tomaselli, Gordon; Nan, Fajun; Laugwitz, Karl-Ludwig; Li, Min

2012-01-01

Long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in an electrocardiogram (ECG), leading to higher risk of sudden cardiac death. Among the 12 identified genes causal to heritable LQTS, ∼90% of affected individuals harbor mutations in either KCNQ1 or human ether-a-go-go related genes (hERG), which encode two repolarizing potassium currents known as IKs and IKr. The ability to quantitatively assess contributions of different current components is therefore important for investigating disease phenotypes and testing effectiveness of pharmacological modulation. Here we report a quantitative analysis by simulating cardiac action potentials of cultured human cardiomyocytes to match the experimental waveforms of both healthy control and LQT syndrome type 1 (LQT1) action potentials. The quantitative evaluation suggests that elevation of IKr by reducing voltage sensitivity of inactivation, not via slowing of deactivation, could more effectively restore normal QT duration if IKs is reduced. Using a unique specific chemical activator for IKr that has a primary effect of causing a right shift of V1/2 for inactivation, we then examined the duration changes of autonomous action potentials from differentiated human cardiomyocytes. Indeed, this activator causes dose-dependent shortening of the action potential durations and is able to normalize action potentials of cells of patients with LQT1. In contrast, an IKr chemical activator of primary effects in slowing channel deactivation was not effective in modulating action potential durations. Our studies provide both the theoretical basis and experimental support for compensatory normalization of action potential duration by a pharmacological agent. PMID:22745159

Bifurcation diagrams of frequency dependence of repolarization during long QT syndrome using the Luo-Rudy model of cardiac repolarization

NASA Astrophysics Data System (ADS)

Bondarenko, V. E.; Doedel, E. J.; Rasmusson, R. L.

2000-02-01

We applied bifurcation analysis to the Luo-Rudy model of the guinea pig cardiac ventricular cell to investigate the behavior of repolarization in response to a simulated form of inherited arrhythmia, long QT syndrome. In this paper, we simulate pathological changes in cardiac repolarization through reductions in IKr. Decreased expression of this current has been linked to an inherited form of long QT syndrome which results in a high mortality, presumably due to sudden cardiac death from ventricular fibrillation.

A KCNH2 branch point mutation causing aberrant splicing contributes to an explanation of genotype-negative long QT syndrome.

PubMed

Crotti, Lia; Lewandowska, Marzena A; Schwartz, Peter J; Insolia, Roberto; Pedrazzini, Matteo; Bussani, Erica; Dagradi, Federica; George, Alfred L; Pagani, Franco

2009-02-01

Genetic screening of long QT syndrome (LQTS) fails to identify disease-causing mutations in about 30% of patients. So far, molecular screening has focused mainly on coding sequence mutations or on substitutions at canonical splice sites. The purpose of this study was to explore the possibility that intronic variants not at canonical splice sites might affect splicing regulatory elements, lead to aberrant transcripts, and cause LQTS. Molecular screening was performed through DHPLC and sequence analysis. The role of the intronic mutation identified was assessed with a hybrid minigene splicing assay. A three-generation LQTS family was investigated. Molecular screening failed to identify an obvious disease-causing mutation in the coding sequences of the major LQTS genes but revealed an intronic A-to-G substitution in KCNH2 (IVS9-28A/G) cosegregating with the clinical phenotype in family members. In vitro analysis proved that the mutation disrupts the acceptor splice site definition by affecting the branch point (BP) sequence and promoting intron retention. We further demonstrated a tight functional relationship between the BP and the polypyrimidine tract, whose weakness is responsible for the pathological effect of the IVS9-28A/G mutation. We identified a novel BP mutation in KCNH2 that disrupts the intron 9 acceptor splice site definition and causes LQT2. The present finding demonstrates that intronic mutations affecting pre-mRNA processing may contribute to the failure of traditional molecular screening in identifying disease-causing mutations in LQTS subjects and offers a rationale strategy for the reduction of genotype-negative cases.

Safe drug use in long QT syndrome and Brugada syndrome: comparison of website statistics

PubMed Central

Postema, Pieter G.; Neville, Jon; de Jong, Jonas S.S.G.; Romero, Klaus; Wilde, Arthur A.M.; Woosley, Raymond L.

2013-01-01

Aims We sought to obtain insights into the efficacy of two websites, www.QTdrugs.org and www.BrugadaDrugs.org, that have the intention to prevent fatal arrhythmias due to unsafe drug use in Long QT syndrome and Brugada syndrome. Methods and results Prospective web-use statistical analysis combined with online surveys were employed. Our main outcome measure was the percentage of Long QT syndrome patients and Brugada syndrome patients reporting refraining or discontinuation of possible unsafe drugs. QTdrugs.org has received >3 100 000 visitors from 180 countries. Most visitors originated from the Americas (87%), as compared with Europe (7%), Asia (3%), Oceania (2%), and Africa (1%). The QTdrugs.org survey yielded 340 respondents: 34% were patients and 50% medical professionals. Of the patients, 79% reported that they refrained from, and 61% reported discontinuing drugs due to the website. The website was very much appreciated by 65% of the respondents and 30% found it rather helpful. The BrugadaDrugs.org received >48 000 visitors from 154 countries. Most visitors originated from Europe (46%) and the Americas (39%), but less from Asia (10%), Oceania (4%), and Africa (<1%). The BrugadaDrugs.org survey yielded 178 respondents: 68% were patients and 21% medical professionals. Of the patients, 72% reported refraining from, and 48% discontinuing drugs due to the website. The website was very much appreciated by 72% of the respondents and 25% found it rather helpful. Conclusion These websites are extensively used, they promote drug awareness, and they help patients to avoid possible pro-arrhythmic drugs. Visitors find the websites valuable but should note their limitations. PMID:23533266

Risk of cardiac events in Long QT syndrome patients when taking antiseizure medications.

PubMed

Auerbach, David S; Biton, Yitschak; Polonsky, Bronislava; McNitt, Scott; Gross, Robert A; Dirksen, Robert T; Moss, Arthur J

2018-01-01

Many antiseizure medications (ASMs) affect ion channel function. We investigated whether ASMs alter the risk of cardiac events in patients with corrected QT (QT c ) prolongation. The study included people from the Rochester-based Long QT syndrome (LQTS) Registry with baseline QT c prolongation and history of ASM therapy (n = 296). Using multivariate Anderson-Gill models, we assessed the risk of recurrent cardiac events associated with ASM therapy. We stratified by LQTS genotype and predominant mechanism of ASM action (Na + channel blocker and gamma-aminobutyric acid modifier.) There was an increased risk of cardiac events when participants with QT c prolongation were taking vs off ASMs (HR 1.65, 95% confidence interval [CI] 1.36-2.00, P < 0.001). There was an increased risk of cardiac events when LQTS2 (HR 1.49, 95% CI 1.03-2.15, P = 0.036) but not LQTS1 participants were taking ASMs (interaction, P = 0.016). Na + channel blocker ASMs were associated with an increased risk of cardiac events in participants with QT c prolongation, specifically LQTS2, but decreased risk in LQTS1. The increased risk when taking all ASMs and Na + channel blocker ASMs was attenuated by concurrent beta-adrenergic blocker therapy (interaction, P < 0.001). Gamma-aminobutyric acid modifier ASMs were associated with an increased risk of events in patients not concurrently treated with beta-adrenergic blockers. Female participants were at an increased risk of cardiac events while taking all ASMs and each class of ASMs. Despite no change in overall QT c duration, pharmacogenomic analyses set the stage for future prospective clinical and mechanistic studies to validate that ASMs with predominantly Na + channel blocking actions are deleterious in LQTS2, but protective in LQTS1. Copyright © 2017 Elsevier Inc. All rights reserved.

QT interval prolongation associated with sibutramine treatment

PubMed Central

Harrison-Woolrych, Mira; Clark, David W J; Hill, Geraldine R; Rees, Mark I; Skinner, Jonathan R

2006-01-01

Aims To investigate a possible association of sibutramine with QT interval prolongation. Methods Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. Results The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QTc at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. Conclusions This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. Further studies are required, but in the meantime we would recommend that sibutramine should be avoided in patients with long QT syndrome and in patients taking other medicines that may prolong the QT interval. PMID:16542208

Differential calcium sensitivity in NaV 1.5 mixed syndrome mutants.

PubMed

Abdelsayed, Mena; Baruteau, Alban-Elouen; Gibbs, Karen; Sanatani, Shubhayan; Krahn, Andrew D; Probst, Vincent; Ruben, Peter C

2017-09-15

SCN5a mutations may express gain-of-function (Long QT Syndrome-3), loss-of-function (Brugada Syndrome 1) or both (mixed syndromes), depending on the mutation and environmental triggers. One such trigger may be an increase in cytosolic calcium, accompanying exercise. Many mixed syndromes mutants, including ∆KPQ, E1784K, 1795insD and Q1909R, are found in calcium-sensitive regions. Elevated cytosolic calcium attenuates gain-of-function properties in ∆KPQ, 1795insD and Q1909R, but not in E1784K. By contrast, elevated cytosolic calcium further exacerbates gain-of-function in E1784K by destabilizing slow inactivation. Action potential modelling, using a modified O'Hara Rudy model, suggests that elevated heart rate rescues action potential duration in ∆KPQ, 1795insD and Q1909R, but not in E1784K. Action potential simulations suggest that E1784K carriers have an increased intracellular sodium-to-calcium ratio under bradycardia and tachycardia conditions. Elevated cytosolic calcium, which is common during high heart rates, ameliorates or exacerbates the mixed syndrome phenotype depending on the genetic signature. Inherited arrhythmias may arise from mutations in the gene for SCN5a, which encodes the cardiac voltage-gated sodium channel, Na V 1.5. Mutants in Na V 1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3) or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We aimed to determine the effects of elevated cytosolic calcium, which is common during exercise, in mixed syndrome Na V 1.5 mutants. We used whole-cell patch clamp to assess the biophysical properties of Na V 1.5 wild-type (WT), ∆KPQ, E1784K, 1795insD and Q1909R mutants in human embryonic kidney 293 cells transiently transfected with the Na V 1.5 α subunit (WT or mutants), β1 subunit and enhanced green fluorescent protein. Voltage-dependence and kinetics were measured at cytosolic calcium levels of approximately 0, 500 and 2500�

Expression of a Mutant kcnj2 Gene Transcript in Zebrafish

PubMed Central

Leong, Ivone U. S.; Skinner, Jonathan R.; Shelling, Andrew N.; Love, Donald R.

2013-01-01

Long QT 7 syndrome (LQT7, also known as Andersen-Tawil syndrome) is a rare autosomal-dominant disorder that causes cardiac arrhythmias, periodic paralysis, and dysmorphic features. Mutations in the human KCNJ2 gene, which encodes for the subunit of the potassium inwardly-rectifying channel (IK1), have been associated with the disorder. The majority of mutations are considered to be dominant-negative as mutant proteins interact to limit the function of wild type KCNJ2 proteins. Several LQT7 syndrome mouse models have been created that vary in the physiological similarity to the human disease. To complement the LQT7 mouse models, we investigated the usefulness of the zebrafish as an alternative model via a transient approach. Initial bioinformatic analysis identified the zebrafish orthologue of the human KCNJ2 gene, together with a spatial expression profile that was similar to that of human. The expression of a kcnj2-12 transcript carrying an in-frame deletion of critical amino acids identified in human studies resulted in embryos that exhibited defects in muscle development, thereby affecting movement, a decrease in jaw size, pupil-pupil distance, and signs of scoliosis. These defects correspond to some phenotypes expressed by human LQT7 patients. PMID:27335675

QT and JT dispersion and cardiac performance in children with neonatal Bartter syndrome: a pilot study.

PubMed

Hacihamdioglu, Duygu Ovunc; Fidanci, Kursat; Kilic, Ayhan; Gok, Faysal; Topaloglu, Rezan

2013-10-01

QT dispersion and JT dispersion are simple noninvasive arrhythmogenic markers that can be used to assess the homogeneity of cardiac repolarization. The aim of this study was to assess QT and JT dispersion and their relation with left ventricular systolic and diastolic functions in children with Bartter syndrome (BS). Nine neonatal patients with BS (median age 9.7 years) and 20 controls (median age 8 years) were investigated at rest. Both study and control subjects underwent electrocardiography (ECG) in which the interval between two R waves and QT intervals, corrected QT, QT dispersion, corrected QT dispersion, JT, corrected JT, JT dispersion and corrected JT dispersion were measured with 12-lead ECG. Two-dimensional, Doppler echocardiographic examinations were performed. Patients and controls did not differ for gender and for serum levels of potassium, magnesium, and calcium (p > 0.05). Both study and control subjects had normal echocardiographic examination and baseline myocardial performance indexes. The QT dispersion and JT dispersion were significantly prolonged in patients with BS compared to those of the controls {37.5 ms [interquartile range (IQR) 32.5-40] vs. 25.5 ms (IQR 20-30), respectively, p = 0.014 and 37.5 ms (IQR 27.5-40) vs. 22.5 ms (IQR 20-30), respectively, p = 0.003}. Elevated QT and JT dispersion during asymptomatic and normokalemic periods may be risk factors for the development of cardiac complications and arrhythmias in children with BS. In these patients the need for systematic cardiac screening and management protocol is extremely important for effective prevention.

The genetics underlying acquired long QT syndrome: impact for genetic screening

PubMed Central

Itoh, Hideki; Crotti, Lia; Aiba, Takeshi; Spazzolini, Carla; Denjoy, Isabelle; Fressart, Véronique; Hayashi, Kenshi; Nakajima, Tadashi; Ohno, Seiko; Makiyama, Takeru; Wu, Jie; Hasegawa, Kanae; Mastantuono, Elisa; Dagradi, Federica; Pedrazzini, Matteo; Yamagishi, Masakazu; Berthet, Myriam; Murakami, Yoshitaka; Shimizu, Wataru; Guicheney, Pascale; Schwartz, Peter J.; Horie, Minoru

2016-01-01

Aims 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. Methods and results 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. Conclusion 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. PMID:26715165

Acute coronary syndrome-like presentation with prolonged QT interval: an unusual case of pheochromocytoma.

PubMed

Ozyuncu, Nil; Akturk, Sevinc; Tan Kurklu, Turkan Seda; Erol, Cetin

2016-09-26

Pheochromocytoma is a rare adrenal gland tumour, usually alerting the physician by causing hypertensive tachycardic attacks. Patients with pheochromocytoma can rarely present with clinical signs similar to acute coronary syndrome. QT interval prolongation and ST segment changes due to pheochromocytoma have also been reported in the literature in a few case reports. We report a patient who had been admitted to the emergency department with chest pain, ischaemic ECG changes and marked QT prolongation. Despite a normal coronary angiogram, we observed that the QT interval and ST segment morphologies had changed during the hospitalisation period. Adrenal adenoma was diagnosed incidentally on abdominal CT scan, and the final diagnosis was pheochromocytoma. The tumour was successfully excised and the patient is now symptom free. When there is lack of a typical clinical picture, the diagnosis of pheochromocytoma might be challenging. It is also very crucial, since misdiagnosis can be life-threatening. 2016 BMJ Publishing Group Ltd.

Prenatal diagnosis of long QT syndrome with the superior vena cava-aorta Doppler approach.

PubMed

Chabaneix, Julie; Andelfinger, Gregor; Fournier, Anne; Fouron, Jean-Claude; Raboisson, Marie-Josée

2012-10-01

We describe a fetus at 36 weeks with long QT syndrome presenting with variable types of atrioventricular blocks, ventricular premature beats, and torsades de pointes. All these diagnoses were made with the superior vena cava-aorta Doppler approach and confirmed with postnatal electrocardiography. Copyright © 2012 Mosby, Inc. All rights reserved.

How the knowledge of genetic "makeup" and cellular data can affect the analysis of repolarization in surface electrocardiogram.

PubMed

Shimizu, Wataru

2010-01-01

This review article sought to describe patterns of repolarization on the surface electrocardiogram in inherited cardiac arrhythmias and to discuss how the knowledge of genetic makeup and cellular data can affect the analysis based on the data derived from the experimental studies using arterially perfused canine ventricular wedge preparations. Molecular genetic studies have established a link between a number of inherited cardiac arrhythmia syndromes and mutations in genes encoding cardiac ion channels or membrane components during the past 2 decades. Twelve forms of congenital long QT syndrome have been so far identified, and genotype-phenotype correlations have been investigated especially in the 3 major genotypes-LQT1, LQT2, and LQT3. Abnormal T waves are reported in the LQT1, LQT2, and LQT3, and the differences in the time course of repolarization of the epicardial, midmyocardial, and endocardial cells give rise to voltage gradients responsible for the manifestation of phenotypic appearance of abnormal T waves. Brugada syndrome is characterized by ST-segment elevation in leads V1 to V3 and an episode of ventricular fibrillation, in which 7 genotypes have been reported. An intrinsically prominent transient outward current (I(to))-mediated action potential notch and a subsequent loss of action potential dome in the epicardium, but not in the endocardium of the right ventricular outflow tract, give rise to a transmural voltage gradient, resulting in ST-segment elevation, and a subsequent phase 2 reentry-induced ventricular fibrillation. In conclusion, transmural electrical heterogeneity of repolarization across the ventricular wall profoundly affects the phenotypic manifestation of repolarization patterns on the surface electrocardiogram in inherited cardiac arrhythmias. Copyright © 2010 Elsevier Inc. All rights reserved.

A high-risk patient with long-QT syndrome with no response to cardioselective beta-blockers.

PubMed

Toyota, Naoki; Miyazaki, Aya; Sakaguchi, Heima; Shimizu, Wataru; Ohuchi, Hideo

2015-09-01

We present a case of a high-risk 19-year-old female with long-QT syndrome (LQTS) with compound mutations. She had a history of aborted cardiac arrest and syncope and had received treatment with propranolol for 15 years. However, because she developed adult-onset asthma we tried to switch propranolol, a nonselective beta-blocker, to beta-1-cardioselective agents, bisoprolol and metoprolol. These resulted in both a markedly prolonged corrected QT interval and the development of LQTS-associated arrhythmias. Eventually, propranolol was reinitiated at a higher dose with the addition of verapamil, and she has had no further cardiac or asthmatic events for 5 years.

Enhancing the Predictive Power of Mutations in the C-Terminus of the KCNQ1-Encoded Kv7.1 Voltage-Gated Potassium Channel.

PubMed

Kapplinger, Jamie D; Tseng, Andrew S; Salisbury, Benjamin A; Tester, David J; Callis, Thomas E; Alders, Marielle; Wilde, Arthur A M; Ackerman, Michael J

2015-04-01

Despite the overrepresentation of Kv7.1 mutations among patients with a robust diagnosis of long QT syndrome (LQTS), a background rate of innocuous Kv7.1 missense variants observed in healthy controls creates ambiguity in the interpretation of LQTS genetic test results. A recent study showed that the probability of pathogenicity for rare missense mutations depends in part on the topological location of the variant in Kv7.1's various structure-function domains. Since the Kv7.1's C-terminus accounts for nearly 50 % of the overall protein and nearly 50 % of the overall background rate of rare variants falls within the C-terminus, further enhancement in mutation calling may provide guidance in distinguishing pathogenic long QT syndrome type 1 (LQT1)-causing mutations from rare non-disease-causing variants in the Kv7.1's C-terminus. Therefore, we have used conservation analysis and a large case-control study to generate topology-based estimative predictive values to aid in interpretation, identifying three regions of high conservation within the Kv7.1's C-terminus which have a high probability of LQT1 pathogenicity.

The genetics underlying acquired long QT syndrome: impact for genetic screening.

PubMed

Itoh, Hideki; Crotti, Lia; Aiba, Takeshi; Spazzolini, Carla; Denjoy, Isabelle; Fressart, Véronique; Hayashi, Kenshi; Nakajima, Tadashi; Ohno, Seiko; Makiyama, Takeru; Wu, Jie; Hasegawa, Kanae; Mastantuono, Elisa; Dagradi, Federica; Pedrazzini, Matteo; Yamagishi, Masakazu; Berthet, Myriam; Murakami, Yoshitaka; Shimizu, Wataru; Guicheney, Pascale; Schwartz, Peter J; Horie, Minoru

2016-05-07

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. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Long QT syndrome in African-Americans.

PubMed

Fugate, Thomas; Moss, Arthur J; Jons, Christian; McNitt, Scott; Mullally, Jamie; Ouellet, Gregory; Goldenberg, Ilan; Zareba, Wojciech; Robinson, Jennifer L

2010-01-01

We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients. The study involved 41 African-Americans and 3456 Caucasians with a QTc > or = 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS-related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation. The QTc was 29 ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that beta-blockers were equally effective in reducing cardiac events in the two racial groups. The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from beta-blocker therapy in the two racial groups.

Landiolol suppression of electrical storm of torsades de pointes in patients with congenital long-QT syndrome type 2 and myocardial ischemia.

PubMed

Kitajima, Ryota; Aiba, Takeshi; Kamakura, Tsukasa; Ishibashi, Kohei; Wada, Mitsuru; Inoue, Yuko; Miyamoto, Koji; Okamura, Hideo; Noda, Takashi; Nagase, Satoshi; Kataoka, Yu; Asaumi, Yasuhide; Noguchi, Teruo; Yasuda, Satoshi; Kusano, Kengo

2017-10-01

A 76-year-old man who had been diagnosed with long-QT syndrome type 2 had frequent syncopal attacks. The electrocardiogram was monitored, and frequent torsades de pointes (TdP) was detected despite administration of conventional medications: oral propranolol, verapamil, intravenous magnesium sulfate, verapamil, and lidocaine. In contrast, 2 μg/kg/min landiolol could completely suppress TdP. Subsequently, an implantable cardioverter defibrillator was placed, and he was diagnosed with silent myocardial ischemia using myocardial perfusion scintigraphy and coronary angiography. This is the first case report wherein landiolol effectively suppressed TdP due to long-QT syndrome with silent myocardial ischemia.

Therapeutic effects of a taurine-magnesium coordination compound on experimental models of type 2 short QT syndrome.

PubMed

An, Meng-Yao; Sun, Kai; Li, Yan; Pan, Ying-Ying; Yin, Yong-Qiang; Kang, Yi; Sun, Tao; Wu, Hong; Gao, Wei-Zhen; Lou, Jian-Shi

2018-03-01

Short QT syndrome (SQTS) is a genetic arrhythmogenic disease that can cause malignant arrhythmia and sudden cardiac death. The current therapies for SQTS have application restrictions. We previously found that Mg· (NH 2 CH 2 CH 2 SO 3 )2· H 2 O, a taurine-magnesium coordination compound (TMCC) exerted anti-arrhythmic effects with low toxicity. In this study we established 3 different models to assess the potential anti-arrhythmic effects of TMCC on type 2 short QT syndrome (SQT2). In Langendorff guinea pig-perfused hearts, perfusion of pinacidil (20 μmol/L) significantly shortened the QT interval and QTpeak and increased rTp-Te (P<0.05 vs control). Subsequently, perfusion of TMCC (1-4 mmol/L) dose-dependently increased the QT interval and QTpeak (P<0.01 vs pinacidil). TMCC perfusion also reversed the rTp-Te value to the normal range. In guinea pig ventricular myocytes, perfusion of trapidil (1 mmol/L) significantly shortened the action potential duration at 50% (APD 50 ) and 90% repolarization (APD 90 ), which was significantly reversed by TMCC (0.01-1 mmol/L, P<0.05 vs trapidil). In HEK293 cells that stably expressed the outward delayed rectifier potassium channels (I Ks ), perfusion of TMCC (0.01-1 mmol/L) dose-dependently inhibited the IKs current with an IC 50 value of 201.1 μmol/L. The present study provides evidence that TMCC can extend the repolarization period and inhibit the repolarizing current, I Ks , thereby representing a therapeutic candidate for ventricular arrhythmia in SQT2.

Electromechanical heterogeneity in the heart : A key to long QT syndrome?

PubMed

Dressler, F F; Brado, J; Odening, K E

2018-03-01

In the healthy heart, physiological heterogeneities in structure and in electrical and mechanical activity are crucial for normal, efficient excitation and pumping. Alterations of heterogeneity have been linked to arrhythmogenesis in various cardiac disorders such as long QT syndrome (LQTS). This inherited arrhythmia disorder is caused by mutations in different ion channel genes and is characterized by (heterogeneously) prolonged cardiac repolarization and increased risk for ventricular tachycardia, syncope and sudden cardiac death. Cardiac electrical and mechanical function are not independent of each other but interact in a bidirectional manner by electromechanical and mechano-electrical coupling. Therefore, changes in either process will affect the other. Recent experimental and clinical evidence suggests that LQTS, which is primarily considered an "electrical" disorder, also exhibits features of disturbed mechanical function and heterogeneity, which in turn appears to correlate with the risk of arrhythmia in the individual patient. In this review, we give a short overview of the current knowledge about physiological and pathological, long QT-related electrical and mechanical heterogeneity in the heart. Also, their respective roles for future risk prediction approaches in LQTS are discussed.

[Long QT syndrome and polymorphic ventricular tachycardia due to hypopituitarism. Report of one case].

PubMed

García-Castro, José Miguel; García-Martín, Antonia; Guirao-Arrabal, Emilio; Carrillo-Alascio, Pedro Luis

2017-07-01

Symptoms of hypopituitarism are usually chronic and nonspecific, but rarely the disease can have acute and life threatening manifestations. We report a 53 years old female with a pituitary adenoma that was admitted to our hospital because of syncope. The electrocardiogram showed sinus bradycardia with a prolonged QT interval. Frequent runs of non-sustained polymorphic ventricular tachycardia were noted on telemetry. The patient had a history of severe acute headaches in the previous days and laboratory tests revealed severe secondary hypothyroidism, adrenal insufficiency and a decrease in pituitary hormones. A magnetic resonance imaging of the head showed changes in the size and contrast enhancement of the adenoma. A diagnosis of hypopituitarism secondary to pituitary apoplexy was made and treatment with hydrocortisone and, subsequently, levothyroxine was started. Hormonal disorders such as hypothyroidism, adrenal insufficiency or hypopituitarism should be considered as unusual causes for reversible cardiomyopathy, long QT syndrome and ventricular arrhythmias.

Long-term high-intensity interval training associated with lifestyle modifications improves QT dispersion parameters in metabolic syndrome patients.

PubMed

Drigny, J; Gremeaux, V; Guiraud, T; Gayda, M; Juneau, M; Nigam, A

2013-07-01

QT dispersion (QTd) is a marker of myocardial electrical instability, and is increased in metabolic syndrome (MetS). Moderate intensity continuous exercise (MICE) training was shown to improve QTd in MetS patients. To describe long-term effects of MICE and high-intensity interval exercise training (HIIT) on QTd parameters in MetS. Sixty-five MetS patients (53 ± 9 years) were assigned to either a MICE (60% of peak power output [PPO]), or a HIIT program (alternating phases of 15-30 s at 80% of PPO interspersed by passive recovery phases of equal duration), twice weekly during 9 months. Ventricular repolarization indices (QT dispersion=QTd, standard deviation of QT = sdQT, relative dispersion of QT = rdQT, QT corrected dispersion = QTcd), metabolic, anthropometric and exercise parameters were measured before and after the intervention. No adverse events were noted during exercise. QTd decreased significantly in both groups (51 vs 56 ms in MICE, P < 0.05; 34 vs 38 ms in HIIT, P < 0.05). Changes in QTd were correlated with changes in maximal heart rate (r = -0.69, P < 0.0001) and in heart rate recovery (r = -0.49, P < 0.01) in the HIIT group only. When compared to MICE, HIIT training induced a greater decrease in weight, BMI and waist circumference. Exercise capacity significantly improved by 0.82 and 1.25 METs in MICE and HIIT groups respectively (P < 0.0001). Lipid parameters also improved to the same degree in both groups. In MetS, long-term HIIT and MICE training led to comparable effects on ventricular repolarization indices, and HIIT might be associated with greater improvements in certain cardiometabolic risk factors. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

PubMed

Goutelle, Sylvain; Sidolle, Elodie; Ducher, Michel; Caron, Jacques; Timour, Quadiri; Nony, Patrice; Gouraud, Aurore

2014-08-01

Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS. In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n = 125) and LQTS without TdP (n = 81) in patients ≥65 years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP. The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577 ± 79 vs. 519 ± 68 ms; p = 0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95 % confidence interval 0.64-0.88) and a QT cutoff of 550 ms. The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

Dilated cardiomyopathy with short QT interval: is it a new clinical entity?

PubMed

Bohora, Shomu; Namboodiri, Narayanan; Tharakan, Jaganmohan; Vk, Ajit Kumara; Nayyar, Sachin

2009-05-01

Short QT syndrome is a rare autosomal dominant channelopathy of structurally normal hearts characterized by atrial fibrillation, ventricular arrhythmias, and sudden cardiac death. We report a case having short QT, dilated ventricles, and severe ventricular dysfunction, an unreported association so far.

Multigenerational Inheritance of Long QT Syndrome Type 2 in a Japanese Family.

PubMed

Ichikawa, Mari; Ohno, Seiko; Fujii, Yusuke; Ozawa, Junichi; Sonoda, Keiko; Fukuyama, Megumi; Kato, Koichi; Kimura, Hiromi; Itoh, Hideki; Hayashi, Hideki; Horie, Minoru

2016-01-01

Congenital long QT syndrome (LQTS) is an important cause of sudden cardiac death in young people without any other structural disease. Mutations in the genes encoding the cardiac ion channels or associated proteins have been shown to result in ion channel dysfunction and thereby causing LQTS. We investigated a Japanese family with LQTS for four generations, with the female family members showing severe symptoms. We performed genetic tests for LQTS-related genes and identified a heterozygous KCNH2 mutation (p.K638del). In the family, the KCNH2 mutation had a very high multigenerational inheritance, and female genotype positives showed more severe phenotypes.

Emotional stress as a cause of syncope and torsade de pointes in patients with long QT syndrome.

PubMed

Vukmirović, Mihailo; Vukmirović, Irena Tomašević; Angelkov, Lazar; Vukmirović, Filip

2015-02-01

Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by the prolongation of QT interval and high risk propensity of torsade de pointes (TdP) that can lead to syncope, cardiac arrest and sudden death. Episodes may be provoked by various stimuli depending on the type of the condition. A 25-year-old famele patient was hospitalized due to syncope that occurred immediately after her solo concert, first time in her life. The patient studied solo singing and after intensive preparations the first solo concert was organized. Electrocardiography (ECG) on admission registered frequent ventricular premature beats (VES), followed by polymorphic ventricular tachycardia--TdP that degenerated into ventricular fibrilation (VF). After immediate cardioversion magnesium and beta-blockers were administered. TdP was registered again several times preceded by VES. The corrected QT interval (QTc) was 516 msec. For secondary prevention of sudden cardiac death, a cardioverter defibrillator was implanted, and beta-blockers continued. After a 1-year follow-up there were no recurrent episodes of TdP, and measured QTc was reduced to 484 msec. Patients with syncope following intensive emotional stress should be evaluated for malignant arrhythmias in the context of LQTS.

QT prolongation in the newborn and maternal alcoholism.

PubMed

Krasemann, Thomas

2004-10-01

I discuss a newborn whose mother is addicted to alcohol. On the third day of life, the newborn was found to have ventricular tachycardia. After spontaneous termination of the abnormal rhythm, the duration of the corrected QT interval was 0.48 s. During the next days, the duration of the interval normalized, and has now remained stable for 5 years. I conclude that the so-called "alcohol withdrawal syndrome of the newborn" might cause postnatal prolongation of the QT interval.

Two markers in predicting the cardiovascular events in patients with polycystic ovary syndrome: increased P-wave and QT dispersion.

PubMed

Akdag, S; Cim, N; Yildizhan, R; Akyol, A; Ozturk, F; Babat, N

2015-09-01

Polycystic ovary syndrome (PCOS) is a prevalent disease with many potential long-term cardiovascular risks. P-wave dispersion (Pdis) and QT dispersion (QTdis) have been shown to be noninvasive electrocardiographic predictors for development of cardiac arrhythmias. In this study we aimed to search Pdis and QTdis parameters in patients with PCOS. The study included 82 patients with PCOS and 74 age- and sex-matched healthy controls. Baseline 12-lead electrocardiographic and transthoracic echocardiographic measurements were evaluated. P-wave maximum duration (Pmax), P-wave minimum duration (Pmin), Pdis, QT interval, heart rate-corrected QT dispersion and QTdis were calculated by two cardiologists. Patients wirh PCOS had significantly higher QT dispersion (49.5 ± 14.1 vs. 37.9 ± 12.6 ms, p < 0.001), and P wave dispersion (54.2 ± 11.4 vs. 45.9 ± 10.1 ms, p < 0.001) than the controls. Serum testosterone and estradiol levels was correlated with the Pdis (r = 0.677, p < 0.001 and r = 0.415, p < 0.001 respectively) and QTdis (r = 0.326, p < 0.001 and r = 0.321, p < 0.001 respectively). Pdis and QTdis are simple and useful electrocardiographic markers which may be used in the prediction of the risk of adverse cardiovascular events in PCOS patients.

Contribution of a KCNH2 variant in genotyped long QT syndrome: Romano-Ward syndrome under double mutations and acquired long QT syndrome under heterozygote.

PubMed

Fujii, Yusuke; Matsumoto, Yuichi; Hayashi, Kenshi; Ding, Wei-Guang; Tomita, Yukinori; Fukumoto, Daisuke; Wada, Yuko; Ichikawa, Mari; Sonoda, Keiko; Ozawa, Junichi; Makiyama, Takeru; Ohno, Seiko; Yamagishi, Masakazu; Matsuura, Hiroshi; Horie, Minoru; Itoh, Hideki

2017-07-01

Long QT syndrome (LQTS) presents two clinical phenotypes, congenital and acquired forms. This study aims to evaluate the genetic contribution of a KCNH2 variant for the two LQTS phenotypes. From 1996 to 2014, genetic screening for LQTS probands was performed for five major genes: KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 and 389 probands were found to be mutation carriers. We analyzed the clinical phenotypes of p.His492Tyr carriers in KCNH2. Heterozygous p.His492Tyr variant was identified in 10 LQTS families. Six probands (mean age, 26±23 years) carried another mutation, and two of six had syncope associated with emotional stress or telephone ringing. The remaining four probands were significantly older at diagnosis (mean age, 42±33 years) and carried no other compound mutations. All the four probands had fatal arrhythmic events in the presence of additional precipitating factors such as culprit drugs in 2, hypokalemia in 1, and bradycardia in 1. The QTc interval of carriers with p.His492Tyr alone was 445±10ms and significantly shorter than that in double mutation carriers (481±40ms, p=0.041). KCNH2 p.His492Tyr variant presented Romano-Ward syndrome in the presence of another mutation and heterozygous carriers had mild phenotypes while even heterozygous carriers should be cared for not to encounter secondary factors because incidental factors could manifest "latent" form of p.His492Tyr heterozygous carriers. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome

PubMed Central

Romero, Lucia; Trenor, Beatriz; Yang, Pei-Chi; Saiz, Javier; Clancy, Colleen E.

2014-01-01

Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired Long-QT Syndrome (aLTQS). We developed a computational approach to reveal the pharmacological properties of IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed “in silico mutagenesis” by altering discrete kinetic transition rates of the Fink et al. Markov model of human IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired Long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr channels were incorporated into the O’Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of IKr-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr channel are key to amplify variants underlying susceptibility to acquired Long QT Syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical

Relationship of QT dispersion with sex hormones and insulin in young women with polycystic ovary syndrome: an observational study.

PubMed

Gazi, Emine; Gencer, Meryem; Hancı, Volkan; Temiz, Ahmet; Altun, Burak; Cakır Güngör, Ayşe Nur; Oztürk, Ufuk; Kırılmaz, Bahadır

2013-12-01

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in reproductive women. Cardiovascular disease risk factors are more frequent in this population. We aimed in this study to investigate presence of QT dispersion and effects of sex hormones and insulin on QT duration in young PCOS patients. This present study was cross-sectional observational study. A total of 47 women, 25 patients with PCOS and 22 healthy, were included. Serum testosterone, estradiol and insulin levels were studied and electrocardiography was performed at 2nd or 3th days of menstrual cycle. The study population was divided into groups according to serum testosterone and estradiol levels. Sub-groups and pairwise groups were compared by Mann-Whitney U or student t-test. The associations of QTc durations with hormone levels were calculated using Spearman rank correlation analysis. The results were evaluated at the p<0.05 significance level. No differences found between groups regarding to demographic parameters. Estradiol and testosterone levels were higher in patients with PCOS (41.12 ± 13.59 vs. 35.57 ± 19.29 pg/mL, p=0.09 and 105 ± 58.5 vs. 17.6 ± 10.9 ng/dL, p=0.01, respectively). QT dispersion was significantly longer in PCOS patients (47.1 vs. 32.7 ms, p=0.01). A positive correlation was found between the serum insulin level and QTc min, QTc max, and QTc mean (r=0.402, p=0.011; r=0.341, p=0.033; r=0.337, p=0.036; respectively). QT dispersion with serum testosterone and estradiol levels were positively correlated (r=0.525, p=0.001 and r=0.326, p=0.046; respectively). Our results suggest that QT dispersion is prolonged and testosterone, estradiol and insulin are associated with QT duration in young PCOS patients.

Glucose ingestion causes cardiac repolarization disturbances in type 1 long QT syndrome patients and healthy subjects.

PubMed

Hyltén-Cavallius, Louise; Iepsen, Eva W; Christiansen, Michael; Graff, Claus; Linneberg, Allan; Pedersen, Oluf; Holst, Jens J; Hansen, Torben; Torekov, Signe S; Kanters, Jørgen K

2017-08-01

Both hypoglycemia and severe hyperglycemia constitute known risk factors for cardiac repolarization changes potentially leading to malignant arrhythmias. Patients with loss of function mutations in KCNQ1 are characterized by long QT syndrome (LQTS) and may be at increased risk for glucose-induced repolarization disturbances. The purpose of this study was to test the hypothesis that KCNQ1 LQTS patients are at particular risk for cardiac repolarization changes during the relative hyperglycemia that occurs after an oral glucose load. Fourteen KCNQ1 LQTS patients and 28 control participants matched for gender, body mass index, and age underwent a 3-hour oral 75-g glucose tolerance test with ECGs obtained at 7 time points. Fridericia corrected QT interval (QTcF), Bazett corrected QT interval (QTcB), and the Morphology Combination Score (MCS) were calculated. QTc and MCS increased in both groups. MCS remained elevated until 150 minutes after glucose ingestion, and the maximal change from baseline was larger among KCNQ1 LQTS patients compared with control subjects (0.28 ± 0.27 vs 0.15 ± 0.13; P <.05). Relative hyperglycemia induced by ingestion of 75-g glucose caused cardiac repolarization disturbances that were more severe in KCNQ1 LQTS patients compared with control subjects. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Novel insight into the natural history of short QT syndrome.

PubMed

Mazzanti, Andrea; Kanthan, Ajita; Monteforte, Nicola; Memmi, Mirella; Bloise, Raffaella; Novelli, Valeria; Miceli, Carlotta; O'Rourke, Sean; Borio, Gianluca; Zienciuk-Krajka, Agnieszka; Curcio, Antonio; Surducan, Andreea Elena; Colombo, Mario; Napolitano, Carlo; Priori, Silvia G

2014-04-08

This study intends to gain further insights into the natural history, the yield of familial and genetic screening, and the arrhythmogenic mechanisms in the largest cohort of short QT syndrome (SQTS) patients described so far. SQTS is a rare genetic disorder associated with life-threatening arrhythmias, and its natural history is incompletely ascertained. Seventy-three SQTS patients (84% male; age, 26 ± 15 years; corrected QT interval, 329 ± 22 ms) were studied, and 62 were followed for 60 ± 41 months (median, 56 months). Cardiac arrest (CA) was the most frequent presenting symptom (40% of probands; range, <1 month to 41 years). The rate of CA was 4% in the first year of life and 1.3% per year between 20 and 40 years; the probability of a first occurrence of CA by 40 years of age was 41%. Despite the male predominance, female patients had a risk profile superimposable to that of men (p = 0.49). The yield of genetic screening was low (14%), despite familial disease being present in 44% of kindreds. A history of CA was the only predictor of recurrences at follow-up (p < 0.0000001). Two patterns of onset of ventricular fibrillation were observed and were reproducible in patients with multiple occurrences of CA. Arrhythmias occurred mainly at rest. SQTS is highly lethal; CA is often the first manifestation of the disease with a peak incidence in the first year of life. Survivors of CA have a high CA recurrence rate; therefore, implantation of a defibrillator is strongly recommended in this group of patients. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

RNA interference-based therapeutics for inherited long QT syndrome.

PubMed

Li, Guoliang; Ma, Shuting; Sun, Chaofeng

2015-08-01

Inherited long QT syndrome (LQTS) is an electrical heart disorder that manifests with syncope, seizures, and increased risk of torsades de pointes and sudden cardiac death. Dominant-negative current suppression is a mechanism by which pathogenic proteins disrupt the function of ion channels in inherited LQTS. However, current approaches for the management of inherited LQTS are inadequate. RNA interference (RNAi) is a powerful technique that is able to suppress or silence the expression of mutant genes. RNAi may be harnessed to knock out mRNAs that code for toxic proteins, and has been increasingly recognized as a potential therapeutic intervention for a range of conditions. The present study reviews the literature for RNAi-based therapeutics in the treatment of inherited LQTS. Furthermore, this review discusses the combined use of RNAi with the emerging technology of induced pluripotent stem cells for the treatment of inherited LQTS. In addition, key challenges that must be overcome prior to RNAi-based therapies becoming clinically applicable are addressed. In summary, RNAi-based therapy is potentially a powerful therapeutic intervention, although a number of difficulties remain unresolved.

RNA interference-based therapeutics for inherited long QT syndrome

PubMed Central

LI, GUOLIANG; MA, SHUTING; SUN, CHAOFENG

2015-01-01

Inherited long QT syndrome (LQTS) is an electrical heart disorder that manifests with syncope, seizures, and increased risk of torsades de pointes and sudden cardiac death. Dominant-negative current suppression is a mechanism by which pathogenic proteins disrupt the function of ion channels in inherited LQTS. However, current approaches for the management of inherited LQTS are inadequate. RNA interference (RNAi) is a powerful technique that is able to suppress or silence the expression of mutant genes. RNAi may be harnessed to knock out mRNAs that code for toxic proteins, and has been increasingly recognized as a potential therapeutic intervention for a range of conditions. The present study reviews the literature for RNAi-based therapeutics in the treatment of inherited LQTS. Furthermore, this review discusses the combined use of RNAi with the emerging technology of induced pluripotent stem cells for the treatment of inherited LQTS. In addition, key challenges that must be overcome prior to RNAi-based therapies becoming clinically applicable are addressed. In summary, RNAi-based therapy is potentially a powerful therapeutic intervention, although a number of difficulties remain unresolved. PMID:26622327

Left ventricular epicardial activation increases transmural dispersion of repolarization in healthy, long QT, and dilated cardiomyopathy dogs.

PubMed

Bai, Rong; Lü, Jiagao; Pu, Jun; Liu, Nian; Zhou, Qiang; Ruan, Yanfei; Niu, Huiyan; Zhang, Cuntai; Wang, Lin; Kam, Ruth

2005-10-01

Benefits of cardiac resynchronization therapy (CRT) are well established. However, less is understood concerning its effects on myocardial repolarization and the potential proarrhythmic risk. Healthy dogs (n = 8) were compared to a long QT interval (LQT) model (n = 8, induced by cesium chloride, CsCl) and a dilated cardiomyopathy with congestive heart failure (DCM-CHF, induced by rapid ventricular pacing, n = 5). Monophasic action potential (MAP) recordings were obtained from the subendocardium, midmyocardium, subepicardium, and the transmural dispersion of repolarization (TDR) was calculated. The QT interval and the interval from the peak to the end of the T wave (T(p-e)) were measured. All these characteristics were compared during left ventricular epicardial (LV-Epi), right ventricular endocardial (RV-Endo), and biventricular (Bi-V) pacing. In healthy dogs, TDR prolonged to 37.54 ms for Bi-V pacing and to 47.16 ms for LV-Epi pacing as compared to 26.75 ms for RV-Endo pacing (P < 0.001), which was parallel to an augmentation in T(p-e) interval (Bi-V pacing, 64.29 ms; LV-Epi pacing, 57.89 ms; RV-Endo pacing, 50.29 ms; P < 0.01). During CsCl exposure, Bi-V and LV-Epi pacing prolonged MAPD, TDR, and T(p-e) interval as compared to RV-Endo pacing. The midmyocardial MAPD (276.30 ms vs 257.35 ms, P < 0.0001) and TDR (33.80 ms vs 27.58 ms, P=0.002) were significantly longer in DCM-CHF dogs than those in healthy dogs. LV-Epi and Bi-V pacing further prolonged the MAPD and TDR in this model. LV-Epi and Bi-V pacing result in prolongation of ventricular repolarization time, and increase of TDR accounted for a parallel augmentation of the T(p-e) interval, which provides evidence that T(p-e) interval accurately represents TDR. These effects are magnified in the LQT and DCM-CHF canine models in addition to their intrinsic transmural heterogeneity in the intact heart. This mechanism may contribute to the development of malignant ventricular arrhythmias, such as torsades de

QT-RR relationships and suitable QT correction formulas for halothane-anesthetized dogs.

PubMed

Tabo, Mitsuyasu; Nakamura, Mikiko; Kimura, Kazuya; Ito, Shigeo

2006-10-01

Several QT correction (QTc) formulas have been used for assessing the QT liability of drugs. However, they are known to under- and over-correct the QT interval and tend to be specific to species and experimental conditions. The purpose of this study was to determine a suitable formula for halothane-anesthetized dogs highly sensitive to drug-induced QT interval prolongation. Twenty dogs were anesthetized with 1.5% halothane and the relationship between the QT and RR intervals were obtained by changing the heart rate under atrial pacing conditions. The QT interval was corrected for the RR interval by applying 4 published formulas (Bazett, Fridericia, Van de Water, and Matsunaga); Fridericia's formula (QTcF = QT/RR(0.33)) showed the least slope and lowest R(2) value for the linear regression of QTc intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. An optimized formula (QTcX = QT/RR(0.3879)) is defined by analysis of covariance and represents a correction algorithm superior to Fridericia's formula. For both Fridericia's and the optimized formula, QT-prolonging drugs (d,l-sotalol, astemizole) showed QTc interval prolongation. A non-QT-prolonging drug (d,l-propranolol) failed to prolong the QTc interval. In addition, drug-induced changes in QTcF and QTcX intervals were highly correlated with those of the QT interval paced at a cycle length of 500 msec. These findings suggest that Fridericia's and the optimized formula, although the optimized is a little bit better, are suitable for correcting the QT interval in halothane-anesthetized dogs and help to evaluate the potential QT prolongation of drugs with high accuracy.

Effect of mood states on QT interval and QT dispersion in eating disorder patients.

PubMed

Takimoto, Yoshiyuki; Yoshiuchi, Kazuhiro; Akabayashi, Akira

2008-04-01

Prolonged QT interval and QT dispersion have been reported in patients with eating disorders. Although the factors that cause prolongation remain unclear, mood states such as anxiety have been reported to influence QT interval and dispersion, probably via the autonomic nervous system. Therefore the aim of the present paper was to investigate mood effect on prolonged QT interval and QT dispersion. The subjects were 47 female anorexia nervosa (AN) and 48 female bulimia nervosa (BN) patients. In all of the patients, serum electrolyte levels were normal. QT interval and QT dispersion were measured from 12-lead electrocardiographic recordings. Mood states in each patient were measured using a Profile of Mood States (POMS) evaluation, and the patients were divided into high- and low-score groups for each POMS subscale. The differences in QT variables were compared between the two groups for each subscale. In the BN group, QT interval and QT dispersion in the high depression score group were significantly longer than those in the low depression score group, and QT dispersion was significantly greater in the high anxiety score group than in the low anxiety score group. In addition, QT interval and QT dispersion were significantly correlated with depression scores. In the AN group there were no significant differences in QT interval or QT dispersion between the high- and low-score groups for any POMS subscale. BN patients with worse states of depression or anxiety had longer QT intervals and larger QT dispersion. In BN patients, mood disturbance might increase the risk of arrhythmias.

A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs.

PubMed

van der Linde, H; Van de Water, A; Loots, W; Van Deuren, B; Lu, H R; Van Ammel, K; Peeters, M; Gallacher, D J

2005-01-01

Instability of QT duration is a marker to predict Torsade de Pointes (TdP) associated with both congenital and drug-induced long QT syndrome. We describe a new method for the quantification of instability of repolarization. Female, adult beagle dogs anesthetized with a potent morphinomimetic were treated with either solvent (n=7) or dofetilide (n=7). Poincaré plots with QT(n) versus QT(n+1) were constructed to visualize the beat-to-beat variation in QT intervals from the lead II ECG. Short-term instability (STI), long-term instability (LTI) and total instability (TI) were quantified by calculating the distances of 30 consecutive data-points from the x and y-coordinate to the "centre of gravity" of the data cluster. Dofetilide at 0.0025 to 0.04 mg/kg i.v. (plasma concentrations of 4+/-0.6 to 41+/-2.7 ng/ml), dose-dependently prolonged QT and QTcV (at 0.04 mg/kg i.v.: QT: 280+/-ms versus 236+/-5 ms with solvent; p<0.05 and QTcV: 290+/-9 ms versus 252+/-4 ms with solvent; p<0.05). Concomitantly, the compound induced an increase in the instability parameters in a similar dose-dependent manner (at 0.04 mg/kg i.v.: TI: 6.8+/-0.9 ms versus 1.7+/-0.3 ms; p<0.05, LTI: 3.6+/-0.5 ms versus 1.0+/-0.2 ms; p<0.05 and STI: 4.2+/-0.6 ms versus 1.0+/-0.2 ms; p<0.05). The increases induced by dofetilide were associated with a high incidence of early afterdepolarizations (EADs) in the endocardial monophasic action potential (in 6 out of the 7 compound-treated animals versus 0 out of the 7 solvent animals; p<0.05). Quantification of beat-to-beat QT instability by our method clearly detects changes in short-term, long-term and total instability induced by dofetilide, already at pre-arrhythmic doses. Dofetilide administration to anesthetized dogs prolongs ventricular repolarization, concomitantly increases beat-to-beat QT instability and induces early after depolarizations (EADs). As such, the use of these parameters in this in vivo model shows clear potential for risk identification

Autre cause de mort subite du nourrisson: à propos d'un cas clinique de syndrome du QT long congenital

PubMed Central

Seka, Zena; Mols, Pierre; Gobin, Eric; Ngatchou, William

2014-01-01

Le syndrome du QT long congénital est une maladie rythmique liée à une mutation génétique et caractérisée par un espace QT allongé sur l’électrocardiogramme, des arythmies malignes type torsade de pointe et fibrillation ventriculaire entraînant une mort subite. Les gènes impliqués dans ces mutations codent pour des sous unités des canaux ioniques responsables de l'activité électrique cardiaque. Le diagnostic est basé sur l’électrocardiogramme, une enquête familiale et l’étude génétique. Le traitement repose sur les bêtabloquants, la sympathectomie et le stimulateur cardiaque. Nous rapportons le cas d'un nourrisson de 2 ans retrouvé en état de mort apparente. Nous discutons de sa prise en charge initiale, de l'enquête familiale et de son suivi ultérieur. PMID:25667708

Cardiovascular drugs inducing QT prolongation: facts and evidence.

PubMed

Taira, Carlos A; Opezzo, Javier A W; Mayer, Marcos A; Höcht, Christian

2010-01-01

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

Hyperglycemia and subsequent torsades de pointes with marked QT prolongation during refeeding.

PubMed

Nakashima, Takashi; Kubota, Tomoki; Takasugi, Nobuhiro; Kitagawa, Yuichiro; Yoshida, Takahiro; Ushikoshi, Hiroaki; Kawasaki, Masanori; Nishigaki, Kazuhiko; Ogura, Shinji; Minatoguchi, Shinya

2017-01-01

A fatal cardiac complication can occasionally present in malnourished patients during refeeding; this is known as refeeding syndrome. However, to our knowledge, hyperglycemia preceding torsades de pointes with QT prolongation during refeeding has not been reported. In the present study, we present a case in which hyperglycemia preceded torsades de pointes with QT prolongation during refeeding. The aim of this study was to determine the possible mechanism underlying QT prolongation during refeeding and indicate how to prevent it. A 32-y-old severely malnourished woman (body mass index 14.57 kg/m 2 ) was admitted to the intensive care unit of our institution after resuscitation from cardiopulmonary arrest due to ventricular fibrillation. She was diagnosed with anorexia nervosa. Although no obvious electrolyte abnormalities were observed, her blood glucose level was 11 mg/dL. A 12-lead electrocardiogram at admission showed sinus rhythm with normal QT interval (QTc 0.448). Forty mL of 50% glucose (containing 20 g of glucose) was intravenously injected, followed by a drip infusion of glucose to maintain blood glucose level within normal range. After 9 h, the patient's blood glucose level increased to 569 mg/dL. However, after 38 h, an episode of marked QT prolongation (QTc 0.931) followed by torsades de pointes developed. Hyperglycemia during refeeding can present with QT prolongation; consequently, monitoring blood glucose levels may be useful in avoiding hyperglycemia, which can result in QT prolongation. Furthermore, additional monitoring of QT intervals using a 12-lead electrocardiogram should allow the early detection of QT prolongation when glucose solution is administered to a malnourished patient with (severe) hypoglycemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France

PubMed Central

Molokhia, Mariam; Pathak, Atul; Lapeyre-Mestre, Maryse; Caturla, Laetitia; Montastruc, Jean Louis; McKeigue, Paul

2008-01-01

AIMS The aim of this study was to investigate the incidence and reporting rate of drug-induced long-QT syndrome (LQTS) in France [defined by evidence of torsades de pointes (TdP), QT prolongation and exposure to a relevant drug] and to assess feasibility of case collection for drug-induced LQTS. METHODS A retrospective population-based study was carried out in Southwest France in five institutions: three main hospitals, one private clinic and one cardiac emergency unit, searched from 1 January 1999 to 1 January 2005 (population coverage of 614 000). The study population consisted of 861 cases with International Classification of Diseases-10 diagnostic codes for ventricular tachycardia (I147.2), ventricular fibrillation (I149.0) and sudden cardiac death (I146.1) from hospital discharge summaries, supplemented by cases reported to national or regional pharmacovigilance systems, and voluntary reporting by physicians, validated according to internationally defined criteria for drug-induced LQTS. RESULTS Of 861 patients coded with arrhythmias or sudden cardiac death, there were 40 confirmed surviving acquired cases of drug-induced LQTS. We estimated that the incidence of those who survive to reach hospital drug-induced LQTS is approximately 10.9 per million annually in France (95% confidence interval 7.8, 14.8). CONCLUSIONS Many cases of drug-induced LQTS may not survive before they reach hospital, as the reporting rate for drug-induced LQTS identified through the cardiology records and also reported to pharmacovigilance systems for the Midi-Pyrenees area is 3/40 (7.5%). Using the methods outlined it is possible to assemble cases to study genetic susceptibility to drug-induced LQTS and adapt these methods more widely. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Drug-induced long-QT syndrome (LQTS) is a potentially fatal condition that has led to a number of postmarketing withdrawals in recent years. However, many cases may not survive long enough to reach hospital, and

Biophysical Properties of 9 KCNQ1 Mutations Associated with Long QT Syndrome (LQTS)

PubMed Central

Yang, Tao; Chung, Seo-Kyung; Zhang, Wei; Mullins, Jonathan G.L.; McCulley, Caroline H.; Crawford, Jackie; MacCormick, Judith; Eddy, Carey-Anne; Shelling, Andrew N.; French, John K.; Yang, Ping; Skinner, Jonathan R.; Roden, Dan M.; Rees, Mark I.

2009-01-01

Background Inherited long QT syndrome (LQTS) is characterized by prolonged QT interval on the EKG, syncope and sudden death due to ventricular arrhythmia. Causative mutations occur mostly in cardiac potassium and sodium channel subunit genes. Confidence in mutation pathogenicity is usually reached through family genotype-phenotype tracking, control population studies, molecular modelling and phylogenetic alignments, however, biophysical testing offers a higher degree of validating evidence. Methods and Results By using in-vitro electrophysiological testing of transfected mutant and wild-type LQTS constructs into Chinese Hamster Ovary cells, we investigated the biophysical properties of 9 KCNQ1 missense mutations (A46T, T265I, F269S, A302V, G316E, F339S, R360G, H455Y, and S546L) identified in a New Zealand based LQTS screening programme. We demonstrate through electrophysiology and molecular modeling that seven of the missense mutations have profound pathological dominant negative loss-of-function properties confirming their likely disease-causing nature. This supports the use of these mutations in diagnostic family screening. Two mutations (A46T, T265I) show suggestive evidence of pathogenicity within the experimental limits of biophysical testing, indicating that these variants are disease-causing via delayed or fast activation kinetics. Further investigation of the A46T family has revealed an inconsistent co-segregation of the variant with the clinical phenotype. Conclusions Electrophysiological characterisation should be used to validate LQTS pathogenicity of novel missense channelopathies. When such results are inconclusive, great care should be taken with genetic counselling and screening of such families, and alternative disease causing mechanisms should be considered. PMID:19808498

Prolonged QT Syndrome and Seizure Secondary to Alkaline Earth Metal Deficiency: A Case Report.

PubMed

McKinney, A; Keegan, B C

2011-01-01

Introduction. Alkaline earth metal deficiency is recognized as a cause of both seizure and long QT syndrome. Their deficiency can have significant repercussions on the function of cells, tissues, and organs of the body. An understanding of the role of electrolytes allows an appreciation of the significance of depleted levels on cell function. Case Report. A 65-year-old lady was admitted with symptoms of chest discomfort, vomiting, increased stoma output, and dizziness. Two days following admission she suffered a tonic-clonic seizure. ECG review demonstrated a prolonged QTc interval, raising the possibility of an underlying Torsades de Pointes as the precipitant. This was attributed to electrolyte disturbance arising as a result of multiple aetiologies. Discussion. This paper highlights the multisystem effects of electrolyte disturbance, with emphasis upon its role in precipitating cardiac arrhythmia and neurological symptoms.

Evaluation of QT and P wave dispersion and mean platelet volume among inflammatory bowel disease patients.

PubMed

Dogan, Yuksel; Soylu, Aliye; Eren, Gulay A; Poturoglu, Sule; Dolapcioglu, Can; Sonmez, Kenan; Duman, Habibe; Sevindir, Isa

2011-01-01

In inflammatory bowel disease (IBD) number of thromboembolic events are increased due to hypercoagulupathy and platelet activation. Increases in mean platelet volume (MPV) can lead to platelet activation, this leads to thromboembolic events and can cause acute coronary syndromes. In IBD patients, QT-dispersion and P-wave dispersion are predictors of ventricular arrhythmias and atrial fibrilation; MPV is accepted as a risk factor for acute coronary syndromes, we aimed at evaluating the correlations of these with the duration of disease, its localization and activity. The study group consisted of 69 IBD (Ulcerative colitis n: 54, Crohn's Disease n: 15) patients and the control group included 38 healthy individuals. Disease activity was evaluated both endoscopically and clinically. Patients with existing cardiac conditions, those using QT prolonging medications and having systemic diseases, anemia and electrolyte imbalances were excluded from the study. QT-dispersion, P-wave dispersion and MPV values of both groups were compared with disease activity, its localization, duration of disease and the antibiotics used. The P-wave dispersion values of the study group were significantly higher than those of the control group. Duration of the disease was not associated with QT-dispersion, and MPV levels. QT-dispersion, P-wave dispersion, MPV and platelet count levels were similar between the active and in mild ulcerative colitis patients. QT-dispersion levels were similar between IBD patients and the control group. No difference was observed between P-wave dispersion, QT-dispersion and MPV values; with regards to disease duration, disease activity, and localization in the study group (p>0.05). P-wave dispersion which is accepted as a risk factor for the development of atrial fibirilation was found to be high in our IBD patients. This demonstrates us that the risk of developing atrial fibrillation may be high in patients with IBD. No significant difference was found in the QT

[Factors related to the QT prolongation in chronic renal failure].

PubMed

Kurosu, M; Ando, Y; Akimoto, T; Ono, S; Kusano, E; Asano, Y

1999-04-01

QT prolongation, a risk factor for arrhythmia and cardiac death, is observed in uremic patients. Though hypocalcemia, autonomic nerve dysfunction and cardiac hypertrophy are assumed to cause the uremic QT prolongation, the exact mechanism remains unspecified. We therefore examined factors related to the QT interval in chronic renal failure (CRF). Corrected QT interval (QTc) was significantly prolonged in CRF just before the induction of dialysis therapy (group A) compared with nephrotic syndrome with the intact or mildly impaired renal function (group B). QTc was also prolonged in acute renal failure (group C). Cardio-thoracic ratio, serum albumin and Ca correlated with QTc in group A, but not in B or C. A single HD session in group A failed to shorten QTc, despite a significant increase in serum Ca++. Autonomic dysfunction did not appear to be a major determinant of QT prolongation, since QTc was not different between diabetics and non-diabetics in group A and in chronic HD patients (group D). In group D, QTc did not correlate with SV1 + RV5 on ECG or left ventricular wall thickness (LVWT) on echocardiography. In another group of chronic HD patients (group E), there was no significant correlation between QTc and the parameters of left ventricular mass, plasma brain natriuretic peptide (BNP). However, in the patients subjected to repeated echocardiography in group D, QTc and LVWT changed in parallel. In a retrospective analysis of QTc in group D, QTc was maximally prolonged at the time of starting HD therapy, and gradually improved in the following 1-5 years in both diabetics and non-diabetics. In contrast, chronic CAPD patients (group F) revealed no improvement of QTc. Thus, uremic QT prolongation cannot be explained simply by any of the previously assumed factors, but appears to be affected by multiple factors, which are partially correctable by chronic HD therapy.

Effect of hyperventilation on rate corrected QT interval of children.

PubMed

Kannivelu, Arivalagan; Kudumula, Vikram; Bhole, Vinay

2013-02-01

Hyperventilation is known to cause ST segment changes and QT variability in adults, but this has not been systematically studied in children. To investigate the effect of hyperventilation on rate corrected QT interval (QTc) in children. 25 children (male=10) with a median age of 14 (range 8.3-17.6) years were asked to hyperventilate for 1 min before exercise testing using the modified Bruce protocol. Mean QTc at rest, after hyperventilation, at peak exercise and at 1 min of recovery was 425(±31), 460(±30), 446(±38) and 420(±32) ms, respectively. Mean increase (95% CI) in QTc after hyperventilation was 35(19 to 51) ms (p<0.001), while there was minimal difference between QT interval at rest and after hyperventilation (mean QT 352(±41) vs 357(±44) ms). In six children, there were abnormalities in T wave morphology following hyperventilation. The QTc increment following hyperventilation was more pronounced in children with resting QTc <440 ms (n=14, mean increment (95% CI): 55 (33 to 78) ms) compared to children with QTc ≥440 ms (n=11, mean increment (95% CI): 9 (-4 to 22) ms) (p=0.001). QTc prolongation following hyperventilation was seen in children with both low and intermediate probability of long QT syndrome (LQTS). Peak exercise and early recovery did not cause a statistically significant change in QTc in either of these groups. Hyperventilation produces repolarisation abnormalities, including prolongation of QTc and T wave abnormalities in children with low probability of LQTS. The likely mechanism is delayed adaptation of QT interval with increased heart rate. Thus, a hyperventilation episode can be misdiagnosed as LQTS, especially in an emergency department.

Epidemiology of symptomatic drug-induced long QT syndrome and Torsade de Pointes in Germany.

PubMed

Sarganas, Giselle; Garbe, Edeltraut; Klimpel, Andreas; Hering, Rolf C; Bronder, Elisabeth; Haverkamp, Wilhelm

2014-01-01

Drug-induced long QT syndrome (diLQTS) leading to Torsade de Pointes (TdP) is a potentially lethal condition, which has led to several post-marketing drug withdrawals in the past decade. The true incidence of diLQTS/TdP is largely unknown. One explanation is under-reporting of this potentially life-threatening adverse event by physicians and other medical staff to pharmacovigilance agencies. To gain more insight into the incidence of diLQTS and TdP, the Berlin Pharmacovigilance Center (PVZ-FAKOS) has actively and prospectively identified patients who developed this particular type of drug-induced adverse event. Here, the basic characteristics of the affected patients are summarized and suspected drugs are discussed. Furthermore, an extrapolation of the Berlin incidence rates to the German Standard Population is presented. Using a Berlin-wide network of 51 collaborating hospitals (>180 clinical departments), adult patients presenting with long QT syndrome (LQTS/TdP) between 2008 and 2011 were identified by active surveillance of these hospitals. Drug exposures as well as other possible risk factors were obtained from the patient's files and in a face-to-face interview with the patient. One-hundred and seventy patients of possible LQTS/TdP were reported to the Pharmacovigilance Center of whom 58 cases were confirmed in a thorough validation process. The majority (66%) of these cases were female and 60% had developed LQTS/TdP in the outpatient setting. Thirty-five (60%) of 58 confirmed cases were assessed as drug-related based on a standardized causality assessment applying the criteria of the World Health Organization. Drugs assessed as related in more than two cases were metoclopramide, amiodarone, melperone, citalopram, and levomethadone. The age-standardized incidence of diLQTS/TdP in Berlin was estimated to be 2.5 per million per year for males and 4.0 per million per year for females. While European annual reporting rates based on spontaneous reports suggest an

Genetics Home Reference: Jervell and Lange-Nielsen syndrome

MedlinePlus

... KCNQ1 or KCNE1 mutation have a long QT interval with related heart abnormalities, but their hearing is ... disease Jervell-Lange Nielsen syndrome JLNS prolonged QT interval in EKG and sudden death surdo-cardiac syndrome ...

Dynamic QT Interval Changes from Supine to Standing in Healthy Children.

PubMed

Dionne, Audrey; Fournier, Anne; Dahdah, Nagib; Abrams, Dominic; Khairy, Paul; Abadir, Sylvia

2018-01-01

QT-interval variations in response to exercise-induced increases in heart rate have been reported in children and adults in the diagnosis of long QT syndrome (LQTS). A quick standing challenge has been proposed as an alternative provocative test in adults, with no pediatric data yet available. A standing test was performed in 100 healthy children (mean age, 9.7 ± 3.1 years) after 10 minutes in a supine position with continuous electrocardiographic recording. QT intervals were measured at baseline, at maximal heart rate, at maximal QT, and at each minute of a 5-minute recovery while standing. Measurements were taken in leads II/V 5 and were corrected for heart rate (QTc). On standing, the heart rate increased by 29 ± 10 beats per minute (bpm). The QT interval was similar at baseline and on standing (394 ± 34 ms vs 394 ± 34 ms; P = 1.0). However, QTc increased from 426 ± 21 to 509 ± 41 ms (P < 0.001). The 95th percentile for QTc at baseline and maximal heart rate was 457 ms and 563 ms, respectively. At 1 minute of recovery, the QT interval was shorter (375 ± 31 ms) compared with baseline (394 ± 34 ms; P < 0.001) and standing (394 ± 34 ms; P < 0.001). QTc reached baseline values after 1 minute of recovery and remained stable thereafter (423 ± 23 ms at 1 minute; 426 ± 22 ms at 5 minutes; P = 1.0). This first characterization of QTc changes on standing in children shows substantial alterations, which are greater than those seen in adults. Two-thirds of the children would have been misclassified as having LQTS by adult criteria, indicating the need to create child-specific standards. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

The prevalence and significance of a short QT interval in 18,825 low-risk individuals including athletes.

PubMed

Dhutia, Harshil; Malhotra, Aneil; Parpia, Sameer; Gabus, Vincent; Finocchiaro, Gherardo; Mellor, Greg; Merghani, Ahmed; Millar, Lynne; Narain, Rajay; Sheikh, Nabeel; Behr, Elijah R; Papadakis, Michael; Sharma, Sanjay

2016-01-01

The short QT syndrome is a cardiac channelopathy characterised by accelerated repolarisation which manifests as a short QT interval on the ECG. The definition of a short QT interval is debated, ranging from <390 to ≤320 ms, and its clinical significance in healthy young individuals is unknown. We assessed the prevalence and medium-term significance of an isolated short QT interval in a diverse young British population. Between 2005 and 2013, 18 825 apparently healthy people aged 14-35 years underwent cardiovascular evaluation with history, physical examination and ECG. QT intervals were measured by cardiologists using 4 recommended guidelines (Seattle 2013, Heart Rhythm Society 2013, European Society of Cardiology 2010 and American Heart Association 2009). The prevalence of a short QT interval was 0.1% (26 patients, ≤320 ms), 0.2% (44 patients, ≤330 ms), 7.9% (1478 patients, <380 ms), 15.8% (2973 patients, <390 ms). Male gender and Afro-Caribbean ethnicity had the strongest association with short QT intervals. Athletes had shorter QT intervals than non-athletes but athletic status did not predict short QT intervals. Individuals with short QT intervals ≤320 ms did not report syncope or a sinister family history, and during a follow-up period of 5.3±1.2 years, there were no deaths in this group. The prevalence of a short QT interval depends on the recommended cut-off value. Even at values ≤320 ms, there was an excellent medium-term prognosis among 14 people followed. We conclude that a definition of ≤320 ms is realistic to prevent overdiagnosis and excessive investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Prevalence and Outcome of High-Risk QT Prolongation Recorded in the Emergency Department from an Institution-Wide QT Alert System.

PubMed

Anderson, Heather N; Bos, J Martijn; Haugaa, Kristina H; Morlan, Bruce W; Tarrell, Robert F; Caraballo, Pedro J; Ackerman, Michael J

2018-01-01

QT prolongation is an independent risk factor for sudden death, stroke, and all-cause mortality. However, additional studies have shown that in certain settings, QT prolongation may be transient and a result of external factors. In this study, we evaluated the clinical characteristics and outcomes of patients seen in the emergency department (ED) with QT prolongation. Between November 2010 and June 2011, 7522 patients had an electrocardiogram (ECG) obtained during their evaluation in the ED. Clinical, laboratory, and therapeutic information was collected for all patients with QT prolongation (i.e., ≥ 500 ms and QRS < 120 ms). Potential QT-inciting factors (drugs, electrolyte disturbances, and comorbidities) were synthesized into a pro-QT score. Among the 7522 patients with an ECG obtained in the ED, a QT alert was activated in 93 (1.2%; mean QTc 521 ± 34 ms). The majority of ED patients (64%) had more than one underlying condition associated with QT prolongation, with electrolyte disturbances in 51%, a QT prolonging condition in 56%, and QT-prolonging drugs in 77%. Thirty-day mortality was 13% for patients with QT prolongation noted in the ED. One percent of patients evaluated with an ECG in the ED activated our prolonged QTc warning system, with most demonstrating > 1 QT-prolonging condition. Thirty-day mortality was significant, but it requires further investigation to determine whether the QTc simply provided a non-invasive indicator of increased risk or heralded the presence of a vulnerable host at risk of a QT-mediated sudden dysrhythmic death. Copyright © 2017 Elsevier Inc. All rights reserved.

Heterogeneous Phenotype of Long QT Syndrome Caused by the KCNH2-H562R Mutation: Importance of Familial Genetic Testing.

PubMed

Muñoz-Esparza, Carmen; García-Molina, Esperanza; Salar-Alcaraz, Mariela; Peñafiel-Verdú, Pablo; Sánchez-Muñoz, Juan J; Martínez Sánchez, Juan; Cabañas-Perianes, Valentín; Valdés Chávarri, Mariano; García Alberola, Arcadio; Gimeno-Blanes, Juan R

2015-10-01

Long QT syndrome is an inherited ion channelopathy that leads to syncope and sudden death. Because of the heterogeneous phenotype of this disease, genetic testing is fundamental to detect individuals with concealed long QT syndrome. In this study, we determined the features of a family with 13 carriers of the KCNH2-H562R missense mutation, which affects the pore region of the HERG channel. We identified the KCNH2-H562R mutation in a 65-year-old man with a prolonged QTc interval who had experienced an episode of torsade de pointes. Subsequently, a total of 13 mutation carriers were identified in the family. Carriers (age 48 [26] years; 46% males) underwent clinical evaluation, electrocardiography and echocardiography. The mean (standard deviation) QTc in carriers was 493 (42) ms (3 [23%] showed normal QTc); 6 (46%) had symptoms (4, syncope; 1, sudden death; 1, aborted sudden death [proband]). While under treatment with beta-blockers, 11 of 12 carriers (92%) remained asymptomatic at 5 years of follow-up (1 patient required left cardiac sympathectomy). The QTc shortening with beta-blockers was 50 (37) ms. There was 1 sudden death in a patient who refused treatment. Family study is essential in the interpretation of a genetic testing result. This article describes the heterogeneous and variable phenotype of a large family with the KCNH2-H562R mutation and highlights the role of genetic study for the appropriate identification of at-risk individuals who would benefit from treatment. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Update on the slow delayed rectifier potassium current (I(Ks)): role in modulating cardiac function.

PubMed

Liu, Zhenzhen; Du, Lupei; Li, Minyong

2012-01-01

The slow delayed rectifier current (I(Ks)) is the slow component of cardiac delayed rectifier current and is critical for the late phase repolarization of cardiac action potential. This current is also an important target for Sympathetic Nervous System (SNS) to regulate the cardiac electivity to accommodate to heart rate alterations in response to exercise or emotional stress and can be up-regulated by β- adrenergic or other signal molecules. I(Ks) channel is originated by the co-assembly of pore-forming KCNQ1 α-subunit and accessory KCNE1 β-subunit. Mutations in any subunit can bring about severe long QT syndrome (LQT-1, LQT-5) as characterized by deliquium, seizures and sudden death. This review summarizes the normal physiological functions and molecular basis of I(Ks) channels, as well as illustrates up-to-date development on its blockers and activators. Therefore, the current extensive survey should generate fundamental understanding of the role of I(Ks) channel in modulating cardiac function and donate some instructions to the progression of I(Ks) blockers and activators as potential antiarrhythmic agents or pharmacological tools to determine the physiological and pathological function of I(Ks).

The analysis of QT interval and repolarization morphology of the heart in chronic exposure to lead.

PubMed

Kiełtucki, J; Dobrakowski, M; Pawlas, N; Średniawa, B; Boroń, M; Kasperczyk, S

2017-10-01

There are no common recommendations regarding electrocardiographic monitoring in occupationally exposed workers. Therefore, the present study was designed to investigate whether exposure to lead results in an increase of selected electrocardiography (ECG) pathologies, such as QT interval prolongation and repolarization disorders, in occupationally exposed workers. The study group included 180 workers occupationally exposed to lead compounds. The exposed group was divided according to the median of the mean blood lead level (PbB mean ) calculated based on a series of measurements performed during 5-year observation period (35 µg/dl) into two subgroups: low exposure (LE, PbB mean = 20.0-35.0 µg/dl) and high exposure (HE, PbB mean = 35.1-46.4 µg/dl). The control group consisted of 69 healthy workers without occupational exposure to lead. ECG evaluation included the analysis of heart rate (HR), QT interval and repolarization abnormalities. Mean QT interval was significantly greater in the exposed population than in the control group by 2%. In the HE group, mean QT interval was significantly greater than in the control group by 4% and significantly different from those noted in the LE group. Positive correlations between QT interval and lead exposure indices were also reported. Besides, there was a negative correlation between HR and blood lead level. Increased concentration of lead in the blood above 35 μg/dl is associated with the QT interval prolongation, which may trigger arrhythmias when combined with other abnormalities, such as long QT syndrome. Therefore, electrocardiographic evaluation should be a part of a routine monitoring of occupationally exposed populations.

Mapping of a gene for long QT syndrome to chromosome 4q25-27

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schott, J.J.; Charpentier, F.; Peltier, S.

1995-11-01

Long QT syndrome (LQTS) is a heterogeneous inherited disorder causing syncope and sudden death from ventricular arrhythmias. A first locus for this disorder was mapped to chromosome 11p15.5. However, locus heterogeneity has been demonstrated in several families, and two other loci have recently been located on chromosomes 7q35-36 and 3p21-24. We used linkage analysis to map the locus in a 65-member family in which LQTS was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction. Linkage to chromosome 11p15.5, 7q35-36, or 3p21-24 was excluded. Positive linkage was obtained for markers located on chromosome 4q25-27. A maximalmore » LOD score of 7.05 was found for marker D4S402. The identification of a fourth locus for LQTS confirms its genetic heterogeneity. Locus 4q25-27 is associated with a peculiar phenotype within the LQTS entity. 42 refs., 4 figs., 3 tabs.« less

Cardiovascular Effects of Energy Drinks in Familial Long QT Syndrome: A Randomized Cross-Over Study.

PubMed

Gray, Belinda; Ingles, Jodie; Medi, Caroline; Driscoll, Timothy; Semsarian, Christopher

2017-03-15

Caffeinated energy drinks may trigger serious cardiac effects. The aim of this study was to determine the cardiovascular effects of caffeinated energy drink consumption in patients with familial long QT syndrome (LQTS). From 2014-2016, 24 LQTS patients aged 16-50 years were recruited to a randomized, double-blind, cross-over study of energy drink (ED) versus control (CD) with participants acting as their own controls (one week washout). The primary study outcome was an increase in corrected QT interval (QTc) by >20ms. Secondary outcomes were changes in systolic and diastolic blood pressure. In 24 patients with LQTS (no dropout), mean age was 29±9 years, 13/24 (54%) were female, and 8/24 (33%) were probands. Intention to treat analysis revealed no significant change in QTc with ED compared with CD (12±28ms vs 16±27ms, 3% vs 4%, p=0.71). The systolic and diastolic blood pressure significantly increased with ED compared to CD (peak change 7±16mmHg vs 1±16mmHg, 6% vs 0.8%, p=0.046 and 8±10 vs 2±9mmHg, 11% vs 3% p=0.01 respectively). These changes correlated with significant increases in serum caffeine (14.6±11.3 vs 0.5±0.1μmol/L, p<0.001) and serum taurine (737±199 vs -59±22μmol/L, p<0.001). There were three patients with dangerous QTc prolongation of ≥50ms following energy drink consumption. Caffeinated energy drinks have significant haemodynamic effects in patients with LQTS, especifically an acute increase in blood pressure. Since dangerous QTc prolongation was seen in some LQTS patients, we recommend caution in young patients with LQTS consuming energy drinks. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Assessment of the predictive accuracy of five in silico prediction tools, alone or in combination, and two metaservers to classify long QT syndrome gene mutations.

PubMed

Leong, Ivone U S; Stuckey, Alexander; Lai, Daniel; Skinner, Jonathan R; Love, Donald R

2015-05-13

Long QT syndrome (LQTS) is an autosomal dominant condition predisposing to sudden death from malignant arrhythmia. Genetic testing identifies many missense single nucleotide variants of uncertain pathogenicity. Establishing genetic pathogenicity is an essential prerequisite to family cascade screening. Many laboratories use in silico prediction tools, either alone or in combination, or metaservers, in order to predict pathogenicity; however, their accuracy in the context of LQTS is unknown. We evaluated the accuracy of five in silico programs and two metaservers in the analysis of LQTS 1-3 gene variants. The in silico tools SIFT, PolyPhen-2, PROVEAN, SNPs&GO and SNAP, either alone or in all possible combinations, and the metaservers Meta-SNP and PredictSNP, were tested on 312 KCNQ1, KCNH2 and SCN5A gene variants that have previously been characterised by either in vitro or co-segregation studies as either "pathogenic" (283) or "benign" (29). The accuracy, sensitivity, specificity and Matthews Correlation Coefficient (MCC) were calculated to determine the best combination of in silico tools for each LQTS gene, and when all genes are combined. The best combination of in silico tools for KCNQ1 is PROVEAN, SNPs&GO and SIFT (accuracy 92.7%, sensitivity 93.1%, specificity 100% and MCC 0.70). The best combination of in silico tools for KCNH2 is SIFT and PROVEAN or PROVEAN, SNPs&GO and SIFT. Both combinations have the same scores for accuracy (91.1%), sensitivity (91.5%), specificity (87.5%) and MCC (0.62). In the case of SCN5A, SNAP and PROVEAN provided the best combination (accuracy 81.4%, sensitivity 86.9%, specificity 50.0%, and MCC 0.32). When all three LQT genes are combined, SIFT, PROVEAN and SNAP is the combination with the best performance (accuracy 82.7%, sensitivity 83.0%, specificity 80.0%, and MCC 0.44). Both metaservers performed better than the single in silico tools; however, they did not perform better than the best performing combination of in silico

Sex Hormones and the QT Interval: A Review

PubMed Central

Sedlak, Tara; Shufelt, Chrisandra; Iribarren, Carlos

2012-01-01

Abstract A prolonged QT interval is a marker for an increased risk of ventricular tachyarrhythmias. Both endogenous and exogenous sex hormones have been shown to affect the QT interval. Endogenous testosterone and progesterone shorten the action potential, and estrogen lengthens the QT interval. During a single menstrual cycle, progesterone levels, but not estrogen levels, have the dominant effect on ventricular repolarization in women. Studies of menopausal hormone therapy (MHT) in the form of estrogen-alone therapy (ET) and estrogen plus progesterone therapy (EPT) have suggested a counterbalancing effect of exogenous estrogen and progesterone on the QT. Specifically, ET lengthens the QT, whereas EPT has no effect. To date, there are no studies on oral contraception (OC) and the QT interval, and future research is needed. This review outlines the current literature on sex hormones and QT interval, including the endogenous effects of estrogen, progesterone, and testosterone and the exogenous effects of estrogen and progesterone therapy in the forms of MHT and hormone contraception. Further, we review the potential mechanisms and pathophysiology of sex hormones on the QT interval. PMID:22663191

Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?

PubMed Central

Shah, Rashmi R

2013-01-01

Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure–response (E–R) analysis may be more sensitive than simple changes in QTc interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT studyfrom one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E–R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn. PMID:22882246

Genotype-phenotype aspects of type 2 long QT syndrome.

PubMed

Shimizu, Wataru; Moss, Arthur J; Wilde, Arthur A M; Towbin, Jeffrey A; Ackerman, Michael J; January, Craig T; Tester, David J; Zareba, Wojciech; Robinson, Jennifer L; Qi, Ming; Vincent, G Michael; Kaufman, Elizabeth S; Hofman, Nynke; Noda, Takashi; Kamakura, Shiro; Miyamoto, Yoshihiro; Shah, Samit; Amin, Vinit; Goldenberg, Ilan; Andrews, Mark L; McNitt, Scott

2009-11-24

The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS). Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology. Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contributions of clinical and genetic factors to the first cardiac events. For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (hazard ratio [HR]: 2.87 and 1.86, respectively), but the transmembrane nonpore (S1-S4) region was not (HR: 1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane nonpore regions (HR: 1.54 and 2.42, respectively). However, for nonmissense mutations, these other regions were no longer riskier than the C-terminus (HR: 1.13, 0.77, and 0.46, respectively). Likewise, subjects with nonmissense mutations were at significantly higher risk than were subjects with missense mutations in the C-terminus region (HR: 2.00), but that was not the case in other regions. This mutation location-type interaction was significant (p = 0.008). A significantly higher risk was found in subjects with mutations located in alpha-helical domains than in subjects with mutations in beta-sheet domains or other locations (HR: 1.74 and 1.33, respectively). Time-dependent beta-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p < 0.001). The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.

Avoiding sports-related sudden cardiac death in children with congenital channelopathy : Recommendations for sports activities.

PubMed

Lang, C N; Steinfurt, J; Odening, K E

2017-04-01

For the past few years, children affected by an inherited channelopathy have been counseled to avoid (recreational) sports activities and all competitive sports so as to prevent exercise-induced arrhythmia and sudden cardiac death. An increased understanding of the pathophysiological mechanisms, better anti-arrhythmic strategies, and, in particular, more epidemiological data on exercise-induced arrhythmia in active athletes with channelopathies have changed the universal recommendation of "no sports," leading to revised, less strict, and more differentiated guidelines (published by the American Heart Association/American College of Cardiology in 2015). In this review, we outline the disease- and genotype-specific mechanisms of exercise-induced arrhythmia; give an overview of trigger-, symptom-, and genotype-dependent guidance in sports activities for children with long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), or short QT syndrome (SQTS); and highlight the novelties in the current guidelines compared with previous versions. While it is still recommended for patients with LQT1 and CPVT (even when asymptomatic) and all symptomatic LQTS patients (independent of genotype) to avoid any competitive and high-intensity sports, other LQTS patients successfully treated with anti-arrhythmic therapies and phenotype-negative genotype-positive patients may be allowed to perform sports at different activity levels - provided they undergo regular, sophisticated evaluations to detect any changes in arrhythmogenic risk.

The Role of Spatial Dispersion of Repolarization in Inherited and Acquired Sudden Cardiac Death Syndromes

PubMed Central

Antzelevitch, Charles

2007-01-01

This review examines the role of spatial electrical heterogeneity within ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in the long QT, short QT and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia (CPVT) are critically examined. In the long QT Syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada Syndrome, it is thought to be due to selective abbreviation of the APD of right ventricular (RV) epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, the long QT, short QT, Brugada and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but which share a common final pathway in causing sudden cardiac death. PMID:17586620

The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens.

PubMed

Elming, H; Holm, E; Jun, L; Torp-Pedersen, C; Køber, L; Kircshoff, M; Malik, M; Camm, J

1998-09-01

To evaluate the prognostic value of the QT interval and QT interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population. The QT interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30-60 years. QT interval dispersion was calculated from the maximal difference between QT intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2.9 for the QT interval (95% confidence interval 1.1-7.8) and 4.4 for QT interval dispersion (95% confidence interval 1.0-19-1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2.7 (95% confidence interval 1.4-5.5) for the QT interval and 2.2 (95% confidence interval 1.1-4.0) for QT interval dispersion. Prolongation of the QT interval and QT interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.

Sports Participation in Genotype Positive Children With Long QT Syndrome

PubMed Central

Aziz, Peter F.; Sweeten, Tammy; Vogel, Ramon L.; Bonney, William J.; Henderson, Jacqueline; Patel, Akash R.; Shah, Maully J.

2015-01-01

OBJECTIVE The study sought to examine the prevalence and outcomes of sports participation (both competitive and recreational) in our single-center LQTS genotype positive pediatric population. BACKGROUND The risks of sports participation in patients with long QT syndrome (LQTS) are not clearly elucidated. METHODS A retrospective review was performed on genotype positive patients referred for the evaluation and management of LQTS between 1998 and 2013 at the Children’s Hospital of Philadelphia. Pediatric patients participating in competitive or recreational sports were included in the analysis and their charts were reviewed for documented LQTS events during follow-up. RESULTS The cohort of genotype-positive LQTS patients included 212 patients, and 103 patients (49%, female n = 53, average follow-up 7.1 ± 4.0 years, average QTc 468 ± 42 ms) participated in sports. A total of 105 LQTS disease-causing mutations were identified: KCNQ1 n = 60 (58%), KCNH2 n = 36 (35%), SCN5A n = 6 (6%), KCNE1 n = 1 (1%), and KCNE2 n = 2 (2%). All patients were treated with beta-blockade, with noncompliance in 1 patient and intolerance in 1 patient. Twenty-six patients participated in competitive sports (26%, female n = 15, average follow-up 6.9 ± 4.1 years, average QTc 461 ± 35 ms). Seventy-seven patients (75%, female n = 35, average follow-up 7.3 ± 3.9 years, average QTc 470 ± 43 ms) participated in recreational sports. No patients had LQTS symptoms during sports participation. Five appropriate implantable cardioverter-defibrillator shocks occurred in 2 patients, though none were related to sports participation. CONCLUSIONS In this series no cardiac events and no deaths were observed in treatment-compliant LQTS children while participating in sports in 755 patient-years of follow-up. PMID:26301263

Long-QT Syndrome and Therapy for Attention Deficit/Hyperactivity Disorder.

PubMed

Zhang, Claire; Kutyifa, Valentina; Moss, Arthur J; McNitt, Scott; Zareba, Wojciech; Kaufman, Elizabeth S

2015-10-01

Stimulants are the mainstay therapy for attention deficit/hyperactivity disorder (ADHD) and are associated with adrenergic side effects. There are limited data on the clinical course of patients treated for ADHD who have long-QT syndrome (LQTS), for which β-blockade is the goal of therapy. LQTS patients from the Rochester-based LQTS Registry (open-enrollment between 1979 and 2003; follow-up from 1979 to present) treated with stimulant or nonstimulant ADHD medications (n = 48) were compared to a 2:1 age-, gender-, and QTc-duration matched LQTS control group not exposed to ADHD medications (n = 96). Kaplan-Meier and Cox proportional hazards regression analyses were used to evaluate risk of cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) in LQTS patients treated with ADHD medications. During a mean follow-up of 7.9 ± 5.4 years after initiation of ADHD medication at a mean age 10.7 ±7.3 years, there was a 62% cumulative probability of cardiac events in the ADHD treatment group compared to 28% in the matched LQTS control group (P < 0.001). Time-dependent use of ADHD medication was associated with an increased risk for cardiac events (HR = 3.07; P = 0.03) in the multivariate Cox model adjusted for time-dependent β-blocker use and prior cardiac events. Subgroup gender analyses showed that time-dependent ADHD medication was associated with an increased risk in male LQTS patients (HR = 6.80, P = 0.04). LQTS patients treated with ADHD medications have increased risk for cardiac events, particularly syncope, and this risk is augmented in males. The findings highlight the importance of heightened surveillance for LQTS patients on ADHD medications. © 2015 Wiley Periodicals, Inc.

Oxidative Inactivation of the Lipid Phosphatase Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) as a Novel Mechanism of Acquired Long QT Syndrome*

PubMed Central

Wan, Xiaoping; Dennis, Adrienne T.; Obejero-Paz, Carlos; Overholt, Jeffrey L.; Heredia-Moya, Jorge; Kirk, Kenneth L.; Ficker, Eckhard

2011-01-01

The most common cause of cardiac side effects of pharmaco-therapy is acquired long QT syndrome, which is characterized by abnormal cardiac repolarization and most often caused by direct blockade of the cardiac potassium channel human ether a-go-go-related gene (hERG). However, little is known about therapeutic compounds that target ion channels other than hERG. We have discovered that arsenic trioxide (As2O3), a very potent antineoplastic compound for the treatment of acute promyelocytic leukemia, is proarrhythmic via two separate mechanisms: a well characterized inhibition of hERG/IKr trafficking and a poorly understood increase of cardiac calcium currents. We have analyzed the latter mechanism in the present study using biochemical and electrophysiological methods. We find that oxidative inactivation of the lipid phosphatase PTEN by As2O3 enhances cardiac calcium currents in the therapeutic concentration range via a PI3Kα-dependent increase in phosphatidylinositol 3,4,5-triphosphate (PIP3) production. In guinea pig ventricular myocytes, even a modest reduction in PTEN activity is sufficient to increase cellular PIP3 levels. Under control conditions, PIP3 levels are kept low by PTEN and do not affect calcium current amplitudes. Based on pharmacological experiments and intracellular infusion of PIP3, we propose that in guinea pig ventricular myocytes, PIP3 regulates calcium currents independently of the protein kinase Akt along a pathway that includes a secondary oxidation-sensitive target. Overall, our report describes a novel form of acquired long QT syndrome where the target modified by As2O3 is an intracellular signaling cascade. PMID:21097842

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome.

PubMed

Altmann, Helene M; Tester, David J; Will, Melissa L; Middha, Sumit; Evans, Jared M; Eckloff, Bruce W; Ackerman, Michael J

2015-06-09

Long-QT syndrome (LQTS) may result in syncope, seizures, or sudden cardiac arrest. Although 16 LQTS-susceptibility genes have been discovered, 20% to 25% of LQTS remains genetically elusive. We performed whole-exome sequencing child-parent trio analysis followed by recessive and sporadic inheritance modeling and disease-network candidate analysis gene ranking to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. After whole-exome sequencing and variant filtration, a homozygous p.D18fs*13 TRDN-encoded triadin frameshift mutation was discovered in a 10-year-old female patient with LQTS with a QTc of 500 milliseconds who experienced recurrent exertion-induced syncope/cardiac arrest beginning at 1 year of age. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frameshift mutations in 4 of 33 unrelated cases of LQTS (12%). All 5 TRDN-null patients displayed extensive T-wave inversions in precordial leads V1 through V4, with either persistent or transient QT prolongation and severe disease expression of exercise-induced cardiac arrest in early childhood (≤3 years of age) and required aggressive therapy. The overall yield of TRDN mutations was significantly greater in patients ≤10 years of age (5 of 10, 50%) compared with older patients (0 of 24, 0%; P=0.0009). We identified TRDN as a novel underlying genetic basis for recessively inherited LQTS. All TRDN-null patients had strikingly similar phenotypes. Given the recurrent nature of potential lethal arrhythmias, patients fitting this phenotypic profile should undergo cardiac TRDN genetic testing. © 2015 American Heart Association, Inc.

Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

PubMed

Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

2016-05-01

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

PubMed Central

Cubeddu, Luigi X.

2016-01-01

Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended. PMID:26926294

Semiconductor Whole Exome Sequencing for the Identification of Genetic Variants in Colombian Patients Clinically Diagnosed with Long QT Syndrome.

PubMed

Burgos, Mariana; Arenas, Alvaro; Cabrera, Rodrigo

2016-08-01

Inherited long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of QT interval and the risk of syncope, cardiac arrest, and sudden cardiac death. Genetic diagnosis of LQTS is critical in medical practice as results can guide adequate management of patients and distinguish phenocopies such as catecholaminergic polymorphic ventricular tachycardia (CPVT). However, extensive screening of large genomic regions is required in order to reliably identify genetic causes. Semiconductor whole exome sequencing (WES) is a promising approach for the identification of variants in the coding regions of most human genes. DNA samples from 21 Colombian patients clinically diagnosed with LQTS were enriched for coding regions using multiplex polymerase chain reaction (PCR) and subjected to WES using a semiconductor sequencer. Semiconductor WES showed mean coverage of 93.6 % for all coding regions relevant to LQTS at >10× depth with high intra- and inter-assay depth heterogeneity. Fifteen variants were detected in 12 patients in genes associated with LQTS. Three variants were identified in three patients in genes associated with CPVT. Co-segregation analysis was performed when possible. All variants were analyzed with two pathogenicity prediction algorithms. The overall prevalence of LQTS and CPVT variants in our cohort was 71.4 %. All LQTS variants previously identified through commercial genetic testing were identified. Standardized WES assays can be easily implemented, often at a lower cost than sequencing panels. Our results show that WES can identify LQTS-causing mutations and permits differential diagnosis of related conditions in a real-world clinical setting. However, high heterogeneity in sequencing depth and low coverage in the most relevant genes is expected to be associated with reduced analytical sensitivity.

The QT Interval and Risk of Incident Atrial Fibrillation

PubMed Central

Mandyam, Mala C.; Soliman, Elsayed Z.; Alonso, Alvaro; Dewland, Thomas A.; Heckbert, Susan R.; Vittinghoff, Eric; Cummings, Steven R.; Ellinor, Patrick T.; Chaitman, Bernard R.; Stocke, Karen; Applegate, William B.; Arking, Dan E.; Butler, Javed; Loehr, Laura R.; Magnani, Jared W.; Murphy, Rachel A.; Satterfield, Suzanne; Newman, Anne B.; Marcus, Gregory M.

2013-01-01

BACKGROUND Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. OBJECTIVE To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. METHODS We examined a prolonged QT corrected by the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (Health ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by other formulae. RESULTS Among 14,538 ARIC participants, a prolonged QTFram predicted a roughly two-fold increased risk of AF (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.42–2.96, p<0.001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in CHS and Health ABC and were similar across various QT correction methods. Also in ARIC, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14, 95%CI 1.10–1.17, p<0.001) and adjusted (HR 1.11, 95%CI 1.07–1.14, p<0.001) risk of AF. Findings regarding a short QT were inconsistent across cohorts. CONCLUSIONS A prolonged QT interval is associated with an increased risk of incident AF. PMID:23872693

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1

PubMed Central

Kapplinger, Jamie D; Erickson, Anders; Asuri, Sirisha; Tester, David J; McIntosh, Sarah; Kerr, Charles R; Morrison, Julie; Tang, Anthony; Sanatani, Shubhayan; Arbour, Laura; Ackerman, Michael J

2017-01-01

Background Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. Methods 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. Results For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. Conclusions Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants. PMID:28264985

No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

PubMed

Yu, Rosie Z; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert S; Mahmood, Asif; Grundy, John S; Singleton, Walter; Geary, Richard; Wang, Yanfeng

2016-03-01

The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.

Left Ventricular Isovolumetric Relaxation Time Is Prolonged in Fetal Long-QT Syndrome.

PubMed

Clur, Sally-Ann B; Vink, Arja S; Etheridge, Susan P; Robles de Medina, Pascale G; Rydberg, Annika; Ackerman, Michael J; Wilde, Arthur A; Blom, Nico A; Benson, D Woodrow; Herberg, Ulrike; Donofrio, Mary T; Cuneo, Bettina F

2018-04-01

Long-QT syndrome (LQTS), an inherited cardiac repolarization disorder, is an important cause of fetal and neonatal mortality. Detecting LQTS prenatally is challenging. A fetal heart rate (FHR) less than third percentile for gestational age is specific for LQTS, but the sensitivity is only ≈50%. Left ventricular isovolumetric relaxation time (LVIRT) was evaluated as a potential diagnostic marker for fetal LQTS. LV isovolumetric contraction time, LV ejection time, LVIRT, cycle length, and FHR were measured using pulsed Doppler waveforms in fetuses. Time intervals were expressed as percentages of cycle length, and the LV myocardial performance index was calculated. Single measurements were stratified by gestational age and compared between LQTS fetuses and controls. Receiver-operator curves were performed for FHR and normalized LVIRT (N-LVIRT). A linear mixed-effect model including multiple measurements was used to analyze trends in FHR, N-LVIRT, and LV myocardial performance index. There were 33 LQTS fetuses and 469 controls included. In LQTS fetuses, the LVIRT was prolonged in all gestational age groups ( P <0.001), as was the N-LVIRT. The best cutoff to diagnose LQTS was N-LVIRT ≥11.3 at ≤20 weeks (92% sensitivity, 70% specificity). Simultaneous analysis of N-LVIRT and FHR improved the sensitivity and specificity for LQTS (area under the curve=0.96; 95% confidence interval, 0.82-1.00 at 21-30 weeks). N-LVIRT, LV myocardial performance index, and FHR trends differed significantly between LQTS fetuses and controls through gestation. The LVIRT is prolonged in LQTS fetuses. Findings of a prolonged N-LVIRT and sinus bradycardia can improve the prenatal detection of fetal LQTS. © 2018 American Heart Association, Inc.

Implantable cardioverter-defibrillator explantation for overdiagnosed or overtreated congenital long QT syndrome.

PubMed

Gaba, Prakriti; Bos, J Martijn; Cannon, Bryan C; Cha, Yong-Mei; Friedman, Paul A; Asirvatham, Samuel J; Ackerman, Michael J

2016-04-01

Primary treatment of long QT syndrome (LQTS) currently consists of beta-blocker therapy, although an implantable cardioverter-defibrillator (ICD) is considered for high-risk patients. However, both overdiagnosis and overtreatment must be avoided because their sequelae can be significant. The purpose of this study was to evaluate the prevalence and details of ICD explants in a cohort of patients from a tertiary genetic heart rhythm clinic for a previously rendered diagnosis of LQTS. Overall, 1227 consecutive patients were included in the study. All patients had been referred to the Mayo Clinic for evaluation of possible LQTS and subsequently were either diagnosed with LQTS or dismissed as normal. Further stratification of patients was conducted to assess how many patients had an ICD and how many had a subsequent ICD explant. In total, 170 patients (14%) had an ICD, including 157 of 670 patients (23%) with confirmed LQTS and 13 of 557 patients (2%) who did not have LQTS. Among these, 12 of 1227 (1%) had the ICD removed: 7 of 157 LQTS patients (4.5%) compared to 5 of 14 non-LQTS patients (36%). Before explant, 5 of 12 patients (42%) experienced inappropriate shocks, ranging from 2 to as many as 54 shocks. In addition, 4 had a device-related infection, and 9 had device malfunction (including lead dysfunction or fracture). None of these patients had a breakthrough cardiac event since removal of their ICD during 5.5 ± 3.5 years of follow-up. Implications of overdiagnosis and overtreatment are profound because unnecessary ICD placement can be associated with infection, malfunction, inappropriate shocks, and subsequent anxiety. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

A Precision Medicine Approach to the Rescue of Function on Malignant Calmodulinopathic Long QT Syndrome

PubMed Central

Limpitikul, Worawan B.; Dick, Ivy E.; Tester, David J.; Boczek, Nicole J.; Limphong, Pattraranee; Yang, Wanjun; Choi, Myoung Hyun; Babich, Jennifer; DiSilvestre, Deborah; Kanter, Ronald J.; Tomaselli, Gordon F.; Ackerman, Michael J.; Yue, David T.

2017-01-01

Rationale Calmodulinopathies comprise a new category of potentially life-threatening genetic arrhythmia syndromes capable of producing severe long QT syndrome (LQTS) with mutations involving either CALM1, CALM2, or CALM3. The underlying basis of this form of LQTS is a disruption of Ca2+/CaM-dependent inactivation (CDI) of L-type Ca2+ channels (LTCCs). Objective To gain insight into the mechanistic underpinnings of calmodulinopathies and devise new therapeutic strategies for the treatment of this form of LQTS. Methods and Results We generated and characterized the functional properties of iPSC-derived cardiomyocytes (iPSC-CMs) from a patient with D130G-CALM2-mediated LQTS, thus creating a platform with which to devise and test novel therapeutic strategies. The patient-derived iPSC-CMs display (1) significantly prolonged action potentials (APs), (2) disrupted Ca2+ cycling properties, and (3) diminished CDI of LTCCs. Next, taking advantage of the fact that calmodulinopathy patients harbor a mutation in only one of six redundant CaM-encoding alleles, we devised a strategy using CRISPR interference (CRISPRi) to selectively suppress the mutant gene while sparing the wild-type counterparts. Indeed, suppression of CALM2 expression produced a functional rescue in iPSC-CMs with D130G-CALM2, as shown by the normalization of AP duration and CDI following treatment. Moreover, CRISPRi can be designed to achieve selective knockdown of any of the three CALM genes, making it a generalizable therapeutic strategy for any calmodulinopathy. Conclusions Overall, this therapeutic strategy holds great promise for calmodulinopathy patients as it represents a generalizable intervention capable of specifically altering CaM expression and potentially attenuating LQTS-triggered cardiac events, thus initiating a path towards precision medicine. PMID:27765793

A Precision Medicine Approach to the Rescue of Function on Malignant Calmodulinopathic Long-QT Syndrome.

PubMed

Limpitikul, Worawan B; Dick, Ivy E; Tester, David J; Boczek, Nicole J; Limphong, Pattraranee; Yang, Wanjun; Choi, Myoung Hyun; Babich, Jennifer; DiSilvestre, Deborah; Kanter, Ronald J; Tomaselli, Gordon F; Ackerman, Michael J; Yue, David T

2017-01-06

Calmodulinopathies comprise a new category of potentially life-threatening genetic arrhythmia syndromes capable of producing severe long-QT syndrome (LQTS) with mutations involving CALM1, CALM2, or CALM3. The underlying basis of this form of LQTS is a disruption of Ca 2+ /calmodulin (CaM)-dependent inactivation of L-type Ca 2+ channels. To gain insight into the mechanistic underpinnings of calmodulinopathies and devise new therapeutic strategies for the treatment of this form of LQTS. We generated and characterized the functional properties of induced pluripotent stem cell-derived cardiomyocytes from a patient with D130G-CALM2-mediated LQTS, thus creating a platform with which to devise and test novel therapeutic strategies. The patient-derived induced pluripotent stem cell-derived cardiomyocytes display (1) significantly prolonged action potentials, (2) disrupted Ca 2+ cycling properties, and (3) diminished Ca 2+ /CaM-dependent inactivation of L-type Ca 2+ channels. Next, taking advantage of the fact that calmodulinopathy patients harbor a mutation in only 1 of 6 redundant CaM-encoding alleles, we devised a strategy using CRISPR interference to selectively suppress the mutant gene while sparing the wild-type counterparts. Indeed, suppression of CALM2 expression produced a functional rescue in induced pluripotent stem cell-derived cardiomyocytes with D130G-CALM2, as shown by the normalization of action potential duration and Ca 2+ /CaM-dependent inactivation after treatment. Moreover, CRISPR interference can be designed to achieve selective knockdown of any of the 3 CALM genes, making it a generalizable therapeutic strategy for any calmodulinopathy. Overall, this therapeutic strategy holds great promise for calmodulinopathy patients as it represents a generalizable intervention capable of specifically altering CaM expression and potentially attenuating LQTS-triggered cardiac events, thus initiating a path toward precision medicine. © 2016 American Heart

Downregulation of Long Non-Coding RNA Kcnq1ot1: An Important Mechanism of Arsenic Trioxide-Induced Long QT Syndrome.

PubMed

Jiang, Yanan; Du, Weijie; Chu, Qun; Qin, Ying; Tuguzbaeva, Gulnara; Wang, Hui; Li, Anqi; Li, Guiyang; Li, Yanyao; Chai, Lu; Yue, Er; Sun, Xi; Wang, Zhiguo; Pavlov, Valentin; Yang, Baofeng; Bai, Yunlong

2018-01-01

Arsenic trioxide (ATO) is a known anti-acute promyelocytic leukemia (APL) reagent, whose clinical applications are limited by its serious cardiac toxicity and fatal adverse effects, such as sudden cardiac death resulting from long QT syndrome (LQTS). The mechanisms of cardiac arrhythmia due to ATO exposure still need to be elucidated. Long non-coding RNAs (lncRNAs) are emerging as major regulators of various pathophysiological processes. This study aimed to explore the involvement of lncRNAs in ATO-induced LQTS in vivo and in vitro. For in vivo experiments, mice were administered ATO through the tail vein. For in vitro experiments, ATO was added to the culture medium of primary cultured neonatal mouse cardiomyocytes. To evaluate the effect of lncRNA Kcnq1ot1, siRNA and lentivirus-shRNA were synthesized to knockdown lncRNA Kcnq1ot1. After ATO treatment, the Kcnq1ot1 and Kcnq1 expression levels were down regulated. lncRNA Kcnq1ot1 knockdown prolonged the action potential duration (APD) in vitro and exerted LQTS in vivo. Correspondingly, Kcnq1 expression was decreased after silencing lncRNA Kcnq1ot1. However, the knockdown of Kcnq1 exerted no effect on lncRNA Kcnq1ot1 expression. To our knowledge, this report is the first to demonstrate that lncRNA Kcnq1ot1 downregulation is responsible for QT interval prolongation induced by ATO at least partially by repressing Kcnq1 expression. lncRNA Kcnq1ot1 has important pathophysiological functions in the heart and could become a novel antiarrhythmic target. © 2018 The Author(s). Published by S. Karger AG, Basel.

Increased QT interval variability index in acute alcohol withdrawal.

PubMed

Bär, Karl-Jürgen; Boettger, Michael Karl; Koschke, Mandy; Boettger, Silke; Grotelüschen, Marei; Voss, Andreas; Yeragani, Vikram K

2007-07-10

Acute alcohol withdrawal is associated with increased cardiovascular mortality, most likely due to cardiac arrhythmias. As the QT interval reflects the most critical phase for the generation of reentry and thus for arrhythmia, we examined QT variability in patients suffering from acute alcohol withdrawal. High resolution electrocardiographic recordings were performed in 18 male unmedicated patients suffering from acute alcohol withdrawal, 18 matched controls and 15 abstained alcoholics. From these, parameters of beat-to-beat heart rate and QT variability such as approximate entropy and QT variability index (QTvi) were calculated. Measures were correlated with the severity of withdrawal symptoms and with serum electrolyte concentrations. Heart rate and QTvi were significantly increased in acute alcohol withdrawal. Abstained alcoholics did not significantly differ from controls. While QTvi correlated with the severity of alcohol withdrawal symptoms, the mean QT interval duration showed an inverse relationship with serum potassium concentrations. Our data indicate increased QT variability and thus increased repolarization lability in acute alcohol withdrawal. This might add to the elevated risk for serious cardiac arrhythmias. In part, these changes might be related to increased cardiac sympathetic activity or low potassium, thus suggesting the latter as possible targets for adjuvant pharmacological therapy during withdrawal.

Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials.

PubMed

Yang, Haichen; Laurenza, Antonio; Williams, Betsy; Patten, Anna; Hussein, Ziad; Ferry, Jim

2015-08-01

Perampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled Phase III studies. The Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6 mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12 mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N = 261). Electrocardiograms were recorded at baseline, Day 7 (post 6 mg dose), and Day 16 (post 12 mg dose). Statistical comparisons were between the highest approved perampanel dose (12 mg) versus placebo, a "mid-therapeutic" dose (6 mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I thorough QT study could not incorporate a true "supratherapeutic" dose due to length of titration and tolerability concerns in healthy subjects, Phase III studies of perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration-QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses ≤ 12 mg (N = 1038, total perampanel; and N=442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas. In the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (ΔΔ) QTcF of 12.15 ms at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Δ) QTcF versus nominal time curves were

QT Prolongation, Torsades de Pointes, and Psychotropic Medications: A 5-Year Update.

PubMed

Beach, Scott R; Celano, Christopher M; Sugrue, Alan M; Adams, Caitlin; Ackerman, Michael J; Noseworthy, Peter A; Huffman, Jeff C

Some psychotropic medications have been associated with prolongation of the QT interval and QT prolongation, especially in those with medical illness, and are linked to lethal ventricular arrhythmias, such as Torsades de Pointes (TdP). In 2013, we published a review of QT prolongation, TdP, and psychotropic medications. We provide an update over the past 5 years on the specific concerns most relevant to clinicians who see medically ill patients. In this nonsystematic review, we aimed to carefully and intensively identify new articles by utilizing a structured PubMed search from 2012-present. QT prolongation remains an imperfect, though well-established marker of risk for TdP. Among antidepressant medications, citalopram does appear to prolong the QT interval more than other selective serotonin reuptake inhibitors, though the clinical significance of this prolongation remains unclear. Escitalopram appears to prolong the QT interval to a lesser extent. Haloperidol carries a risk for QT prolongation, but the assertion that intravenous haloperidol is inherently riskier may be confounded by its primary use in medically ill populations. Among atypical antipsychotic agents, ziprasidone-and possibly iloperidone-is associated with the greatest QT prolongation, whereas aripiprazole appears safest from this standpoint. The evidence for clinically meaningful QT prolongation with most classes of psychiatric agents remains minimal. The most important risk-reducing intervention clinicians can make is undertaking a careful analysis of other QT risk factors when prescribing psychiatric medications. Copyright © 2017 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.

Drug Screening Using a Library of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals Disease Specific Patterns of Cardiotoxicity

PubMed Central

Liang, Ping; Lan, Feng; Lee, Andrew S.; Gong, Tingyu; Sanchez-Freire, Veronica; Wang, Yongming; Diecke, Sebastian; Sallam, Karim; Knowles, Joshua W.; Wang, Paul J.; Nguyen, Patricia K.; Bers, Donald M.; Robbins, Robert C.; Wu, Joseph C.

2013-01-01

Background Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with pre-existing heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds. Methods and Results Action potential duration (APD) and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome (LQT), familial hypertrophic cardiomyopathy (HCM), and familial dilated cardiomyopathy (DCM). Disease phenotypes were verified in LQT, HCM, and DCM iPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene (hERG) expressing human embryonic kidney (HEK293) cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in HEK293 cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by APD and quantification of drug-induced arrhythmias such as early after depolarizations (EADs) and delayed after depolarizations (DADs). Conclusions We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, LQT, HCM, and DCM patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than standard hERG test or healthy control hiPSC-CM/hESC-CM screening assays. PMID:23519760

A comparative study of QT prolongation with serotonin reuptake inhibitors.

PubMed

Ojero-Senard, Ana; Benevent, Justine; Bondon-Guitton, Emmanuelle; Durrieu, Geneviève; Chebane, Leila; Araujo, Melanie; Montastruc, Francois; Montastruc, Jean-Louis

2017-10-01

QT interval prolongations were described with citalopram and escitalopram. However, the effects of the other serotonin reuptake inhibitors (SRIs) remained discussed. In order to identify a putative signal with other SRIs, the present study investigates the reports of QT interval prolongation with SRIs in two pharmacovigilance databases (PVDB). Two kinds of investigations were performed: (1) a comparative study in VigiBase®, the WHO PVDB, where notifications of QT prolongation with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were selected. Cases with overdose or pregnancy were excluded. The relationship between the "suspected" SRI and occurrence of QT prolongation was assessed by calculating reporting odds ratio (ROR) in a case/non-case design. (2) A descriptive study of QT prolongation reports with citalopram and escitalopram in the French FPVD. In VigiBase®, 855 notifications were identified (mean age 56.2 years, mainly women 73%). Among them, 172 (20.1%) were associated to escitalopram; 299 (35.0%), to citalopram; 186 (21.8%), to fluoxetine; 94 (11.0%), to sertraline; 66 (7.7%), to paroxetine; and 38 (4.4%) to fluvoxamine. A significant ROR value (higher than 1) was only found for citalopram (3.35 CI95% [2.90-3.87]) or escitalopram (2.50 [2.11-2.95]). In the FPVD, eight reports of QT prolongation were found with citalopram and 27 with escitalopram, mainly in women (77.1%) with a mean age of 73.2 years. In 23 cases (66%), SRIs were associated with other suspected drugs, mainly cardiotropic or psychotropic ones. Hypokalemia was associated in six patients. This study, performed in real conditions of life, shows a clear signal of QT prolongation with only two SRIs, citalopram and escitalopram, indicating that QT prolongation is not a SRI class effect.

Abnormalities of the QT interval in primary disorders of autonomic failure

NASA Technical Reports Server (NTRS)

Choy, A. M.; Lang, C. C.; Roden, D. M.; Robertson, D.; Wood, A. J.; Robertson, R. M.; Biaggioni, I.

1998-01-01

BACKGROUND: Experimental evidence shows that activation of the autonomic nervous system influences ventricular repolarization and, therefore, the QT interval on the ECG. To test the hypothesis that the QT interval is abnormal in autonomic dysfunction, we examined ECGs in patients with severe primary autonomic failure and in patients with congenital dopamine beta-hydroxylase (DbetaH) deficiency who are unable to synthesize norepinephrine and epinephrine. SUBJECTS AND METHODS: Maximal QT and rate-corrected QT (QTc) intervals and adjusted QTc dispersion [(maximal QTc - minimum QTc on 12 lead ECG)/square root of the number of leads measured] were determined in blinded fashion from ECGs of 67 patients with primary autonomic failure (36 patients with multiple system atrophy [MSA], and 31 patients with pure autonomic failure [PAF]) and 17 age- and sex-matched healthy controls. ECGs of 5 patients with congenital DbetaH deficiency and 6 age- and sex-matched controls were also analyzed. RESULTS: Patients with MSA and PAF had significantly prolonged maximum QTc intervals (492+/-58 ms(1/2) and 502+/-61 ms(1/2) [mean +/- SD]), respectively, compared with controls (450+/-18 ms(1/2), P < .05 and P < .01, respectively). A similar but not significant trend was observed for QT. QTc dispersion was also increased in MSA (40+/-20 ms(1/2), P < .05 vs controls) and PAF patients (32+/-19 ms(1/2), NS) compared with controls (21+/-5 ms(1/2)). In contrast, patients with congenital DbetaH deficiency did not have significantly different RR, QT, QTc intervals, or QTc dispersion when compared with controls. CONCLUSIONS: Patients with primary autonomic failure who have combined parasympathetic and sympathetic failure have abnormally prolonged QT interval and increased QT dispersion. However, QT interval in patients with congenital DbetaH deficiency was not significantly different from controls. It is possible, therefore, that QT abnormalities in patients with primary autonomic failure are not

Abnormalities of the QT interval in primary disorders of autonomic failure.

PubMed

Choy, A M; Lang, C C; Roden, D M; Robertson, D; Wood, A J; Robertson, R M; Biaggioni, I

1998-10-01

Experimental evidence shows that activation of the autonomic nervous system influences ventricular repolarization and, therefore, the QT interval on the ECG. To test the hypothesis that the QT interval is abnormal in autonomic dysfunction, we examined ECGs in patients with severe primary autonomic failure and in patients with congenital dopamine beta-hydroxylase (DbetaH) deficiency who are unable to synthesize norepinephrine and epinephrine. Maximal QT and rate-corrected QT (QTc) intervals and adjusted QTc dispersion [(maximal QTc - minimum QTc on 12 lead ECG)/square root of the number of leads measured] were determined in blinded fashion from ECGs of 67 patients with primary autonomic failure (36 patients with multiple system atrophy [MSA], and 31 patients with pure autonomic failure [PAF]) and 17 age- and sex-matched healthy controls. ECGs of 5 patients with congenital DbetaH deficiency and 6 age- and sex-matched controls were also analyzed. Patients with MSA and PAF had significantly prolonged maximum QTc intervals (492+/-58 ms(1/2) and 502+/-61 ms(1/2) [mean +/- SD]), respectively, compared with controls (450+/-18 ms(1/2), P < .05 and P < .01, respectively). A similar but not significant trend was observed for QT. QTc dispersion was also increased in MSA (40+/-20 ms(1/2), P < .05 vs controls) and PAF patients (32+/-19 ms(1/2), NS) compared with controls (21+/-5 ms(1/2)). In contrast, patients with congenital DbetaH deficiency did not have significantly different RR, QT, QTc intervals, or QTc dispersion when compared with controls. Patients with primary autonomic failure who have combined parasympathetic and sympathetic failure have abnormally prolonged QT interval and increased QT dispersion. However, QT interval in patients with congenital DbetaH deficiency was not significantly different from controls. It is possible, therefore, that QT abnormalities in patients with primary autonomic failure are not solely caused by lesions of the sympathetic nervous system

Psychotropic Pharmacotherapy Associated With QT Prolongation Among Veterans With Posttraumatic Stress Disorder.

PubMed

Stock, Eileen M; Zeber, John E; McNeal, Catherine J; Banchs, Javier E; Copeland, Laurel A

2018-04-01

In 2012, the Food and Drug Administration issued Drug Safety Communications on several drugs associated with QT prolongation and fatal ventricular arrhythmias. Among these was citalopram, a selective serotonin reuptake inhibitor (SSRI) approved for depression and commonly used for posttraumatic stress disorder (PTSD). Evaluation of the risk for QT prolongation among other psychotropic drugs for individuals with PTSD remains limited. Explore psychotropic drugs associated with QT prolongation among veterans with PTSD. Patients in the Veterans Health Administration in 2006-2009 with PTSD and QT prolongation (176 cases) were matched 1:4 on age, gender, visit date and setting, and physical comorbidity. Classification trees assessed QT prolongation risk among prescribed medications (n=880). Receipt of any drug with known risk of QT prolongation varied by group (23% QT cases vs 15% control, p<0.01). Psychotropic medications conferring significant risks included ziprasidone (3% vs 1%, p=0.02) and buspirone (6% vs 2%, p=0.01). Increased risk was not observed for the SSRIs, citalopram and fluoxetine. Classification trees found that sotalol and amitriptyline carried greater risk among cardiac patients and methadone, especially if prescribed with quetiapine, among noncardiac patients. Per adjusted survival model, patients with QT prolongation were at increased risk for death (hazard ratio=1.60; 95% CI=1.04-2.44). Decision models are particularly advantageous when exploring nonlinear relationships or nonadditive interactions. These findings may potentially affect clinical decision-making concerning treatment for PTSD. For patients at higher risk of QT prolongation, antidepressants other than amitriptyline should be considered. Medications for comorbid conditions should also be closely monitored for heightened QT prolongation risk.

[The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor].

PubMed

Ceker, Zahit; Takmaz, Suna Akın; Baltaci, Bülent; Başar, Hülya

2015-01-01

The importance of minimizing the exaggerated sympatho-adrenergic responses and QT interval and QT interval dispersion changes that may develop due to laryngoscopy and tracheal intubation during anesthesia induction in the hypertensive patients is clear. Esmolol decreases the hemodynamic response to laryngoscopy and intubation. However, the effect of esmolol in decreasing the prolonged QT interval and QT interval dispersion as induced by laryngoscopy and intubation is controversial. We investigated the effect of esmolol on the hemodynamic, and corrected-QT interval and corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients using angiotensin converting enzyme inhibitors. 60 ASA I-II patients, with essential hypertension using angiotensin converting enzyme inhibitors were included in the study. The esmolol group received esmolol at a bolus dose of 500mcg/kg followed by a 100mcg/kg/min infusion which continued until the 4th min after intubation. The control group received 0.9% saline similar to the esmolol group. The mean blood pressure, heart rate values and the electrocardiogram records were obtained as baseline values before the anesthesia, 5min after esmolol and saline administration, 3min after the induction and 30s, 2min and 4min after intubation. The corrected-QT interval was shorter in the esmolol group (p=0.012), the corrected-QT interval dispersion interval was longer in the control group (p=0.034) and the mean heart rate was higher in the control group (p=0.022) 30s after intubation. The risk of arrhythmia frequency was higher in the control group in the 4-min period following intubation (p=0.038). Endotracheal intubation was found to prolong corrected-QT interval and corrected-QT interval dispersion, and increase the heart rate during anesthesia induction with propofol in hypertensive patients using angiotensin converting enzyme inhibitors. These effects were prevented with esmolol (500mcg/kg bolus, followed by

Evaluation of Tp-Te Interval and Tp-Te/QT Ratio in Patients with Coronary Slow Flow Tp-Te/QT Ratio and Coronary Slow Flow.

PubMed

Tenekecioglu, Erhan; Karaagac, Kemal; Yontar, Osman Can; Agca, Fahriye Vatansever; Ozluk, Ozlem Arican; Tutuncu, Ahmet; Arslan, Burhan; Yilmaz, Mustafa

2015-06-01

Coronary slow flow (CSF) phenomenon is described by angiographically normal coronary arteries with delayed opacification of the distal vasculature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-Te) may correspond to the transmural dispersion of the repolarization and that increased Tp-Te interval and Tp-Te/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate the ventricular repolarization by using Tp-Te interval and Tp-Te/QT ratio in patients with CSF. This study included 50 CSF patients (40 male, mean age 48.6±12.5 years) and 40 control individuals (23 male, mean age 47.8±12.5 years). Tp-Te interval and Tp-Te/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared in groups. Baseline characteristics of the study groups were comparable. In electrocardiographic parameters analysis, QT and corrected QT were similar in CSF patients compared to the controls (357±35.2 vs 362±38.0 milliseconds and 419±25.8 vs 430±44.2 milliseconds, all p value >0.05). Tp-Te interval, Tp-Te/QT and Tp-Te/QTc ratio were significantly higher in CSF patients (85±13.7 vs 74±9.9 milliseconds and 0.24±0.03 vs 0.20±0.02 and 0.20±0.03 vs 0.17±0.02 all p value <0.001). Our study revealed that QTd, Tp-Te interval and Tp-Te/QT ratio are prolonged in patients with CSF.

Fine-mapping and initial characterization of QT interval loci in African Americans.

PubMed

Avery, Christy L; Sethupathy, Praveen; Buyske, Steven; He, Qianchuan; Lin, Dan-Yu; Arking, Dan E; Carty, Cara L; Duggan, David; Fesinmeyer, Megan D; Hindorff, Lucia A; Jeff, Janina M; Klein, Liviu; Patton, Kristen K; Peters, Ulrike; Shohet, Ralph V; Sotoodehnia, Nona; Young, Alicia M; Kooperberg, Charles; Haiman, Christopher A; Mohlke, Karen L; Whitsel, Eric A; North, Kari E

2012-01-01

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple

Fine-Mapping and Initial Characterization of QT Interval Loci in African Americans

PubMed Central

Avery, Christy L.; Sethupathy, Praveen; Buyske, Steven; He, Qianchuan; Lin, Dan-Yu; Arking, Dan E.; Carty, Cara L.; Duggan, David; Fesinmeyer, Megan D.; Hindorff, Lucia A.; Jeff, Janina M.; Klein, Liviu; Patton, Kristen K.; Peters, Ulrike; Shohet, Ralph V.; Sotoodehnia, Nona; Young, Alicia M.; Kooperberg, Charles; Haiman, Christopher A.; Mohlke, Karen L.; Whitsel, Eric A.; North, Kari E.

2012-01-01

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10−4): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10−5): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple

Prevalence and risk factors for prolonged QT interval and QT dispersion in patients with type 2 diabetes.

PubMed

Ninkovic, Vladan M; Ninkovic, Srdjan M; Miloradovic, Vanja; Stanojevic, Dejan; Babic, Marijana; Giga, Vojislav; Dobric, Milan; Trenell, Michael I; Lalic, Nebojsa; Seferovic, Petar M; Jakovljevic, Djordje G

2016-10-01

Prolonged QT interval is associated with cardiac arrhythmias and sudden death. The present study determined the prevalence of prolonged QT interval and QT dispersion and defined their clinical and metabolic predictors in patients with type 2 diabetes. Cross-sectional study included 501 patients with type 2 diabetes. A standard 12-lead electrocardiogram was recorded. QT corrected for heart rate (QTc) >440 ms and QT dispersion (QTd) >80 ms were considered abnormally prolonged. QTc ≥ 500 ms was considered a high-risk QTc prolongation. Demographic, clinical and laboratory data were collected. Independent risk factors for prolonged QTc and QTd were assessed using logistic regression analysis. Prevalence of QTc > 440 ms and QTd > 80 ms were 44.1 and 3.6 %, respectively. Prevalence of high-risk QTc (≥500 ms) was 2 % only. Independent risk factors for QTc prolongation >440 ms were mean blood glucose (β = 2.192, p < 0.001), treatment with sulphonylurea (β = 5.198, p = 0.027), female gender (β = 8.844, p < 0.001), and coronary heart disease (β = 8.636, p = 0.001). Independent risk factors for QTc ≥ 500 ms were coronary heart disease (β = 4.134, p < 0.001) and mean blood glucose level (β = 1.735, p < 0.001). The independent risk factor for prolonged QTd was only coronary heart disease (β = 5.354, p < 0.001). Although the prevalence of prolonged QTc > 440 ms is significant, the prevalence of high-risk QTc (≥500 ms) and QTd > 80 ms is very low in patients with type 2 diabetes. Hyperglycaemia and coronary heart disease are strong predictors of high-risk QTc.

Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients

PubMed Central

Schächtele, Simone; Tümena, Thomas; Gaßmann, Karl-Günter; Fromm, Martin F.; Maas, Renke

2016-01-01

Background Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited. Objective This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs. Methods In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria–Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs). Results Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions. Conclusion In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT

Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients.

PubMed

Schächtele, Simone; Tümena, Thomas; Gaßmann, Karl-Günter; Fromm, Martin F; Maas, Renke

2016-01-01

Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited. This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs. In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria-Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs). Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions. In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT-drugs with higher risk only could be detected by

Prevalence of QT interval prolongation in patients admitted to cardiac care units and frequency of subsequent administration of QT interval-prolonging drugs: a prospective, observational study in a large urban academic medical center in the US.

PubMed

Tisdale, James E; Wroblewski, Heather A; Overholser, Brian R; Kingery, Joanna R; Trujillo, Tate N; Kovacs, Richard J

2012-06-01

Cardiac arrest due to torsades de pointes (TdP) is a rare but catastrophic event in hospitals. Patients admitted to cardiac units are at higher risk of drug-induced QT interval prolongation and TdP, due to a preponderance of risk factors. Few data exist regarding the prevalence of QT interval prolongation in patients admitted to cardiac units or the frequency of administering QT interval-prolonging drugs to patients presenting with QT interval prolongation. The aim of this study was to determine the prevalence of Bazett's-corrected QT (QT(c)) interval prolongation upon admission to cardiac units and the proportion of patients presenting with QT(c) interval prolongation who are subsequently administered QT interval-prolonging drugs during hospitalization. This was a prospective, observational study conducted over a 1-year period (October 2008-October 2009) in 1159 consecutive patients admitted to two cardiac units in a large urban academic medical centre located in Indianapolis, IN, USA. Patients were enrolled into the study at the time of admission to the hospital and were followed daily during hospitalization. Exclusion criteria were age <18 years, ECG rhythm of complete ventricular pacing, and patient designation as 'outpatient' in a bed and/or duration of stay <24 hours. Data collected included demographic information, past medical history, daily progress notes, medication administration records, laboratory data, ECGs, telemetry monitoring strips and diagnostic reports. All patients underwent continuous cardiac telemetry monitoring and/or had a baseline 12-lead ECG obtained within 4 hours of admission. QT intervals were determined manually from lead II of 12-lead ECGs or from continuous lead II telemetry monitoring strips. QT(c) interval prolongation was defined as ≥470 ms for males and ≥480 ms for females. In both males and females, QT(c) interval >500 ms was considered abnormally high. A medication was classified as QT interval-prolonging if there

Molecular Diagnosis of Long-QT syndrome at 10 Days of Life by Rapid Whole Genome Sequencing

PubMed Central

Priest, James R.; Ceresnak, Scott R.; Dewey, Frederick E.; Malloy-Walton, Lindsey E.; Dunn, Kyla; Grove, Megan E.; Perez, Marco V.; Maeda, Katsuhide; Dubin, Anne M.; Ashley, Euan A.

2014-01-01

Background The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians. Objective A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies. Methods We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life. Results We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene. Conclusions Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test. PMID:24973560

Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Long QT Syndrome

PubMed Central

Angrist, Misha; Chandrasekharan, Subhashini; Heaney, Christopher; Cook-Deegan, Robert

2010-01-01

Genetic testing for Long QT syndrome (LQTS) exemplifies patenting and exclusive licensing with different outcomes at different times. Exclusive licensing from the University of Utah changed the business model from sole provider to two US providers of LQTS testing. LQTS is associated with mutations in many genes, ten of which are now tested by two competing firms in the United States, PGxHealth and GeneDx. Until 2009, PGxHealth was sole provider, based largely on exclusive rights to patents from the University of Utah and other academic institutions. University of Utah patents were initially licensed to DNA Sciences, whose patent rights were acquired by Gennaissance, and then by Clinical Data, Inc., which owns PGxHealth. In 2002, DNA Sciences “cleared the market” by sending cease and desist patent enforcement letters to university and reference laboratories offering LQTS genetic testing. There was no test on the market for a one- to two-year period. From 2005-2008, most LQTS-related patents were controlled by Clinical Data, Inc., and its subsidiary PGxHealth. BioReference Laboratories, Inc., secured countervailing exclusive patent rights starting in 2006, also from the University of Utah, and broke the PGxHealth monopoly in early 2009, creating a duopoly for genetic testing in the United States, and expanding the number of genes for which commercial testing is available from five to ten. PMID:20393304

The QT Scale: A Weight Scale Measuring the QTc Interval.

PubMed

Couderc, Jean-Philippe; Beshaw, Connor; Niu, Xiaodan; Serrano-Finetti, Ernesto; Casas, Oscar; Pallas-Areny, Ramon; Rosero, Spencer; Zareba, Wojciech

2017-01-01

Despite the strong evidence of the clinical utility of QTc prolongation as a surrogate marker of cardiac risk, QTc measurement is not part of clinical routine either in hospital or in physician offices. We evaluated a novel device ("the QT scale") to measure heart rate (HR) and QTc interval. The QT scale is a weight scale embedding an ECG acquisition system with four limb sensors (feet and hands: lead I, II, and III). We evaluated the reliability of QT scale in healthy subjects (cohort 1) and cardiac patients (cohorts 2 and 3) considering a learning (cohort 2) and two validation cohorts. The QT scale and the standard 12-lead recorder were compared using intraclass correlation coefficient (ICC) in cohorts 2 and 3. Absolute value of heart rate and QTc intervals between manual and automatic measurements using ECGs from the QT scale and a clinical device were compared in cohort 1. We enrolled 16 subjects in cohort 1 (8 w, 8 m; 32 ± 8 vs 34 ± 10 years, P = 0.7), 51 patients in cohort 2 (13 w, 38 m; 61 ± 16 vs 58 ± 18 years, P = 0.6), and 13 AF patients in cohort 3 (4 w, 9 m; 63 ± 10 vs 64 ± 10 years, P = 0.9). Similar automatic heart rate and QTc were delivered by the scale and the clinical device in cohort 1: paired difference in RR and QTc were -7 ± 34 milliseconds (P = 0.37) and 3.4 ± 28.6 milliseconds (P = 0.64), respectively. The measurement of stability was slightly lower in ECG from the QT scale than from the clinical device (ICC: 91% vs 80%) in cohort 3. The "QT scale device" delivers valid heart rate and QTc interval measurements. © 2016 Wiley Periodicals, Inc.

A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death.

PubMed

Sauer, Charles W; Marc-Aurele, Krishelle L

2016-07-28

BACKGROUND This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. CASE REPORT A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. CONCLUSIONS We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby.

Identifying QT prolongation from ECG impressions using a general-purpose Natural Language Processor

PubMed Central

Denny, Joshua C.; Miller, Randolph A.; Waitman, Lemuel Russell; Arrieta, Mark; Peterson, Joshua F.

2009-01-01

Objective Typically detected via electrocardiograms (ECGs), QT interval prolongation is a known risk factor for sudden cardiac death. Since medications can promote or exacerbate the condition, detection of QT interval prolongation is important for clinical decision support. We investigated the accuracy of natural language processing (NLP) for identifying QT prolongation from cardiologist-generated, free-text ECG impressions compared to corrected QT (QTc) thresholds reported by ECG machines. Methods After integrating negation detection to a locally-developed natural language processor, the KnowledgeMap concept identifier, we evaluated NLP-based detection of QT prolongation compared to the calculated QTc on a set of 44,318 ECGs obtained from hospitalized patients. We also created a string query using regular expressions to identify QT prolongation. We calculated sensitivity and specificity of the methods using manual physician review of the cardiologist-generated reports as the gold standard. To investigate causes of “false positive” calculated QTc, we manually reviewed randomly selected ECGs with a long calculated QTc but no mention of QT prolongation. Separately, we validated the performance of the negation detection algorithm on 5,000 manually-categorized ECG phrases for any medical concept (not limited to QT prolongation) prior to developing the NLP query for QT prolongation. Results The NLP query for QT prolongation correctly identified 2,364 of 2,373 ECGs with QT prolongation with a sensitivity of 0.996 and a positive predictive value of 1.000. There were no false positives. The regular expression query had a sensitivity of 0.999 and positive predictive value of 0.982. In contrast, the positive predictive value of common QTc thresholds derived from ECG machines was 0.07–0.25 with corresponding sensitivities of 0.994–0.046. The negation detection algorithm had a recall of 0.973 and precision of 0.982 for 10,490 concepts found within ECG impressions

A Framework of Knowledge Integration and Discovery for Supporting Pharmacogenomics Target Predication of Adverse Drug Events: A Case Study of Drug-Induced Long QT Syndrome.

PubMed

Jiang, Guoqian; Wang, Chen; Zhu, Qian; Chute, Christopher G

2013-01-01

Knowledge-driven text mining is becoming an important research area for identifying pharmacogenomics target genes. However, few of such studies have been focused on the pharmacogenomics targets of adverse drug events (ADEs). The objective of the present study is to build a framework of knowledge integration and discovery that aims to support pharmacogenomics target predication of ADEs. We integrate a semantically annotated literature corpus Semantic MEDLINE with a semantically coded ADE knowledgebase known as ADEpedia using a semantic web based framework. We developed a knowledge discovery approach combining a network analysis of a protein-protein interaction (PPI) network and a gene functional classification approach. We performed a case study of drug-induced long QT syndrome for demonstrating the usefulness of the framework in predicting potential pharmacogenomics targets of ADEs.

Translating QT interval prolongation from conscious dogs to humans.

PubMed

Dubois, Vincent F S; Smania, Giovanni; Yu, Huixin; Graf, Ramona; Chain, Anne S Y; Danhof, Meindert; Della Pasqua, Oscar

2017-02-01

In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms μM -1 and 6.1 ms μM -1 in dogs and -10 ms μM -1 and 90 ms μM -1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R 2  = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans. © 2016 The British Pharmacological Society.

Food and Insulin Effect on QT/QTC Interval of ECG

ClinicalTrials.gov

2014-08-19

Effects of Different Meals on the QT/QTc Interval; Insulin and Oral Hypoglycemic [Antidiabetic] Drugs Causing Adverse Effects in Therapeutic Use; C-Peptide Effects on the QT/QTc Interval; Moxifloxacin ECG Profile in Fed and Fasted State; Japanese vs. Caucasian TQT Comparison

Dispersion of the corrected QT interval in the electrocardiogram of the ex-prisoners of war.

PubMed

Corović, Naima; Duraković, Zijad; Misigoj-Duraković, Marjeta

2003-04-01

The study of electrocardiograms (ECGs) was performed in a subgroup of 181 men, ex-prisoners of war with mean age 35.8+/-11.0 years and mean duration of imprisonment 164.5+/-87.1 days, chosen at random from the total sample of released prisoners (N=1458). The control group was pair-matched. The analysis of ECGs was done according to the Minnesota code, and Bazett's formula gave the values of the corrected QT interval (QT(c)). The dispersion of the QT(c) interval is determined by the difference between the longest and the shortest measured QT(c) interval in each ECG lead. The results of descriptive statistics in the group of ex-prisoners showed the range of QT(c) dispersion of 8.0-122.0 ms (mean 52.4+/-21.6 ms), while in the control group the range was 6.0-72.0 ms (mean 30.4+/-13.8 ms) (df=360, t=11.536; P<0.001). The QT(c) interval from 422.0 to 480.0 ms had 60.2% ex-prisoners and 30.4% controls, while a QT(c) interval over 480.0 ms had 19.3% ex-prisoners and 1.10% controls (P<0.0001). In the ex-prisoners group, the QT(c) dispersion over 50 ms was present in 51.4%; of those, a dispersion of 95 ms and more was found in 3.9%, while in the controls a QT(c) dispersion over 50 ms was found in 8.3%, but a dispersion of 95 ms and more was not recorded (P<0.0001). The odds ratio estimated for the prolonged QT(c) interval was 8.467 and for enlarged QT(c) dispersion it was 11.695 in the ex-prisoners versus controls (P<0.001). In conclusion, persons exposed to long-term maltreatment in detention camps have significantly greater QT(c) dispersion, as well as a higher relative risk of prolonged QT(c) interval and greater QT(c) dispersion than a control group.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

PubMed

Zablocki, Jeff A; Elzein, Elfatih; Li, Xiaofen; Koltun, Dmitry O; Parkhill, Eric Q; Kobayashi, Tetsuya; Martinez, Ruben; Corkey, Britton; Jiang, Haibo; Perry, Thao; Kalla, Rao; Notte, Gregory T; Saunders, Oliver; Graupe, Michael; Lu, Yafan; Venkataramani, Chandru; Guerrero, Juan; Perry, Jason; Osier, Mark; Strickley, Robert; Liu, Gongxin; Wang, Wei-Qun; Hu, Lufei; Li, Xiao-Jun; El-Bizri, Nesrine; Hirakawa, Ryoko; Kahlig, Kris; Xie, Cheng; Li, Cindy Hong; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Soohoo, Daniel; Lepist, Eve-Irene; Murray, Bernard; Rhodes, Gerry; Belardinelli, Luiz; Desai, Manoj C

2016-10-03

Late sodium current (late I Na ) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I Na , is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC 50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

[Risk management of QT-prolonging drugs by community pharmacists using a mobile electrocardiograph].

PubMed

Shinozaki, Kohki

2010-11-01

Prolongation of the QT interval is associated with a high risk of serious arrhythmia, i.e., torsades de pointes (TdP). However, in many cases, the QT-prolonging drug(s) is prescribed without performing a thorough check-up of the patient's condition, especially an electrocardiogram. In addition to patient interview, we used an electrocardiogram obtained with a mobile electrocardiograph (RMH-ECG) in a community pharmacy in order to improve the risk management for QT-prolonging drugs. A comparison of the results obtained using RMH-ECG (modified I) and 12-lead ECG (I) revealed that both corrected QT (QTc) values were almost identical, and the correlation coefficient was 0.96. In one month, 5 of 948 patients who visited our pharmacy and continuously took QT-prolonging drugs had additional risk factors for TdP (advanced age, female, and drug-drug interaction). We monitored the QT interval of one of these patients. She had received erythromycin for 19 months along with other drugs metabolized by a P450 (CYP3A4); benidipine and prednisolone (for over 2 years), and tacrolimus (for 13 weeks). Three RMH-ECG tests at every 2 weeks revealed that QTcs were normal (0.43-0.45 s); therefore, we dispensed drugs without any change in the prescription. Approximately 1 in 1200 individuals has a prolonged QT interval without any subjective symptoms, and the time window of drug-induced TdP is considered to be from several hours to months after taking these drugs. Therefore, we think that an ECG test should be performed in community pharmacies before dispensing QT-prolonging drugs and that the QT interval should be monitored.

QT dispersion and rate-corrected QT dispersion during electroconvulsive therapy in elderly patients.

PubMed

Yamaguchi, Shigeki; Nagao, Masaru; Ikeda, Tomohisa; Fukagawa, Daigo; Kimura, Yoshiyuki; Kitajima, Toshimitsu; Minami, Junichi

2011-09-01

Electroconvulsive therapy (ECT) induces increase of QT dispersion (QTD) and the rate-corrected QTD (QTcD), which are associated with increased risk of ventricular arrhythmias and cardiovascular mortality. The effects of electrical stimulus during ECT on QTD and QTcD in elderly patients are of considerable interest. The purpose of this study was to clarify the differential effects of electrical stimulus caused by ECT on interbeat interval, QT interval, the rate-corrected QT (QTc) interval, QTD, and the QTcD under propofol anesthesia between younger and elderly patients with major depression. Twenty younger psychiatric patients (aged 30-40 years) and 20 elderly patients (aged 65-75 years) scheduled for ECT were studied under propofol anesthesia. A 12-lead electrocardiogram was monitored to measure parameters. Muscle paralysis was achieved by administering 1-mg/kg succinylcholine intravenously, and the efficacy of ECT was determined by the tourniquet technique. The mean arterial pressure in the elderly was significantly higher than that of the younger patients from immediately to 2 minutes after electrical stimulus. The interbeat interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. There was no statistically significant difference in the QT interval between the groups. The baseline value of QTc interval was higher than the normal limits, and the QTc interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. The baseline value of QTD was higher than the normal limits, and the QTD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical stimulus. The baseline value of QTcD was higher than the normal limits, and the QTcD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical

Clinical and genetic features of Australian families with long QT syndrome: A registry-based study.

PubMed

Burns, Charlotte; Ingles, Jodie; Davis, Andrew M; Connell, Vanessa; Gray, Belinda; Hunt, Lauren; McGaughran, Julie; Semsarian, Christopher

2016-12-01

Familial long QT syndrome (LQTS) is a primary arrhythmogenic disorder caused by mutations in ion channel genes. The phenotype ranges from asymptomatic individuals to sudden cardiac arrest and death. LQTS is a rare but significant health problem for which global data should exist. This study sought to provide the first clinical and genetic description of Australian families with LQTS. We performed a cross-sectional study to evaluate clinical and genetic features of families with LQTS. We recruited individuals from the Australian Genetic Heart Disease Registry and Genetic Heart Disease Clinic, in Sydney, Australia, and included those with a diagnosis of LQTS according to the most recent consensus statement. Among 108 families with LQTS, 173 individuals were affected. Twenty-five (32%) probands had a sudden cardiac death (SCD) event (including appropriate implantable cardioverter defibrillator [ICD] therapy, or resuscitated cardiac arrest). There were 64 (82%) probands who underwent genetic testing, and 34 (53%) had a pathogenic or likely pathogenic mutation in. Having a family history of LQTS was significantly associated with identification of a pathogenic result (79% versus 14%, p <0.0001). There were 16 (9%) participants who experienced delay to diagnosis of at least 12 months. This is the first clinical and genetic study in a large cohort of Australian families with LQTS. Findings from this study suggest that the clinical and genetic features in this population are not dissimilar to those described in North American, European, and Asian cohorts. Global-scale information about families with LQTS is an important initiative to ensure diagnostic and management approaches are applicable to different populations and ethnicities.

Iron Metabolism Genes, Low-Level Lead Exposure, and QT Interval

PubMed Central

Park, Sung Kyun; Hu, Howard; Wright, Robert O.; Schwartz, Joel; Cheng, Yawen; Sparrow, David; Vokonas, Pantel S.; Weisskopf, Marc G.

2009-01-01

Background Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave). Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis (HFE), transferrin (TF) C2, and heme oxygenase-1 (HMOX-1)] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men. Methods We used standard 12-lead electrocardiograms, K-shell X-ray fluorescence, and graphite furnace atomic absorption spectrometry to measure QT interval, bone lead, and blood lead levels, respectively. Results A one-interquartile-range increase in tibia lead level (13 μg/g) was associated with a 11.35-msec [95% confidence interval (CI), 4.05–18.65 msec] and a 6.81-msec (95% CI, 1.67–11.95 msec) increase in the heart-rate–corrected QT interval among persons carrying long HMOX-1 alleles and at least one copy of an HFE variant, respectively, but had no effect in persons with short and middle HMOX-1 alleles and the wild-type HFE genotype. The lengthening of the heart-rate–corrected QT interval with higher tibia lead and blood lead became more pronounced as the total number (0 vs. 1 vs. ≥2) of gene variants increased (tibia, p-trend = 0.01; blood, p-trend = 0.04). This synergy seems to be driven by a joint effect between HFE variant and HMOX-1 L alleles. Conclusion We found evidence that gene variants related to iron metabolism increase the impacts of low-level lead exposure on the prolonged QT interval. This is the first such report, so these results should be interpreted cautiously and need to be independently verified. PMID:19165391

Collaborative development of the EPICS Qt framework Phase I Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayssat, Robert E.

At Lyncean, a private company spun-off from technology developed at the SLAC National Lab, we have been using EPICS for over a decade. EPICS is ubiquitous on our flagship product – the Compact Light Source. EPICS is not only used to control our laser and accelerator systems, but also to control our x-ray beamlines. The goal of this SBIR is for Lyncean Technologies to spearhead a worldwide collaborative effort for the development of control system tools for EPICS using the Qt framework, a C++-based coding environment that could serve as a competitive alternative to the Java-based Control System Studio (CSS).more » This grant's Phase I, not unlike a feasibility study, is designed for planning and scoping the preparatory work needed for Phase II or other funding opportunities. The three main objectives of this Phase I are (1) to become better acquainted with the existing EPICS Qt software and Qt framework in order to evaluate the best options for ongoing development, (2) to demonstrate that our engineers can lead the EPICS community and jump-start the Qt collaboration, and (3) to identify a scope for our future work with solicited feedback from the EPICS community. This Phase I report includes key technical findings. It clarifies the differences between the two apparently-competing EPICS Qt implementations, caQtDM and the QE Framework; it explains how to create python-bindings, and compares Qt graphical libraries. But this report is also a personal story that narrates the birth of a collaboration. Starting a collaboration is not the work of a single individual, but the work of many. Therefore this report is also an attempt to publicly give credit to many who supported the effort. The main take-away from this grant is the successful birth of an EPICS Qt collaboration, seeded with existing software from the PSI and the Australian Synchrotron. But a lot more needs to be done for the collaboration founders' vision to be realized, and for the collaboration to reach its

Heat shock protein 70 gene polymorphisms' influence on the electrophysiology of long QT syndrome.

PubMed

Ali, Altaf; Qureshi, Sameera F; Medikare, Veronica; Venkateshwari, Ananthapur; Calambur, Narsimhan; Rao, Hygriv; Jayakrishnan, M P; Shenthar, Jayaprakash; Thangaraj, Kumarasamy; Nallari, Pratibha

2016-03-01

Long QT syndrome (LQTS) is a rare cardiac disorder caused due to mutations in genes encoding ion channels responsible for generation of electrical impulses. The heat shock protein (HSP)-70 gene, expressed under conditions of stress, plays a cardioprotective role when overexpressed and helps in the proper folding of the nascent proteins synthesized by the cellular machinery. We aimed to identify the role played by HSP-70 gene polymorphisms in the pathogenesis of LQTS. Study included 49 LQTS patients, 71 family members, and 219 healthy individuals recruited from an ethnically matched population. Genotyping of the single-nucleotide polymorphisms (SNPs) rs1043618 (HSP-70-1, +190G/C), rs1061581 (HSP-70-2, +1267A/G), and rs2227956 (HSP-70-hom, +2437T/C) was performed by PCR-RFLP analysis, and the results were analyzed statistically at 95 % confidence interval and p ≤ 0. 05. The "C" allele of HSP-70-1 (+190G/C) and "G" allele of HSP-70-2 (+1267A/G) showed strong association with LQTS phenotype. The haplotype group C-G-T consisting of two risk alleles was significantly associated with the disease condition. Multifactor dimensionality reduction analysis further substantiated that the three-allele model influences the outcome of the phenotype highlighting the effect of modifiers in the etiology of LQTS. As HSP-70 influences the channel assembly and maturation/trafficking of the ion channel proteins, the alleles C of the HSP-70-1 and G of the HSP-70-2 loci and the haplotype group C-G-T could be considered a diagnostic biomarker in the identification of the LQTS phenotype with a potential to affect the progression and modification of the disease phenotype.

Pyrilamine-induced prolonged QT interval in adolescent with drug overdose.

PubMed

Paudel, Govinda; Syed, Muhammad; Kalantre, Sarika; Sharma, Jayendra

2011-10-01

The widespread availability of antihistamines in many over-the-counter preparations can lead to significant hazard to the public because of their possible link to potential ventricular arrhythmias secondary to prolongation of QT interval. The effect can be further compounded by the use of other commonly used medications such as macrolides, antifungal agents, antipsychotics, and other antihistamine-containing preparations. The effect of antihistamines on QT interval is not a class effect but is unique to certain medications. Pyrilamine, a first-generation antihistaminic agent, is considered safe as there are no reports regarding its cardiac toxicity available in literature. We report a case of an adolescent with prolonged QT interval after an overdose of pyrilamine.

Automated measurements for individualized heart rate correction of the QT interval.

PubMed

Mason, Jay W; Moon, Thomas E

2015-04-01

Subject-specific electrocardiographic QT interval correction for heart rate is often used in clinical trials with frequent electrocardiographic recordings. However, in these studies relatively few 10-s, 12-lead electrocardiograms may be available for calculating the individual correction. Highly automated QT and RR measurement tools have made it practical to measure electrocardiographic intervals on large volumes of continuous electrocardiogram data. The purpose of this study was to determine whether an automated method can be used in lieu of a manual method. In 49 subjects who completed all treatments in a four-armed crossover study we compared two methods for derivation of individualized rate-correction coefficients: manual measurement on 10-s electrocardiograms and automated measurement of QT and RR during continuous 24-h electrocardiogram recordings. The four treatments, received by each subject in a latin-square randomization sequence were placebo, moxifloxacin, and two doses of an investigational drug. Analysis of continuous electrocardiogram data yielded a lower standard deviation of QT:RR regression values than the manual method, though the differences were not statistically significant. The within-subject and within-treatment coefficients of variation between the manual and automated methods were not significantly different. Corrected QT values from the two methods had similar rates of true and false positive identification of moxifloxacin's QT prolonging effect. An automated method for individualized rate correction applied to continuous electrocardiogram data could be advantageous in clinical trials, as the automated method is simpler, is based upon a much larger volume of data, yields similar results, and requires no human over-reading of the measurements. © The Author(s) 2015.

Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes.

PubMed

Isbister, Geoffrey K; Balit, Corrine R; Macleod, Dawson; Duffull, Stephen B

2010-08-01

This study aimed to describe the effects of the antipsychotic amisulpride in overdose, including the frequency of QT prolongation and torsades de pointes. Cases of amisulpride overdose (>1 g) were recruited from 2 state poison centers and a tertiary toxicology unit over 5 years. A 1-page clinical research form was used to collect clinical information. Copies of all electrocardiograms were obtained. Electrocardiogram parameters (QRS and QT intervals) were manually measured as previously described, and plots of QT-heart rate (HR) pairs were compared with the QT nomogram. There were 83 patients with amisulpride overdoses with a median age of 29 years (interquartile range [IQR], 23-40 years), and 42 (51%) were female. The median dose ingested was 6 g (IQR, 3-13 g, range, 1.2-120 g). The median HR was 66 beats/min (IQR, 60-81 beats/min). Bradycardia occurred in 20 cases (24%), and hypotension in 19 (23%). From 440 electrocardiograms (average of 5 per case; range, 1-15), an abnormal QT-HR pair occurred in 61 cases (73%). Torsades de pointes developed in 6 cases (7%), with doses of 4, 4.6, 18, 24, 32, and 80 g. The patient taking 32 g died after a cardiac arrest. Widened QRS did not occur except transient rate-dependent bundle-branch block in 3 cases. There were significant associations of bradycardia, hypokalemia, and hypocalcaemia, with QT prolongation and torsades de pointes. Central nervous system effects were uncommon with coma in 7 cases, seizures in 2, and dystonic reactions in 2. Amisulpride overdose commonly causes QT prolongation, bradycardia, and hypotension. Torsades de pointes occurred commonly enough to suggest that amisulpride is highly cardiotoxic in overdose.

Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders

PubMed Central

Aronow, Wilbert S.

2018-01-01

Background Drug-induced QT prolongation is associated with higher risk of cardiac arrhythmias and cardiovascular mortality. We investigated the effects of atypical antipsychotic drugs on QT interval in children and adults with mental disorders. Methods We conducted random-effects direct frequentist meta-analyses of aggregate data from randomized controlled trials (RCT) and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to October 2017 identified studies that examined aripiprazole, quetiapine, risperidone, olanzapine, ziprasidone and brexpiprazole. Results Low quality evidence suggests that aripiprazole (four meta-analyses and twelve RCTs), brexpiprazole (one systematic review and four RCTs) or olanzapine (five meta-analyses and twenty RCTs) do not increase QT interval. Low quality evidence suggests that ziprasidone (five meta-analyses and 11 RCTs) increases QT interval and the rates of QT prolongation while risperidone (four meta-analyses, 70 RCTs) and quetiapine (two meta-analyses and seven RCTs) are associated with QT prolongation and greater odds of torsades de pointes ventricular tachycardia especially in cases of drug overdose. Conclusions The main conclusion of our study is that in people with mental disorders and under treatment with atypical antipsychotic drugs, in order to avoid QT prolongation and reduce the risk of ventricular tachycardia clinicians may recommend aripiprazole, brexpiprazole or olanzapine in licensed doses. Long-term comparative safety needs to be established. PMID:29862236

Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing.

PubMed

Stattin, Eva-Lena; Boström, Ida Maria; Winbo, Annika; Cederquist, Kristina; Jonasson, Jenni; Jonsson, Björn-Anders; Diamant, Ulla-Britt; Jensen, Steen M; Rydberg, Annika; Norberg, Anna

2012-10-25

Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort. Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT). In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death. In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the

Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2.

PubMed

Gottlieb, Lisa A; Lubberding, Anniek; Larsen, Anders Peter; Thomsen, Morten B

2017-01-01

Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2 -/- mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT 100 = QT/(RR/100) 1/2 ). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QT mean-RR ). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2 -/- (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2 -/- mice. Circadian rhythms in QT 100 intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2 -/- , respectively (p = 0.15). A diurnal rhythm in QT 100 intervals was only found in WT mice. QT mean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2 -/- . The amplitude of the circadian rhythm in QT mean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2 -/- , respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.

Dispersion durations of P-wave and QT interval in children treated with a ketogenic diet.

PubMed

Doksöz, Önder; Güzel, Orkide; Yılmaz, Ünsal; Işgüder, Rana; Çeleğen, Kübra; Meşe, Timur

2014-04-01

Limited data are available on the effects of a ketogenic diet on dispersion duration of P-wave and QT-interval measures in children. We searched for the changes in these measures with serial electrocardiograms in patients treated with a ketogenic diet. Twenty-five drug-resistant patients with epilepsy treated with a ketogenic diet were enrolled in this study. Electrocardiography was performed in all patients before the beginning and at the sixth month after implementation of the ketogenic diet. Heart rate, maximum and minimum P-wave duration, P-wave dispersion, and maximum and minimum corrected QT interval and QT dispersion were manually measured from the 12-lead surface electrocardiogram. Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increase at month 6 compared with baseline values. Other previously mentioned electrocardiogram parameters also showed no significant changes. A ketogenic diet of 6 months' duration has no significant effect on electrocardiogram parameters in children. Further studies with larger samples and longer duration of follow-up are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion. Copyright © 2014 Elsevier Inc. All rights reserved.

Porting and redesign of Geotool software system to Qt

NASA Astrophysics Data System (ADS)

Miljanovic Tamarit, V.; Carneiro, L.; Henson, I. H.; Tomuta, E.

2016-12-01

Geotool is a software system that allows a user to interactively display and process seismoacoustic data from International Monitoring System (IMS) station. Geotool can be used to perform a number of analysis and review tasks, including data I/O, waveform filtering, quality control, component rotation, amplitude and arrival measurement and review, array beamforming, correlation, Fourier analysis, FK analysis, event review and location, particle motion visualization, polarization analysis, instrument response convolution/deconvolution, real-time display, signal to noise measurement, spectrogram, and travel time model display. The Geotool program was originally written in C using the X11/Xt/Motif libraries for graphics. It was later ported to C++. Now the program is being ported to the Qt graphics system to be more compatible with the other software in the International Data Centre (IDC). Along with this port, a redesign of the architecture is underway to achieve a separation between user interface, control, and data model elements, in line with design patterns such as Model-View-Controller. Qt is a cross-platform application framework that will allow geotool to easily run on Linux, Mac, and Windows. The Qt environment includes modern libraries and user interfaces for standard utilities such as file and database access, printing, and inter-process communications. The Qt Widgets for Technical Applications library (QWT) provides tools for displaying standard data analysis graphics.

Comparison of corrected QT interval as measured on electroencephalography versus 12-lead electrocardiography in children with a history of syncope.

PubMed

Massey, Shavonne L; Wise, Marshall S; Madan, Nandini; Carvalho, Karen; Khurana, Divya; Legido, Agustin; Valencia, Ignacio

2011-11-01

Long QT syndrome can present with neurological manifestations, including syncope and seizure-like activity. These patients often receive an initial neurologic evaluation, including electroencephalography (EEG). Our previous retrospective study suggested an increased prevalence of prolonged corrected QT interval (QTc) measured during the EEG of patients with syncope. The aim of the current study is to assess the accuracy of the EEG QTc reading compared with the nonsimultaneous 12-lead electrocardiography (ECG) in children with syncope. Abnormal QTc was defined as ≥450 ms in boys, ≥460 ms in girls. Forty-two children were included. There was no significant correlation between QTc readings in the EEG and ECG. EEG failed to identify 2 children with prolonged QTc in the ECG and overestimated the QTc in 3 children with normal QTc in the ECG. This study suggests that interpretation of the QTc segment during an EEG is limited. Further studies with simultaneous EEG and 12-lead ECG are warranted.

Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria

PubMed Central

El Harchi, Aziza; Hancox, Jules C.

2017-01-01

Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF. PMID:28609477

Prolonged Tp-e Interval in Down Syndrome Patients with Congenitally Normal Hearts.

PubMed

Kucuk, Mehmet; Karadeniz, Cem; Ozdemir, Rahmi; Meşe, Timur

2018-03-25

Heterogeneity of ventricular repolarization has been assessed by using the QT dispersion in Down syndrome (DS) patients with congenitally normal hearts. However, novel repolarization indexes, the Tp-e interval and Tp-e/QT ratio, have not previously been evaluated in these patients. The aim of this study was to evaluate the Tp-e interval and Tp-e/QT ratio in DS patients without congenital heart defects. Twelve-lead surface electrocardiograms of 160 DS patients and 110 age- and sex-matched healthy controls were used to evaluate and compare the Tp-e interval, Tp-e dispersion, and Tp-e/QT ratio. Heart rate, Tp-e interval, Tp-e dispersion, Tp-e/QT and Tp-e/QTc ratios were significantly higher in DS group than in the controls. Myocardial repolarization indexes in DS patients with congenitally normal hearts were found to be prolonged compared to those in normal controls. Further evaluation is warranted to reveal a relationship between prolonged repolarization indexes and arrhythmic events in these patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The importance of the family history in caring for families with long QT syndrome and dilated cardiomyopathy.

PubMed

Ruiter, Jolien S; Berkenbosch-Nieuwhof, Karin; van den Berg, Maarten P; van Dijk, Rene; Middel, Berrie; van Tintelen, J Peter

2010-03-01

In potentially inherited cardiac diseases, the family history is of great importance. We looked at the way cardiologists take a family history in patients with idiopathic dilated cardiomyopathy (DCM) or long QT syndrome (LQTS) and whether this led to screening of relatives or other follow-up. We performed retrospective cross-sectional analyses of adult index patients with DCM or LQTS in a general hospital (GH) or a University Medical Center (UMC). We identified 82 index patients with DCM (34 GH; 48 UMC) and 20 with LQTS (all UMC) between 1996 and 2005. Mean follow-up was 58 months. A family history was recorded in 90% of both LQTS and DCM patients most of the cases restricted to first-degree family members. The genetic aspects, counseling and screening of family members was discussed significantly more often with LQTS than DCM patients (all P < 0.05). Also follow-up (screening of family members, DNA analysis and referral) was performed significantly more often in LQTS than DCM patients. Cardiologists in the UMC referred DCM index patients for genetic counseling more often than those in the GH (25% vs. 6%; P < 0.05). Only a few index patients with DCM were referred to a clinical genetics department. One-third of DCM cases and nearly all LQTS cases are familial. Since early recognition and treatment may reduce morbidity and mortality we recommend cardiologists take a more thorough family history and always consider referring to a clinical genetics department in such index patients. (c) 2010 Wiley-Liss, Inc.

In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details.

PubMed

Lee, William; Windley, Monique J; Vandenberg, Jamie I; Hill, Adam P

2017-01-01

Acquired long QT syndrome, mostly as a result of drug block of the Kv11. 1 potassium channel in the heart, is characterized by delayed cardiac myocyte repolarization, prolongation of the T interval on the ECG, syncope and sudden cardiac death due to the polymorphic ventricular arrhythmia Torsade de Pointes (TdP). In recent years, efforts are underway through the Comprehensive in vitro proarrhythmic assay (CiPA) initiative, to develop better tests for this drug induced arrhythmia based in part on in silico simulations of pharmacological disruption of repolarization. However, drug binding to Kv11.1 is more complex than a simple binary molecular reaction, meaning simple steady state measures of potency are poor surrogates for risk. As a result, there is a plethora of mechanistic detail describing the drug/Kv11.1 interaction-such as drug binding kinetics, state preference, temperature dependence and trapping-that needs to be considered when developing in silico models for risk prediction. In addition to this, other factors, such as multichannel pharmacological profile and the nature of the ventricular cell models used in simulations also need to be considered in the search for the optimum in silico approach. Here we consider how much of mechanistic detail needs to be included for in silico models to accurately predict risk and further, how much of this detail can be retrieved from protocols that are practical to implement in high throughout screens as part of next generation of preclinical in silico drug screening approaches?

Optimal weighted combinatorial forecasting model of QT dispersion of ECGs in Chinese adults.

PubMed

Wen, Zhang; Miao, Ge; Xinlei, Liu; Minyi, Cen

2016-07-01

This study aims to provide a scientific basis for unifying the reference value standard of QT dispersion of ECGs in Chinese adults. Three predictive models including regression model, principal component model, and artificial neural network model are combined to establish the optimal weighted combination model. The optimal weighted combination model and single model are verified and compared. Optimal weighted combinatorial model can reduce predicting risk of single model and improve the predicting precision. The reference value of geographical distribution of Chinese adults' QT dispersion was precisely made by using kriging methods. When geographical factors of a particular area are obtained, the reference value of QT dispersion of Chinese adults in this area can be estimated by using optimal weighted combinatorial model and reference value of the QT dispersion of Chinese adults anywhere in China can be obtained by using geographical distribution figure as well.

QT dispersion and ventricular arrhythmias in children with primary mitral valve prolapse

PubMed Central

İmamoğlu, Ebru Yalın; Eroğlu, Ayşe Güler

2016-01-01

Aim: To investigate ventricular arrhythmias in children with primary mitral valve prolapse and to evaluate its relation with QT length, QT dispersion, autonomic function tests and heart rate variability measurements. Material and Methods: Fourty two children with mitral valve prolapse and 32 healthy children were enrolled into the study. Twelve-lead electrocardiograms, autonomic function tests, echocardiography and 24-hour rhythm Holter tests were performed. Electrocardiograms were magnified digitally. The QT length was corrected according to heart rate. The patients were grouped according to the number of premature ventricular contractions and presence of complex ventricular arhythmia in the 24-hour rhythm Holter monitor test. Heart rate variability measurements were calculated automatically from the 24-hour rhythm Holter monitor test. Orthostatic hypotension and resting heart rate were used as autonomic function tests. Results: The mean age was 13.9±3.3 years in the patient group and 14.6±3.1 years in the control group (p>0.05). Thirty four of the patients (81%) were female and eight (19%) were male. Twenty five of the control subjects (78%) were female and seven (22%) were male. The QT dispersion and heart rate corrected QT interval were found to be significantly increased in the children with primary mitral valve prolapse when compared with the control group (56±16 ms vs. 43±11 ms, p=0.001; 426±25 ms vs. 407±26 ms, p=0.002, respectively). In 24-hour rhythm Holter monitor tests, ventricular arrhythmias were found in 21 out of 42 patients (50%) and 6 out of 32 control subjects (18.8%) (p=0.006). QT dispersion was found to be significantly increased in patients with premature ventricular contractions ≥ 10/day and/or complex ventricular arrhythmias compared to the control group without ventricular premature beats (p=0.002). There was no significant difference in autonomic function tests and heart rate variability measurements between the patient and control

The Effects of Local Anaesthetics on QT Parameters during Thoracic Epidural Anaesthesia Combined with General Anaesthesia: Ropivacaine versus Bupivacaine

PubMed Central

Güven, Özlem; Sazak, Hilal; Alagöz, Ali; Şavkılıoğlu, Eser; Demirbaş, Çilsem Sevgen; Yıldız, Ali; Karabulut, Erdem

2013-01-01

Background: Many studies focusing on the effects of local anaesthetics on QT intervals have been performed, but the articles evaluating the relationship between thoracic epidural anaesthesia combined with general anaesthesia and QT parameters are very limited. Aims: We aimed to compare the effects of bupivacaine and ropivacaine on QT interval, corrected QT, dispersion of QT, and corrected dispersion of QT in patients undergoing lung resection under thoracic epidural anaesthesia combined with general anaesthesia. Study Design: Prospective clinical study. Methods: Thirty ASA physical status 1–3 patients requiring thoracic epidural anaesthesia combined with general anaesthesia for thoracic surgery. Patients were randomly assigned to two groups, which were allocated to receive either bupivacaine (Group B) or ropivacaine (Group R) during thoracic epidural anaesthesia. Following haemodynamic monitoring, a thoracic epidural catheter was inserted. Local anaesthetic at an average dose of 1.5 mL/ segment was given through an epidural catheter. The same general anaesthesia protocol was administered in both groups. Records and measurements were performed on 10 phases that were between the thoracic epidural catheter insertion to the 5th min of endobronchial intubation. In all phases, systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, heart rate, peripheral O2 saturation, and electrocardiogram monitoring were performed in patients. All QT parameters were recorded by 12-lead electrocardiogram and analysed manually by a cardiologist. Results: QT intervals were similar between two groups. In Group R, corrected QT values at the 20th min of local anaesthetic injection and the 5th min of endobronchial intubation were shorter than those in Group B (p<0.05). The basal dispersion of QT and dispersion of QT values at the 1st min of propofol injection were shorter than those in Group R (p<0.05). The corrected dispersion of QT value at the 1st min of propofol

QT interval dispersion in the patients with central serous chorioretinopathy.

PubMed

Dagli, Necati; Turgut, Burak; Tanyildizi, Rumeysa; Kobat, Sabiha; Kobat, Mehmet Ali; Dogdu, Orhan

2015-01-01

To evaluate QT dispersion (QTD) in patients with central serous chorioretinopathy (CSC). This clinical, comperative, case-control study included 30 patients with CSC at acute phase (Group 1) and 30 age- and sex-matched healthy subjects (Group 2, the control group). From all subjects, a 12-lead surface electrocardiography was obtained. The heart rate (HR), QT maximum (QTmax), QT minimum (QTmin), QT corrected (QTc), QTD and Tmean were manually measured and analyzed. Student's t-test and Pearson's method of correlation were used for statistical analysis. The patient and control groups were matched for age, smoking status (rate and duration) and gender. There were no significant differences with regard to these among the groups (P>0.05). The participants included 19 men (63.3%) and 11 women (36.7%) in Group 1, 20 men (66.7%) and 10 women (33.3%) in Group 2. QTmax, QTD and QTc were significantly higher than those of healthy controls (P<0.001 for QTmax, P=0.01 for QTD and P=0.001 for QTc). QTmin, Tmean and HR did not differ significantly between the study groups (P=0.28 for QTmin, P=0.56 for Tmean and P>0.05 for HR). No significant correlation was found between duration of the disorder and QTD values (r=0.13, P>0.05). These findings suggest that CSC may be associated with an increase in QTD and that the patients might be at risk for ventricular arrhythmia.

A Valuable Tool in Predicting Poor Outcome due to Sepsis in Pediatric Intensive Care Unit: Tp-e/QT Ratio.

PubMed

Ozdemir, Rahmi; Isguder, Rana; Kucuk, Mehmet; Karadeniz, Cem; Ceylan, Gokhan; Katipoglu, Nagehan; Yilmazer, Murat Muhtar; Yozgat, Yilmaz; Mese, Timur; Agin, Hasan

2016-10-01

To assess the feasibility of 12-lead electrocardiographic (ECG) measures such as P wave dispersion (PWd), QT interval, QT dispersion (QTd), Tp-e interval, Tp-e/QT and Tp-e/QTc ratio in predicting poor outcome in patients diagnosed with sepsis in pediatric intensive care unit (PICU). Ninety-three patients diagnosed with sepsis, severe sepsis or septic shock and 103 age- and sex-matched healthy children were enrolled into the study. PWd, QT interval, QTd, Tp-e interval and Tp-e/QT, Tp-e/QTc ratios were obtained from a 12-lead electrocardiogram. PWd, QTd, Tp-e interval and Tp-e/QT, Tp-e/QTc ratios were significantly higher in septic patients compared with the controls. During the study period, 41 patients had died. In multivariate logistic regression analyses, only Tp-e/QT ratio was found to be an independent predictor of mortality. The ECG measurements can predict the poor outcome in patients with sepsis. The Tp-e/QT ratio may be a valuable tool in predicting mortality for patients with sepsis in the PICU. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model

PubMed Central

Yao, X; Anderson, D L; Ross, S A; Lang, D G; Desai, B Z; Cooper, D C; Wheelan, P; McIntyre, M S; Bergquist, M L; MacKenzie, K I; Becherer, J D; Hashim, M A

2008-01-01

Background and purpose: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. Experimental approach: Sixteen marketed drugs from various pharmacological classes with a known incidence—or lack thereof—of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. Key results: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. Conclusions and implications: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization. PMID:18587422

Do Studies Evaluating QT/QTc Interval Prolongation with Dietary Supplements Meet FDA Standards: A Systematic Review.

PubMed

Nguyen, Tinh An; Kurian, Amy; Leong, Jessica; Patel, Umang M; Shah, Sachin A

2017-07-04

Dietary supplement use is continuously increasing, but the safety evaluation of these products remains partial. While dietary supplements have no mandate for assessing cardiovascular safety, all new drug entities (NDE) are required to undergo a thorough QT/corrected QT (QTc) assessment to determine their propensity to impact cardiac repolarization. Independent investigators and manufacturers of dietary supplements voluntarily initiate safety studies; however, the quality of these studies is controversial. We sought to compare studies evaluating the QT/QTc effects of dietary supplements based on the International Conference of Harmonization (ICH)-E14 recommendations for NDE. Twenty-six published dietary supplement studies assessed QT/QTc interval prolongation. Sample sizes ranged from nine subjects to 206 among the 15 crossover studies, six parallel design studies, and five observational studies. A plan to account for electrocardiogram (ECG) morphological abnormalities was included in 10 studies, and two studies reported cardiovascular adverse events. Eight studies found a significant change in QT/QTc intervals. The majority of studies included in this review contained many of the critical elements recommended by the ICH E14, which includes the U.S. Food and Drug Administration guidance document for QT/QTc interval assessment. Compared with the thorough QT (TQT) standards, studies are typically well performed but can be bolstered by some study design changes. More than 30% of the included studies showed some degree of ECG changes, suggesting the need for continued cardiovascular safety assessment of dietary supplements.

A new technique to determine the correlation between the QT interval and heart-rate for control and SIDS babies

NASA Technical Reports Server (NTRS)

Sadeh, D.; Shannon, D. C.; Abboud, S.; Akselrod, S.; Cohen, R. J.

1987-01-01

The ability of the autonomic nervous system to alter the QT interval in response to heart rate changes is essential to cardiovascular control. An accurate way to determine the relation between QT intervals and their corresponding RR intervals is described. A computer algorithm measures the RR intervals using digital filtering and cross-correlating the QRS sections of consecutive waveforms. The QT intervals is calculated by choosing a section of, the ECG that includes the T wave and cross-correlating it with all the consecutive T waves. At least 4000 pairs of QT-RR intervals are computed for each subject and a best fit correlation function determines the relations between the QT and RR intervals. This technique enables to establish a precise correlation between RR and QT in order to distinguish between control and SIDS babies.

Mitigating prolonged QT interval in cancer nanodrug development for accelerated clinical translation.

PubMed

Ranjan, Amalendu P; Mukerjee, Anindita; Helson, Lawrence; Vishwanatha, Jamboor K

2013-12-14

Cardiac toxicity is the foremost reason for drug discontinuation from development to clinical evaluation and post market surveillance [Fung 35:293-317, 2001; Piccini 158:317-326 2009]. The Food and Drug Administration (FDA) has rejected many potential pharmaceutical agents due to QT prolongation effects. Since drug development and FDA approval takes an enormous amount of time, money and effort with high failure rates, there is an increased focus on rescuing drugs that cause QT prolongation. If these otherwise safe and potent drugs were formulated in a unique way so as to mitigate the QT prolongation associated with them, these potent drugs may get FDA approval for clinical use. Rescuing these compounds not only benefit the patients who need them but also require much less time and money thus leading to faster clinical translation. In this study, we chose curcumin as our drug of choice since it has been shown to posses anti-tumor properties against various cancers with limited toxicity. The major limitations with this pharmacologically active drug are (a) its ability to prolong QT by inhibiting the hERG channel and (b) its low bioavailability. In our previous studies, we found that lipids have protective actions against hERG channel inhibition and therefore QT prolongation. Results of the manual patch clamp assay of HEK 293 cells clearly illustrated that our hybrid nanocurcumin formulation prevented the curcumin induced inhibition of hERG K+ channel at concentrations higher than the therapeutic concentrations of curcumin. Comparing the percent inhibition, the hybrid nanocurcumin limited inhibition to 24.8% at a high curcumin equivalent concentration of 18 μM. Liposomal curcumin could only decrease this inhibition upto 30% only at lower curcumin concentration of 6 μM but not at 18 μM concentration. Here we show a curcumin encapsulated lipopolymeric hybrid nanoparticle formulation which could protect against QT prolongation and also render increased

Prevalence and Risk Factors Associated with Use of QT-Prolonging Drugs in Hospitalized Older People.

PubMed

Franchi, C; Ardoino, I; Rossio, R; Nobili, A; Biganzoli, E M; Marengoni, A; Marcucci, M; Pasina, L; Tettamanti, M; Corrao, S; Mannucci, P M

2016-01-01

The objective of this study was to evaluate the prevalence of the prescription of QT-prolonging drugs at hospital admission and discharge and the risk factors associated with their use in older people (aged 65 years and older). Data were obtained from the REPOSI (REgistro POliterapie SIMI [Società Italiana di Medicina Interna]) registry, which enrolled 4035 patients in 2008 (n = 1332), 2010 (n = 1380), and 2012 (n = 1323). Multivariable logistic regression was performed to determine the risk factors independently associated with QT-prolonging drug use. QT-prolonging drugs were classified by the risk of Torsades de Pointes (TdP) (definite, possible, or conditional) according to the Arizona Center for Education and Research on Therapeutics (AzCERT) classification. Specific drug combinations were also assessed. Among 3906 patients prescribed at least one drug at admission, 2156 (55.2%) were taking at least one QT-prolonging drug. Risk factors independently associated with the use of any QT-prolonging drugs were increasing age (odds ratio [OR] 1.02, 95% CI 1.01-1.03), multimorbidity (OR 2.69, 95% CI 2.33-3.10), hypokalemia (OR 2.79, 95% CI 1.32-5.89), atrial fibrillation (OR 1.66, 95% CI 1.40-1.98), and heart failure (OR 3.17, 95% CI 2.49-4.05). Furosemide, alone or in combination, was the most prescribed drug. Amiodarone was the most prescribed drug with a definite risk of TdP. Both the absolute number of QT-prolonging drugs (2890 vs. 3549) and the number of patients treated with them (2456 vs. 2156) increased at discharge. Among 1808 patients not prescribed QT-prolonging drugs at admission, 35.8% were prescribed them at discharge. Despite their risk, QT-prolonging drugs are widely prescribed to hospitalized older persons. The curriculum for both practicing physicians and medical students should be strengthened to provide more education on the appropriate use of drugs in order to improve the management of hospitalized older people.

Influence of gender and types of sports training on QT variables in young elite athletes.

PubMed

Omiya, Kazuto; Sekizuka, Hiromitsu; Kida, Keisuke; Suzuki, Kengo; Akashi, Yoshihiro J; Ohba, Haruo; Musha, Haruki

2014-01-01

Influence of gender and sports training on QT variables such as QT interval and dispersion (QT dispersion: QTD) in young elite athletes were evaluated. Subjects included 104 male and 97 female Japanese elite athletes (mean age 21.6 years). Sports included basketball, fencing, gymnastics, judo, swimming, tennis, track and field and volleyball. Age-matched healthy non-athletes (32 men and 20 women) were enrolled as controls. QT measurements were manually obtained from a 12-lead resting electrocardiogram and QTD was calculated as the difference between the longest and shortest QT intervals. A corrected QT interval (QTc) was obtained using Bazett's formula. Subjects were divided into two groups; an endurance training group and a static training group on the basis of their training types. Maximum and minimum QTc were significantly longer in female athletes than in male athletes (max: 414.2 vs. 404.5 ms, min: 375.1 vs. 359.2 ms, p<0.0001 respectively), whereas QTc dispersion (QTcD) was shorter in female athletes than in male athletes (39.2 vs. 45.3 ms, p<0.0001). QTcD was significantly shorter in female athletes than in the female control group (39.2 vs. 45.2 ms, p<0.05). However, no statistically significant difference was observed between male athletes and the male control group. Male gymnasts exhibited significantly longer QTcD than the control group (p<0.01), but female gymnasts had significantly shorter QTcD than the control group (p<0.05). Maximum QTc intervals were prolonged in the male static training group compared with non-athletes, and QTcDs in the static training group were prolonged compared with the endurance training group. However, no significant difference was observed in the female group. In conclusion, both gender and different characteristics of sports training may affect QT variables even in young elite athletes. Vigorous static exercise training may independently prolong QT variables.

Onset of decreased heart work is correlated with increased heart rate and shortened QT interval in high-carbohydrate fed overweight rats.

PubMed

Durak, Aysegul; Olgar, Yusuf; Tuncay, Erkan; Karaomerlioglu, Irem; Kayki Mutlu, Gizem; Arioglu Inan, Ebru; Altan, Vecdi Melih; Turan, Belma

2017-11-01

Mechanical activity of the heart is adversely affected in metabolic syndrome (MetS) characterized by increased body mass and marked insulin resistance. Herein, we examined the effects of high carbohydrate intake on cardiac function abnormalities by evaluating in situ heart work, heart rate, and electrocardiograms (ECGs) in rats. MetS was induced in male Wistar rats by adding 32% sucrose to drinking water for 22-24 weeks and was confirmed by insulin resistance, increased body weight, increased blood glucose and serum insulin, and increased systolic and diastolic blood pressures in addition to significant loss of left ventricular integrity and increased connective tissue around myofibrils. Analysis of in situ ECG recordings showed a markedly shortened QT interval and decreased QRS amplitude with increased heart rate. We also observed increased oxidative stress and decreased antioxidant defense characterized by decreases in serum total thiol level and attenuated paraoxonase and arylesterase activities. Our data indicate that increased heart rate and a shortened QT interval concomitant with higher left ventricular developed pressure in response to β-adrenoreceptor stimulation as a result of less cyclic AMP release could be regarded as a natural compensation mechanism in overweight rats with MetS. In addition to the persistent insulin resistance and obesity associated with MetS, one should consider the decreased heart work, increased heart rate, and shortened QT interval associated with high carbohydrate intake, which may have more deleterious effects on the mammalian heart.

Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

PubMed

Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Ray; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

2017-04-04

Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide ( r =0.55; 95% confidence interval, 0.09-0.81; P =0.02), 23% in response to quinidine ( r =0.48; 95% confidence interval, -0.03 to 0.79; P =0.06), and 27% in response to ranolazine ( r =0.52; 95% confidence interval, 0.05-0.80; P =0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls ( r 2 =12%, P =1×10 -7 ). We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to

Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel.

PubMed

Smith, Jennifer L; Tester, David J; Hall, Allison R; Burgess, Don E; Hsu, Chun-Chun; Claude Elayi, Samy; Anderson, Corey L; January, Craig T; Luo, Jonathan Z; Hartzel, Dustin N; Mirshahi, Uyenlinh L; Murray, Michael F; Mirshahi, Tooraj; Ackerman, Michael J; Delisle, Brian P

2018-05-01

Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome. Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome-linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential. Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome-linked KCNH2 variants showed that the patients had median heart rate-corrected QT intervals <480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration. We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and therefore do not represent the pathogenic substrate for

QT interval dispersion in the patients with central serous chorioretinopathy

PubMed Central

Dagli, Necati; Turgut, Burak; Tanyildizi, Rumeysa; Kobat, Sabiha; Kobat, Mehmet Ali; Dogdu, Orhan

2015-01-01

AIM To evaluate QT dispersion (QTD) in patients with central serous chorioretinopathy (CSC). METHODS This clinical, comperative, case-control study included 30 patients with CSC at acute phase (Group 1) and 30 age- and sex-matched healthy subjects (Group 2, the control group). From all subjects, a 12-lead surface electrocardiography was obtained. The heart rate (HR), QT maximum (QTmax), QT minimum (QTmin), QT corrected (QTc), QTD and Tmean were manually measured and analyzed. Student's t-test and Pearson's method of correlation were used for statistical analysis. RESULTS The patient and control groups were matched for age, smoking status (rate and duration) and gender. There were no significant differences with regard to these among the groups (P>0.05). The participants included 19 men (63.3%) and 11 women (36.7%) in Group 1, 20 men (66.7%) and 10 women (33.3%) in Group 2. QTmax, QTD and QTc were significantly higher than those of healthy controls (P<0.001 for QTmax, P=0.01 for QTD and P=0.001 for QTc). QTmin, Tmean and HR did not differ significantly between the study groups (P=0.28 for QTmin, P=0.56 for Tmean and P>0.05 for HR). No significant correlation was found between duration of the disorder and QTD values (r=0.13, P>0.05). CONCLUSION These findings suggest that CSC may be associated with an increase in QTD and that the patients might be at risk for ventricular arrhythmia. PMID:25709909

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with ankylosing spondylitis.

PubMed

Acar, Gurkan; Yorgun, Hikmet; Inci, Mehmet Fatih; Akkoyun, Murat; Bakan, Betul; Nacar, Alper Bugra; Dirnak, Imran; Cetin, Gozde Yildirim; Bozoglan, Orhan

2014-03-01

Ankylosing spondylitis (AS) is a chronic multi-systemic inflammatory rheumatic disorder. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with AS, and to assess the relation with inflammation. Sixty-two patients with AS and 50 controls were included. Tp-e interval and Tp-e/QT ratio were measured from a 12-lead electrocardiogram, and the Tp-e interval corrected for heart rate. The plasma level of high sensitive C-reactive protein (hsCRP) was measured. These parameters were compared between groups. In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in AS patients compared to the controls (31.7 ± 9.6 vs 28.2 ± 7.4 and 35.8 ± 11.5 vs 30.6 ± 7.9 ms, P = 0.03 and P = 0.007, respectively). cTp-e interval and Tp-e/QT ratio were also significantly higher in AS patients (92.1 ± 10.2 vs 75.8 ± 8.4 and 0.22 ± 0.02 vs 0.19 ± 0.02 ms, all P values <0.001). cTp-e interval and Tp-e/QT ratio were significantly correlated with hsCRP (r = 0.63, P < 0.001 and r = 0.49, P < 0.001, respectively). Our study revealed that Tp-e interval and Tp-e/QT ratio were increased in AS patients. These electrocardiographic ventricular repolarization indexes were significantly correlated with the plasma level of hsCRP.

Assessment of the QT interval in the electroencephalography (EEG) of children with syncope, epilepsy, and attention-deficit hyperactivity disorder (ADHD).

PubMed

Jha, Om P; Khurana, Divya S; Carvalho, Karen S; Melvin, Joseph J; Legido, Agustin; O'Riordan, Anna C; Valencia, Ignacio

2010-03-01

The interpretation of QT interval is often neglected during electroencephalography (EEG) reading. We compared the incidence of prolonged QT interval, as seen in the electrocardiography (ECG) recording lead of the EEG, in children presenting with seizure, syncope, or attention-deficit hyperactivity disorder (ADHD). Abnormal QT was defined as >460 ms. The incidence of prolonged QT in the seizure, syncope, and ADHD groups was 1/50 (2%), 7/50 (14%), and 2/50 (4%), respectively (P = .036, chi-square). The mean +/- SD of QT were 405 +/- 34, 424 +/- 39, and 414 +/- 36, respectively (P = .035, analysis of variance [ANOVA], syncope group, compared with seizure group). The incidence of prolonged QT as measured in the EEG was unexpectedly high in children presenting with seizure, syncope, or ADHD. These data support the concept that QT evaluation should be emphasized during routine EEG reading, as it may aid in identifying cases of undiagnosed cardiac conduction abnormalities. Prospective studies comparing EEG-ECG tracings with 12-lead ECG are warranted.

Association Between ACE Gene Polymorphism and QT Dispersion in Patients with Acute Myocardial Infarction.

PubMed

Karahan, Zulkuf; Ugurlu, Murat; Ucaman, Berzal; Veysel Ulug, Ali; Kaya, Ilyas; Cevik, Kemal; Sahin Adiyaman, Mehmet; Oztürk, Onder; Iyem, Hikmet; Ozdemir, Ferit

2016-01-01

Angiotensin converting enzyme (ACE) gene polymorphism is associated with high renin-angiotensin system causing myocardial fibrosis and ventricular repolarization abnormality. Based on these findings, this study was designed to determine the association between ACE gene insertion/deletion (I/D) polymorphism and QT dispersion after acute myocardial infarction (MI). The study included 108 patients with acute MI. Blood samples were obtained from all the patients for genomic DNA analysis. ECGs were recorded at baseline and at the end of a 6-month follow up. The OT dispersion was manually calculated. The mean age of the patients was 57.5 ±9.9 years (ranging from 36 to 70). The patients with DD genotype showed longer QT dispersion than patients with II or DI genotype at the baseline, while at the end of the six-month follow up the patients with DI genotype showed longer QT dispersion than patients with DD or II genotypes. However, the magnitude of the QT dispersion prolongation was higher in patients carrying the ACE D allele than patients who were not carrying it, at baseline and at the end of six-month follow up (52.5 ±2.6 msn vs. 47.5±2.1 msn at baseline, 57±3.2 msn vs. 53±2.6 msn in months, P: 0.428 and P: 0.613, respectively). Carriers of the D allele of ACE gene I/D polymorphism may be associated with QT dispersion prolongation in patients with MI.An interaction of QT dispersion and ACE gene polymorphism may be associated with an elevation of serum type I-C terminal pro-collagen concentration, possibly leading to myocardial fibrosis, and increased action potential duration.

Tpeak - Tend and Tpeak - Tend /QT ratio as markers of ventricular arrhythmia risk in cardiac resynchronization therapy patients.

PubMed

Barbhaiya, Chirag; Po, Jose Ricardo F; Hanon, Sam; Schweitzer, Paul

2013-01-01

Cardiac resynchronization therapy (CRT) increases transmural dispersion of repolarization (TDR) and can be pro-arrhythmic. However, overall arrhythmia risk was not increased in large-scale CRT clinical trials. Increased TDR as measured by T(peak ) -T(end) (TpTe) was associated with arrhythmia risk in CRT in a single-center study. This study investigates whether QT interval, TpTe, and TpTe/QT ratio are associated with ventricular arrhythmias in patients with CRT-defibrillator (CRT-D). Post-CRT-D implant electrocardiograms of 128 patients (age 71.3 years ± 10.3) with at least 2 months of follow-up at our institution's device clinic (mean follow-up of 28.5 months ± 17) were analyzed for QT interval, TpTe, and TpTe/QT ratio. Incidence of ventricular arrhythmias was determined based on routine and directed device interrogations. Appropriate implantable cardioverter-defibrillator therapy for sustained ventricular tachycardia or ventricular fibrillation was delivered in 18 patients (14%), and nonsustained ventricular tachycardia (NSVT) was detected but did not require therapy in 58 patients (45%). Patients who received appropriate defibrillator therapy had increased TpTe/QT ratio (0.24 ± 0.03 ms vs 0.20 ± 0.04, P = 0.0002) and increased TpTe (105.56 ± 20.36 vs 87.82 ± 22.32 ms, P = 0.002), and patients with NSVT had increased TpTe/QT ratio (0.22 ± 0.04 vs 0.20 ± 0.04, P = 0.016). Increased QT interval was not associated with risk of ventricular arrhythmia. The relative risk for appropriate defibrillator therapy of T(p) T(e) /QT ratio ≥ 0.25 was 3.24 (P = 0.016). Increased TpTe and increased TpTe/QT ratio are associated with increased incidence of ventricular arrhythmias in CRT-D. The utility of TpTe interval and TpTe/QT ratio as potentially modifiable risk factors for ventricular arrhythmias in CRT requires further study. ©2012, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.

Gene patents still alive and kicking: their impact on provision of genetic testing for long QT syndrome in the Canadian public health-care system

PubMed Central

Ali-Khan, Sarah E; Gold, E Richard

2017-01-01

Purpose Although the Supreme Court of the United States limited their availability in Association for Molecular Pathology v. Myriad Genetics, gene patents remain important around the world. We examine the situation in Canada, where gene patents continue to exist, in light of recent litigation relating to familial long QT syndrome (LQTS). Methods We conducted in-depth semistructured interviews with 25 stakeholders across five Canadian provinces and supplemented this with a case analysis of the litigation. Results The majority of LQTS testing was carried out outside Canada. Rising costs prompted several provinces to attempt to repatriate testing. However, LQTS gene patents stymied efforts, particularly in provinces where testing was more centralized, increasing costs and lowering innovation. It was in this context that a hospital launched a test case against the LQTS patents, resulting in a novel agreement to free Canadian hospitals from the effects of patents. Conclusion Our analysis reveals a rapidly evolving genetic test provision landscape under pressure from gene patents, strained budgets and poor collaboration. The litigation resulted in a blueprint for free public use of gene patents throughout Canada's health-care system, but it will only have value if governments are proactive in its use. PMID:28492533

Multiple Independent Genetic Factors at NOS1AP Modulate the QT Interval in a Multi-Ethnic Population

PubMed Central

Arking, Dan E.; Khera, Amit; Xing, Chao; Kao, W. H. Linda; Post, Wendy; Boerwinkle, Eric; Chakravarti, Aravinda

2009-01-01

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6×10−5) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP × sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63×10−8), as well as the sex-interaction with rs16847548 (P = 8.68×10−6). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval. PMID:19180230

Relationships between QT interval and heart rate variability at rest and the covariates in healthy young adults.

PubMed

Arai, Kaori; Nakagawa, Yui; Iwata, Toyoto; Horiguchi, Hyogo; Murata, Katsuyuki

2013-01-01

To clarify the links between ECG QT-related parameters and heart rate variability (HRV) and the covariates possibly distorting them, the averaged RR and QT intervals in a single lead ECG were measured for 64 male and 86 female subjects aged 18-26. The QT index, defined by Rautaharju et al., in the young adults was not significantly related to any HRV parameters nor heart rate, but the Bazett's corrected QT (QTc) interval was associated negatively with the parasympathetic activity and positively with heart rate. No significant differences in the QTc interval, QT index or heart rate were seen between the men and women, but they significantly differed between both sexes after adjustment for possible covariates such as age and body mass index (BMI). Significant sex differences in parasympathetic parameters of the HRV were unchanged before and after the adjustment, but significant differences observed in the unadjusted sympathetic parameters disappeared after adjusting for covariates. Age, BMI and body fat percentage also were significant covariates affecting these ECG parameters. Consequently, QT index, unaffected by heart rate and HRV parameters, appears to be a more useful indicator than the QTc interval. Instead, the QT index and HRV parameters are recommended to be simultaneously measured in epidemiological research because they are probably complementary in assessing autonomic nervous function. Also, these parameters should be analyzed in men and women separately. Copyright © 2012 Elsevier B.V. All rights reserved.

Prolonged QT interval in a man with anorexia nervosa

PubMed Central

Macías-Robles, María Dolores; Perez-Clemente, Ana María; Maciá-Bobes, Carmen; Alvarez-Rueda, María Asunción; Pozo-Nuevo, Sergio

2009-01-01

Anorexia nervosa is an eating disorder characterized by the avoidance of food intake, which usually leads to a weight loss. Cardiac co-morbility is common and we can find sometimes a mass loss from the left ventricle, which can be seen by echocardiography. But the commonest complications are rhythm variations, typically bradycardia with a prolonged QT interval in up to a 40% of the cases, which altogether elevates ventricular tachycardia and sudden death risk. We present the case of a male who was diagnosed with anorexia nervosa and developed asthenia, a long QT interval and also a severe both hypokalaemia and hypomagnesaemia. We intend to discuss the pathogenic paths as well as prophylactic and therapeutic measures to this potentially-lethal pathology. PMID:19646241

Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective.

PubMed

Pollard, C E; Valentin, J-P; Hammond, T G

2008-08-01

Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

UrQt: an efficient software for the Unsupervised Quality trimming of NGS data.

PubMed

Modolo, Laurent; Lerat, Emmanuelle

2015-04-29

Quality control is a necessary step of any Next Generation Sequencing analysis. Although customary, this step still requires manual interventions to empirically choose tuning parameters according to various quality statistics. Moreover, current quality control procedures that provide a "good quality" data set, are not optimal and discard many informative nucleotides. To address these drawbacks, we present a new quality control method, implemented in UrQt software, for Unsupervised Quality trimming of Next Generation Sequencing reads. Our trimming procedure relies on a well-defined probabilistic framework to detect the best segmentation between two segments of unreliable nucleotides, framing a segment of informative nucleotides. Our software only requires one user-friendly parameter to define the minimal quality threshold (phred score) to consider a nucleotide to be informative, which is independent of both the experiment and the quality of the data. This procedure is implemented in C++ in an efficient and parallelized software with a low memory footprint. We tested the performances of UrQt compared to the best-known trimming programs, on seven RNA and DNA sequencing experiments and demonstrated its optimality in the resulting tradeoff between the number of trimmed nucleotides and the quality objective. By finding the best segmentation to delimit a segment of good quality nucleotides, UrQt greatly increases the number of reads and of nucleotides that can be retained for a given quality objective. UrQt source files, binary executables for different operating systems and documentation are freely available (under the GPLv3) at the following address: https://lbbe.univ-lyon1.fr/-UrQt-.html .

Pharmacokinetics and effect on the corrected QT interval of single-dose escitalopram in healthy elderly compared with younger adults.

PubMed

Chung, Hyewon; Kim, Anhye; Lim, Kyoung Soo; Park, Sang-In; Yu, Kyung-Sang; Yoon, Seo Hyun; Cho, Joo-Youn; Chung, Jae-Yong

2017-01-01

Escitalopram is the (S)-enantiomer of citalopram that has a potential QT prolonging effect. In this study, 12 healthy elderly individuals received a single oral dose of escitalopram (20 mg), and their pharmacokinetics and QT effect data were compared with data from 33 younger adults obtained in a previous study. Serial blood samples for pharmacokinetic analysis were collected and ECG was performed up to 48 h postdose. The elderly and younger adults showed similar pharmacokinetic profiles. The geometric mean ratios (90% confidence interval) of the elderly compared with the younger adults were 1.02 (0.89-1.17) and 1.01 (0.86-1.17) for the maximum plasma concentration and area under the concentration-time curve, respectively. The mean baseline-adjusted QT (dQT) time profiles were similar and the mean values of maximum dQT were not significantly different between the elderly and the younger adults. The linear mixed-effect model indicated a weak but positive relationship between the escitalopram concentration and dQT, with an estimated coefficient of concentration of 0.43-0.54. In conclusion, the pharmacokinetics and QT effect of a single dose of escitalopram observed in the elderly without comorbidities and younger adults were generally similar.

Coffee, alcohol, smoking, physical activity and QT interval duration: results from the Third National Health and Nutrition Examination Survey.

PubMed

Zhang, Yiyi; Post, Wendy S; Dalal, Darshan; Blasco-Colmenares, Elena; Tomaselli, Gordon F; Guallar, Eliseo

2011-02-28

Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration. We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988-1994). Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview. In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were -1.2 ms (95% CI -4.4 to 2.0) for coffee, and -2.0 ms (-11.2 to 7.3) for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (-0.6 to 2.9) while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (-0.5 to 4.0). The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3) and 4.0 ms (1.6 to 6.4), respectively. The corresponding differences in women were 1.1 (-2.9 to 5.2) and 1.7 ms (-2.3 to 5.7). Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was -0.8 ms (-3.0 to 1.4). Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity.

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with ankylosing spondylitis.

PubMed

Acar, Gurkan; Yorgun, Hikmet; Inci, Mehmet Fatih; Akkoyun, Murat; Bakan, Betul; Nacar, Alper Bugra; Dirnak, Imran; Cetin, Gozde Yildirim; Bozoglan, Orhan

2013-04-12

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic multi-systemic inflammatory rheumatic disorder. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with AS, and to assess the relation with inflammation. METHODS: Sixty-two patients with AS and 50 controls were included. Tp-e interval and Tp-e/QT ratio were measured from a 12-lead electrocardiogram, and the Tp-e interval corrected for heart rate. The plasma level of high sensitive C-reactive protein (hsCRP) was measured. These parameters were compared between groups. RESULTS: In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in AS patients compared to the controls (31.7 ± 9.6 vs 28.2 ± 7.4 and 35.8 ± 11.5 vs 30.6 ± 7.9 ms, P = 0.03 and P = 0.007, respectively). cTp-e interval and Tp-e/QT ratio were also significantly higher in AS patients (92.1 ± 10.2 vs 75.8 ± 8.4 and 0.22 ± 0.02 vs 0.19 ± 0.02 ms, all P values <0.001). cTp-e interval and Tp-e/QT ratio were significantly correlated with hsCRP (r = 0.63, P < 0.001 and r = 0.49, P < 0.001, respectively). CONCLUSIONS: Our study revealed that Tp-e interval and Tp-e/QT ratio were increased in AS patients. These electrocardiographic ventricular repolarization indexes were significantly correlated with the plasma level of hsCRP.

The Half RR Rule: A Poor Rule of Thumb and Not a Risk Assessment Tool for QT Interval Prolongation.

PubMed

Berling, Ingrid; Isbister, Geoffrey K

2015-10-01

Measuring the QT interval on an electrocardiogram (ECG) is integral to risk assessment of Torsade de Pointes (TdP). This study aimed to investigate the accuracy of the 1/2 RR rule as a risk assessment tool for drug-induced TdP, comparing it to the QT nomogram, Bazett's corrected QT (QTcB), and Fridericia's corrected QT (QTcF). The authors calculated sensitivity and specificity of the 1/2 RR rule using a published data set of 129 cases of drug-induced TdP and 316 controls (noncardiotoxic overdoses), compared to the QT nomogram, QTcB > 500 msec and QTcF > 500 msec. To further determine the value of the 1/2 RR rule, its observed positive, and negative agreement were calculated when compared to the QT nomogram for determining an abnormal QT in eight samples of different drugs in overdose. The sensitivity and specificity of the 1/2 RR rule were 88% (95% confidence interval [CI] = 80% to 93%) and 53% (95% CI = 47% to 58%), respectively, compared to the QT nomogram (sensitivity = 97%, 95% CI = 92% to 99%; specificity = 99%, 95% CI = 97% to 100%). It was also less sensitive than QTcB > 500 msec and had a lower specificity than QTcB > 500 msec and QTcF > 500 msec. In drug overdose patients, the 1/2 RR rule had poor observed agreement averaging 41%, which was mainly due to poor positive agreement, except for amisulpride where there was good agreement. The 1/2 RR rule was not as sensitive as the QT nomogram or QTcB > 500 msec for drug-induced TdP. It had poor positive agreement in almost all overdose patients, resulting in over half of patients receiving unnecessary cardiac monitoring and repeat ECGs. © 2015 by the Society for Academic Emergency Medicine.

Adjustment of QT dispersion assessed from 12 lead electrocardiograms for different numbers of analysed electrocardiographic leads: comparison of stability of different methods.

PubMed Central

Hnatkova, K; Malik, M; Kautzner, J; Gang, Y; Camm, A J

1994-01-01

OBJECTIVE--Normal electrocardiographic recordings were analysed to establish the influence of measurement of different numbers of electrocardiographic leads on the results of different formulas expressing QT dispersion and the effects of adjustment of QT dispersion obtained from a subset of an electrocardiogram to approximate to the true QT dispersion obtained from a complete electrocardiogram. SUBJECTS AND METHODS--Resting 12 lead electrocardiograms of 27 healthy people were investigated. In each lead, the QT interval was measured with a digitising board and QT dispersion was evaluated by three formulas: (A) the difference between the longest and the shortest QT interval among all leads; (B) the difference between the second longest and the second shortest QT interval; (C) SD of QT intervals in different leads. For each formula, the "true" dispersion was assessed from all measurable leads and then different combinations of leads were omitted. The mean relative differences between the QT dispersion with a given number of omitted leads and the "true" QT dispersion (mean relative errors) and the coefficients of variance of the results of QT dispersion obtained when omitting combinations of leads were compared for the different formulas. The procedure was repeated with an adjustment of each formula dividing its results by the square root of the number of measured leads. The same approach was used for the measurement of QT dispersion from the chest leads including a fourth formula (D) the SD of interlead differences weighted according to the distances between leads. For different formulas, the mean relative errors caused by omitting individual electrocardiographic leads were also assessed and the importance of individual leads for correct measurement of QT dispersion was investigated. RESULTS--The study found important differences between different formulas for assessment of QT dispersion with respect to compensation for missing measurements of QT interval. The

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation.

PubMed

Spätjens, Roel L H M G; Bébarová, Markéta; Seyen, Sandrine R M; Lentink, Viola; Jongbloed, Roselie J; Arens, Yvonne H J M; Heijman, Jordi; Volders, Paul G A

2014-10-01

Mutations in KCNQ1, encoding for Kv7.1, the α-subunit of the IKs channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.Lys557Glu (K557E) Kv7.1 mutation, identified in a Dutch kindred, at baseline and during (mimicked) increased adrenergic tone. K557E carriers had moderate QTc prolongation that augmented significantly during exercise. IKs characteristics were determined after co-expressing Kv7.1-wild-type (WT) and/or K557E with minK and Yotiao in Chinese hamster ovary cells. K557E caused IKs loss of function with slowing of the activation kinetics, acceleration of deactivation kinetics, and a rightward shift of voltage-dependent activation. Together, these contributed to a dominant-negative reduction in IKs density. Confocal microscopy and western blot indicated that trafficking of K557E channels was not impaired. Stimulation of WT IKs by 3'-5'-cyclic adenosine monophosphate (cAMP) generated strong current up-regulation that was preserved for K557E in both hetero- and homozygosis. Accumulation of IKs at fast rates occurred both in WT and in K557E, but was blunted in the latter. In a computational model, K557E showed a loss of action potential shortening during β-adrenergic stimulation, in accordance with the lack of QT shortening during exercise in patients. K557E causes IKs loss of function with reduced fast rate-dependent current accumulation. cAMP-dependent stimulation of mutant IKs is preserved, but incapable of fully compensating for the baseline current reduction, explaining the long QT intervals at baseline and the abnormal QT accommodation during exercise in affected patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Coffee, Alcohol, Smoking, Physical Activity and QT Interval Duration: Results from the Third National Health and Nutrition Examination Survey

PubMed Central

Zhang, Yiyi; Post, Wendy S.; Dalal, Darshan; Blasco-Colmenares, Elena; Tomaselli, Gordon F.; Guallar, Eliseo

2011-01-01

Background Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration. Methods We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988–1994). Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview. Results In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were −1.2 ms (95% CI −4.4 to 2.0) for coffee, and −2.0 ms (−11.2 to 7.3) for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (−0.6 to 2.9) while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (−0.5 to 4.0). The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3) and 4.0 ms (1.6 to 6.4), respectively. The corresponding differences in women were 1.1 (−2.9 to 5.2) and 1.7 ms (−2.3 to 5.7). Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was −0.8 ms (−3.0 to 1.4). Conclusion Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity. PMID

Roles of A-Kinase Anchoring Proteins and Phosphodiesterases in the Cardiovascular System

PubMed Central

Ercu, Maria; Klussmann, Enno

2018-01-01

A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3′-5′ monophosphate (cAMP) signaling cascade. They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. Various members of the AKAP and PDE families are expressed in the cardiovascular system and direct important processes maintaining homeostatic functioning of the heart and vasculature, e.g., the endothelial barrier function and excitation-contraction coupling. Dysregulation of AKAP and PDE function is associated with pathophysiological conditions in the cardiovascular system including heart failure, hypertension and atherosclerosis. A number of diseases, including autosomal dominant hypertension with brachydactyly (HTNB) and type I long-QT syndrome (LQT1), result from mutations in genes encoding for distinct members of the two classes of enzymes. This review provides an overview over the AKAPs and PDEs relevant for cAMP compartmentalization in the heart and vasculature and discusses their pathophysiological role as well as highlights the potential benefits of targeting these proteins and their protein-protein interactions for the treatment of cardiovascular diseases. PMID:29461511

Cardiac conductive disturbance in patients with polycystic ovary syndrome.

PubMed

Huang, Jen-Hung; Tsai, Jen-Chen; Hsu, Ming-I; Chen, Yi-Jen

2010-12-01

Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality of reproductive-aged women and increases the risk of cardiovascular disease. However, the effects of PCOS on electrocardiograms (ECGs) are not fully elucidated. The aim of this study was to evaluate the characteristics of ECGs in patients with PCOS. This study included 24 patients with PCOS and 12 patients without PCOS. The heart rate, PR interval, QRS duration, Sokolow-Lyon voltage (SV1 + RV5/6), Cornell voltage (RaVL + SV3), QT interval and QTc interval were measured in 12-lead ECGs. The QRS duration was wider in patients with PCOS than those without PCOS (91 ± 8 vs. 81 ± 10 ms, p < 0.05). The heart rate, PR interval, Sokolow-Lyon voltage, product of the QRS duration times Cornell voltage combination, QT interval, QTc interval, QT dispersion and QTc dispersion were similar between the two groups. PCOS is associated with a widening QRS duration, which may contribute to its increased cardiovascular risks.

Impact of ancestry and common genetic variants on QT interval in African Americans.

PubMed

Smith, J Gustav; Avery, Christy L; Evans, Daniel S; Nalls, Michael A; Meng, Yan A; Smith, Erin N; Palmer, Cameron; Tanaka, Toshiko; Mehra, Reena; Butler, Anne M; Young, Taylor; Buxbaum, Sarah G; Kerr, Kathleen F; Berenson, Gerald S; Schnabel, Renate B; Li, Guo; Ellinor, Patrick T; Magnani, Jared W; Chen, Wei; Bis, Joshua C; Curb, J David; Hsueh, Wen-Chi; Rotter, Jerome I; Liu, Yongmei; Newman, Anne B; Limacher, Marian C; North, Kari E; Reiner, Alexander P; Quibrera, P Miguel; Schork, Nicholas J; Singleton, Andrew B; Psaty, Bruce M; Soliman, Elsayed Z; Solomon, Allen J; Srinivasan, Sathanur R; Alonso, Alvaro; Wallace, Robert; Redline, Susan; Zhang, Zhu-Ming; Post, Wendy S; Zonderman, Alan B; Taylor, Herman A; Murray, Sarah S; Ferrucci, Luigi; Arking, Dan E; Evans, Michele K; Fox, Ervin R; Sotoodehnia, Nona; Heckbert, Susan R; Whitsel, Eric A; Newton-Cheh, Christopher

2012-12-01

Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN. We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

Evaluation of Tp-E Interval and Tp-E/QT Ratio in Patients with Aortic Stenosis.

PubMed

Yayla, Çağrı; Bilgin, Murat; Akboğa, Mehmet Kadri; Gayretli Yayla, Kadriye; Canpolat, Uğur; Dinç Asarcikli, Lale; Doğan, Mehmet; Turak, Osman; Çay, Serkan; Özeke, Özcan; Akyel, Ahmet; Yeter, Ekrem; Aydoğdu, Sinan

2016-05-01

The risk of syncope and sudden cardiac death due to ventricular arrhythmias increased in patients with aortic stenosis (AS). Recently, it was shown that Tp-e interval, Tp-e/QT, and Tp-e/QTc ratio can be novel indicators for prediction of ventricular arrhythmias and mortality. We aimed to investigate the association between AS and ventricular repolarization using Tp-e interval and Tp-e/QT ratio. Totally, 105 patients with AS and 60 control subjects were enrolled to this study. The severity of AS was defined by transthoracic echocardiographic examination. Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were measured from the 12-lead electrocardiogram. Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were significantly increased in parallel to the severity of AS (P < 0.001, P = 0.001, and P = 0.001, respectively). Also, it was shown that Tp-e/QTc ratio had significant positive correlation with mean aortic gradient (r = 0.192, P = 0.049). In multivariate logistic regression analysis, Tp-e/QTc ratio and left ventricular mass were found to be independent predictors of severe AS (P = 0.03 and P = 0.04, respectively). Our study showed that Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were increased in patients with severe AS. Tp-e/QTc ratio and left ventricular mass were found as independent predictors of severe AS. © 2015 Wiley Periodicals, Inc.

Assessments of the QT/QRS restitution in perfused guinea-pig heart can discriminate safe and arrhythmogenic drugs.

PubMed

Osadchii, Oleg E

2017-09-01

Drug-induced arrhythmia remains a matter of serious clinical concern, partly due to low prognostic value of currently available arrhythmic biomarkers. This study examined whether arrhythmogenic risks can be predicted through assessments of the rate adaptation of QT interval, ventricular effective refractory period (ERP), or the QT/QRS ratio, in perfused guinea-pig hearts. When the maximum restitution slope was taken as a metric of proarrhythmia, neither QT interval nor ERP measurements at progressively increased pacing rates were found to fully discriminate arrhythmogenic drugs (dofetilide, quinidine, flecainide, and procainamide) from those recognized as safe antiarrhythmics (lidocaine and mexiletine). For example, the slope of QT restitution was increased by dofetilide and quinidine, but remained unchanged by flecainide, procainamide, lidocaine, and mexiletine. With ERP rate adaptation, even though the restitution slope was increased by dofetilide, all class I agents reduced the slope value independently of their safety profile. The QRS measurements revealed variable drug effects, ranging from significant use-dependent conduction slowing (flecainide, quinidine, and procainamide) to only modest increase in QRS (lidocaine and mexiletine), or no change at all (dofetilide). However, with the QT/QRS rate adaptation, the restitution slope was significantly increased by all agents which have been reported to produce proarrhythmic effects (dofetilide, quinidine, flecainide, and procainamide), but not changed by lidocaine and mexiletine. These findings suggest that the slope of the QT/QRS rate adaptation can be considered as a novel electrophysiological biomarker in predicting potential arrhythmic risks associated with pharmacotherapy in cardiac patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with non-dipper hypertension.

PubMed

Demir, Mehmet; Uyan, Umut

2014-01-01

Non-dipper hypertension is associated with increased cardiovascular morbidity and mortality. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with non-dipper hypertension. This study included 80 hypertensive patients. Hypertensive patients were divided into two groups: 50 dipper patients (29 male, mean age 51.5 ± 8 years) and 30 non-dipper patients (17 male, mean age 50.6 ± 5.4 years). Tp-e interval and Tp-e/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared between groups. No statistically significant difference was found between two groups in terms of basic characteristics. In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in non-dipper patients compared to the dippers (39.4 ± 11.5 versus 27.3 ± 7.5 ms and 37.5 ± 9.5 versus 29.2 ± 6.5 ms, p = 0.001 and p = 0.01, respectively). Tp-e interval and Tp-e/QT ratio were also significantly higher in non-dipper patients (97.5 ± 11.2 versus 84.2 ± 8.3 ms and 0.23 ± 0.02 versus 0.17 ± 0.02, all p value <0.001). Our study revealed that QTd, Tp-e interval and Tp-e/QT ratio are prolonged in patients with non-dipper hypertension.

PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans.

PubMed

Marostica, Eleonora; Van Ammel, Karel; Teisman, Ard; Gallacher, David; Van Bocxlaer, Jan; De Ridder, Filip; Boussery, Koen; Vermeulen, An

2016-07-01

Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.

MoleCoolQt – a molecule viewer for charge-density research

PubMed Central

Hübschle, Christian B.; Dittrich, Birger

2011-01-01

MoleCoolQt is a molecule viewer for charge-density research. Features include the visualization of local atomic coordinate systems in multipole refinements based on the Hansen and Coppens formalism as implemented, for example, in the XD suite. Residual peaks and holes from XDfft are translated so that they appear close to the nearest atom of the asymmetric unit. Critical points from a topological analysis of the charge density can also be visualized. As in the program MolIso, color-mapped isosurfaces can be generated with a simple interface. Apart from its visualization features the program interactively helps in assigning local atomic coordinate systems and local symmetry, which can be automatically detected and altered. Dummy atoms – as sometimes required for local atomic coordinate systems – are calculated on demand; XD system files are updated after changes. When using the invariom database, potential scattering factor assignment problems can be resolved by the use of an interactive dialog. The following file formats are supported: XD, MoPro, SHELX, GAUSSIAN (com, FChk, cube), CIF and PDB. MoleCoolQt is written in C++ using the Qt4 library, has a user-friendly graphical user interface, and is available for several flavors of Linux, Windows and MacOS. PMID:22477783

The Impact of Ancestry and Common Genetic Variants on QT Interval in African Americans

PubMed Central

Smith, J. Gustav; Avery, Christy L.; Evans, Daniel S.; Nalls, Michael A.; Meng, Yan A.; Smith, Erin N.; Palmer, Cameron; Tanaka, Toshiko; Mehra, Reena; Butler, Anne M.; Young, Taylor; Buxbaum, Sarah G.; Kerr, Kathleen F.; Berenson, Gerald S.; Schnabel, Renate B.; Li, Guo; Ellinor, Patrick T.; Magnani, Jared W.; Chen, Wei; Bis, Joshua C.; Curb, J. David; Hsueh, Wen-Chi; Rotter, Jerome I.; Liu, Yongmei; Newman, Anne B.; Limacher, Marian C.; North, Kari E.; Reiner, Alexander P.; Quibrera, P. Miguel; Schork, Nicholas J.; Singleton, Andrew B.; Psaty, Bruce M.; Soliman, Elsayed Z.; Solomon, Allen J.; Srinivasan, Sathanur R.; Alonso, Alvaro; Wallace, Robert; Redline, Susan; Zhang, Zhu-Ming; Post, Wendy S.; Zonderman, Alan B.; Taylor, Herman A.; Murray, Sarah S.; Ferrucci, Luigi; Arking, Dan E.; Evans, Michele K.; Fox, Ervin R.; Sotoodehnia, Nona; Heckbert, Susan R.; Whitsel, Eric A.; Newton-Cheh, Christopher

2013-01-01

Background Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death (SCD) and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. Methods and Results First, individual estimates of African and European ancestry were inferred from genome-wide single nucleotide polymorphism (SNP) data in seven population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from electrocardiograms. Second, imputation was performed for 2.8 million SNPs and a genome-wide association (GWA) study of QT interval performed in ten cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (p=0.94). Genome-wide significant associations (p<2.5×10−8) were identified with SNPs at two loci, upstream of the genes NOS1AP (rs12143842, p=2×10−15) and ATP1B1 (rs1320976, p=2×10−10). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low p-values (p<10−5) were observed for SNPs at several other loci previously identified in GWA studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF and PLN. Conclusions We observed no difference in duration of cardiac repolarization with global genetic indices of African ancestry. In addition, our GWA study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include African Americans. PMID:23166209

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nozaki, Yumiko, E-mail: yumiko-nozaki@ds-pharma.co.jp; Honda, Yayoi, E-mail: yayoi-honda@ds-pharma.co.jp; Tsujimoto, Shinji, E-mail: shinji-tsujimoto@ds-pharma.co.jp

2014-07-01

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min formore » 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.« less

QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: a prospective study.

PubMed

Piccirillo, Gianfranco; Magrì, Damiano; Matera, Sabrina; Magnanti, Marzia; Torrini, Alessia; Pasquazzi, Eleonora; Schifano, Erika; Velitti, Stefania; Marigliano, Vincenzo; Quaglione, Raffaele; Barillà, Francesco

2007-06-01

The most widely accepted marker for stratifying the risk of sudden cardiac death (SCD) in post myocardial infarction patients is a depressed left ventricular function. Left ventricular ejection fractions (EF) of 35% or less increase the risk of sudden death but values between 35 and 40% raise concern. The underlying pathophysiological mechanism is sustained ventricular tachycardia or fibrillation, both associated with increased cardiac repolarization variability. We assessed whether the indices of QT variability from a short-term electrocardiographic (ECG) recording predict sudden death. A total of 396 subjects with chronic heart failure (CHF) due to post-ischaemic cardiomyopathy, with an EF between 35 and 40% and in NYHA class I, underwent a 5 min ECG recording to calculate the following variables: QT variance (QT(v)), QT normalized for the square of the mean QT (QTVN), and QT variability index (QTVI). Corrected QT (QT(c)) was calculated from a 12-lead ECG recording. All participants were followed for 5 years. A multivariable survival model indicated that a QTVI greater than or equal to the 80th percentile indicated a high risk of SCD [hazards ratio (HR) 4.6, 95% confidence interval (CI) 1.5-13.4, P = 0.006] and, though to a lesser extent, a high risk of total mortality (HR 2.4, 95% CI 1.2-4.9, P = 0.017). The model including QTVI as a continuous variable confirmed a similar high risk for SCD (HR 2.9, 95% CI 1.3-6.5, P = 0.01) and for total mortality (HR 2.6, 95% CI 1.3-5.2, P = 0.008). Although asymptomatic patients with CHF who have a slightly depressed EF are at low risk of sudden death, the category is extraordinarily numerous. The QTVI could be helpful in stratifying the risk of sudden death in this otherwise undertreated population.

A case report of QT prolongation with glycopyrronium bromide in a patient with chronic tamoxifen use.

PubMed

Chiu, Michael H; Al-Majed, Nawaf S; Stubbins, Ryan; Pollmann, Dylan; Sandhu, Roopinder K

2016-06-14

Glycopyrronium bromide has recently been approved as a once daily maintenance inhalation therapy for moderate to severe chronic obstructive pulmonary disease (COPD). Efficacy and safety trial data have found rare cases of significant QT prolongation. To our knowledge, we describe the first case report of QT prolongation >600 ms with initiation of glycopyrronium bromide in a real world setting. A 78-year-old female with moderate COPD recently started on glycopyrronium bromide, presented to Emergency Department (ED) with syncope. Her past medical history was significant for a left total mastectomy and she had been on Tamoxifen for 9 months. One day prior to her presentation, she had visited a naturopathic clinic for a vitamin infusion resulting in emesis. The following day she continued to feel dizzy and had a witnessed syncopal episode without any reported cardiac or neurological symptoms preceding the event or after regaining consciousness. In the emergency department, she reported dizziness and was found to be hypotensive. Her symptoms completely resolved with intravenous fluids. Lab work was normal however her electrocardiogram (ECG) demonstrated a QTc interval of 603 and 631 ms (Friderica and Bazett's respectively) with a normal QT interval on her baseline ECG prior to initiating Tamoxifen. She was admitted to the Cardiology service for further work-up of QT prolongation. Her syncope was felt to be due to orthostatic hypotension and the QT prolongation secondary to medications, which were both discontinued during her admission. After 2 days, her QT interval normalized consistent with the half-life of Glycopyrronium bromide (13-57 h) compared to Tamoxifen (8-14 days). Glycopyrronium bromide is guideline recommended as first line therapy for prevention of exacerbation in moderate to severe COPD however safety data had been limited to select populations. This case report highlights the need for future studies to identify high-risk populations at potential

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with rheumatoid arthritis.

PubMed

Acar, Gu Rkan; Akkoyun, Murat; Nacar, Alper Bugra; Dirnak, Imran; Yıldırım Çetin, Gözde; Nur Yıldırım, Makbule; Zencir, Cemil; Karaman, Kayıhan; Cetin, Mustafa; Sayarlıoğlu, Mehmet

2014-01-01

Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using the Tp-e interval and Tp-e/QT ratio in patients with rheumatoid arthritis (RA), and to assess the relation with inflammation. Ninety-six patients (72 females, 24 males; mean age 43.8±11.8 years) with RA and 50 controls (35 females, 15 males; mean age 44.2±11.1 years) were included. From the 12-lead electrocardiogram, Tp-e interval and Tp-e/QT ratio were measured. Blood samples were taken for erythrocyte sedimentation rate (ESR) and plasma levels of C-reactive protein (CRP). These parameters were compared between groups. The relationship between ventricular repolarization and inflammation was assessed by Pearson correlation coefficients. Tp-e interval and Tp-e/QT ratio were increased in RA patients compared to the controls (72.6±8.2 vs 66.4±8.5 ms, 0.20±0.02 vs 0.18±0.02; p<0.001 and p<0.001, respectively). The Tp-e interval was significantly correlated with CRP, ESR, and disease activity score (DAS-28) (r=0.56, p<0.001, r=0.57, p<0.001, and r=0.29, p=0.02, respectively). The Tp-e/QT ratio was also correlated with CRP, ESR, and DAS-28 score (r=0.43, p<0.001, r=0.53, p<0.001, and r=0.25, p=0.03, respectively). In RA patients, the increased frequency of ventricular arrhythmias may be explained by increased indexes of ventricular repolarization and their relationship with inflammation.

Common founder effects of hereditary hemochromatosis, Wilson´s disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes.

PubMed

Olsson, K Sigvard; Wålinder, Olof; Jansson, Ulf; Wilbe, Maria; Bondeson, Marie-Louise; Stattin, Eva-Lena; Raha-Chowdhury, Ruma; Williams, Roger

2017-01-01

Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p. C282Y mutation is inherited with other recessive disorders such as Wilson´s disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation ( KCNQ1 /p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL).Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. LQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. Of nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder ( b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjällsjö river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of

Toward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine-Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome.

PubMed

Jouni, Mariam; Si-Tayeb, Karim; Es-Salah-Lamoureux, Zeineb; Latypova, Xenia; Champon, Benoite; Caillaud, Amandine; Rungoat, Anais; Charpentier, Flavien; Loussouarn, Gildas; Baró, Isabelle; Zibara, Kazem; Lemarchand, Patricia; Gaborit, Nathalie

2015-09-01

Human genetically inherited cardiac diseases have been studied mainly in heterologous systems or animal models, independent of patients' genetic backgrounds. Because sources of human cardiomyocytes (CMs) are extremely limited, the use of urine samples to generate induced pluripotent stem cell-derived CMs would be a noninvasive method to identify cardiac dysfunctions that lead to pathologies within patients' specific genetic backgrounds. The objective was to validate the use of CMs differentiated from urine-derived human induced pluripotent stem (UhiPS) cells as a new cellular model for studying patients' specific arrhythmia mechanisms. Cells obtained from urine samples of a patient with long QT syndrome who harbored the HERG A561P gene mutation and his asymptomatic noncarrier mother were reprogrammed using the episomal-based method. UhiPS cells were then differentiated into CMs using the matrix sandwich method.UhiPS-CMs showed proper expression of atrial and ventricular myofilament proteins and ion channels. They were electrically functional, with nodal-, atrial- and ventricular-like action potentials recorded using high-throughput optical and patch-clamp techniques. Comparison of HERG expression from the patient's UhiPS-CMs to the mother's UhiPS-CMs showed that the mutation led to a trafficking defect that resulted in reduced delayed rectifier K(+) current (IKr). This phenotype gave rise to action potential prolongation and arrhythmias. UhiPS cells from patients carrying ion channel mutations can be used as novel tools to differentiate functional CMs that recapitulate cardiac arrhythmia phenotypes. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

PubMed

Holzgrefe, Henry; Ferber, Georg; Champeroux, Pascal; Gill, Michael; Honda, Masaki; Greiter-Wilke, Andrea; Baird, Theodore; Meyer, Olivier; Saulnier, Muriel

2014-01-01

In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax. All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the

Tp-e interval and Tp-e/QT ratio in patients with celiac disease.

PubMed

Demirtaş, K; Yayla, Ç; Yüksel, M; Açar, B; Ünal, S; Ertem, A G; Kaplan, M; Akpinar, M Y; Kiliç, Z M Y; Kayaçetin, E

2017-11-01

Celiac disease is a chronic immune-mediated disease of the small intestine. It has been known that dilated cardiomyopathy and ischemic coronary artery disease have become more frequent in patients with celiac disease. The aim of the study was to assess Tp-e interval and Tp-e/QT ratio in patients with celiac disease. This study was conducted at a single center in collaboration with gastroenterology and cardiology clinics. Between January 2014 and June 2015, a total of 76 consecutive patients were enrolled (38 patients with celiac disease and 38 control subjects). Tp-e interval, Tp-e/QT and Tp-e/QTc ratio were measured from the 12-lead electrocardiogram. Tp-e interval (64.2±11.0 vs. 44.5±6.0; p<0.001), Tp-e/QT ratio (0.18±0.02 vs. 0.13±0.02; p<0.001) and Tp-e/QTc ratio (0.16±0.02 vs. 0.11±0.01; p<0.001) were significantly higher in patients with celiac disease than control subjects. There was a significant positive correlation between Tp-e/QTc ratio and disease duration in patients with celiac disease (r=0.480, p=0.003) and also there was a significant positive correlation between Tp-e/QTc ratio and erythrocyte sedimentation rate (r=0.434, p<0.001). Our study showed that Tp-e interval, Tp-e/QT and Tp-e/QTc ratios were increased in patients with celiac disease. Whether these changes increase the risk of ventricular arrhythmia deserve further studies. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Perioperative management of patients with congenital or acquired disorders of the QT interval.

PubMed

O'Hare, M; Maldonado, Y; Munro, J; Ackerman, M J; Ramakrishna, H; Sorajja, D

2018-04-01

QT prolongation can be attributable to various causes that can be categorised as acquired or congenital. Arrhythmias related to QT prolongation can result in clinical presentations, such as syncope and sudden cardiac death. The perioperative period presents a number of issues that may affect a patient's risk of developing polymorphic ventricular tachycardia or torsades de pointes. Although most patients may have an unremarkable perioperative course, some may have complications; this review article aims to help clinicians avoid potential complications, and to help them address treatment for perioperative issues that may occur. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Genetics Home Reference: ankyrin-B syndrome

MedlinePlus

... beats, which is known as a prolonged QT interval (long QT). Some affected individuals have impaired progression ( ... sudden death. When associated with a prolonged QT interval, the condition is sometimes classified as long QT ...

QT/RR relationship in patients after remote anterior myocardial infarction with left ventricular dysfunction and different types of ventricular arrhythmias.

PubMed

Szydlo, Krzysztof; Trusz-Gluza, Maria; Wita, Krystian; Filipecki, Artur; Orszulak, Witold; Urbanczyk, Dagmara; Krauze, Jolanta; Kolasa, Jaroslaw; Tabor, Zbigniew

2008-01-01

QT/RR relationship was found to be both rate-dependent and rate-independent, what suggests the influence of autonomic drive and other not-autonomic related factors on it. The steeper QT/RR slope in patients after acute myocardial infarction (MI) was described, but the relationship to ventricular arrhythmias is unknown. The purpose of this study was to calculate differences in QT/RR relationship in patients after remote anterior MI with left ventricular dysfunction and different types of ventricular arrhythmias. The cohort of 95 patients (age: 63 +/- 11 years, LVEF: 35 +/- 9%) with previous anterior MI (mean 1.1 years) was divided into two well-matched groups-50 patients without episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) (NoVT/VF: 39 males, 64 +/- 12 years, LVEF 37 +/- 8%) and 45 patients with VT and/or VF (all with ICD implanted) (VT/VF: 35 males, 62 +/- 10 years, LVEF 34 +/- 10%). No true antiarrhythmics were used. QT/RR slope was calculated from 24-hour Holter ECG for the entire recording (E), daytime (D) and nighttime (N) periods. Groups did not differ in basic clinical data (age, LVEF, treatment). QT/RR slopes were steeper in VT/VF than in NoVT/VF group in all analyzed periods: E - 0.195 +/- 0.03 versus 0.15 +/- 0.03 (P < 0.001), N - 0.190 +/- 0.03 versus 0.138 +/- 0.03 (P < 0.001) and D - 0.200 +/- 0.04 versus 0.152 +/- 0.03 (P < 0.001). No significant day-to-night differences were found in both groups. Steeper QT/RR slope and complete lack of day-to-night differences in VT/VF patients show inappropriate QT adaptation to the heart rate changes. The prognostic significance of this parameter needs prospective studies.

The QT interval in lightning injury with implications for the cessation of metabolism hypothesis

NASA Technical Reports Server (NTRS)

Andrews, Christopher J.; Colquhoun, David M.; Darveniza, Mat

1991-01-01

An hypothesis is presented to provide an alternative to the Cessation of Metabolism hypothesis often invoked in lightning injury. Cessation of Metabolism has been proposed to explain the observation of good recovery after a prolonged period in cardiac arrest in some lightning injured patients. Reevaluation of EEGs from lightning injured patients show a high incidence of QT prolongation. Reexamination of the cases used to support Cessation of Metabolism also reveals little evidence to justify the hypothesis. The finding of QT prolongation coupled with the hyperadrenergic state said to exist in lightning injury, may promote a state of episodic induction of and recovery from Torsade de Pointes Ventricular Tachycardia (VT). Histological examination of the myocardium supports the new hypothesis. This the first concerted description of lightning injury as one of the general causes of QT prolongation. It appears to occur frequently after lightning injury, is a prerequisite of and predisposes to episodes of Torsade de Pointes VT. These electrocardiographic abnormalities explain Cessation of Metabolism and recognition may change management and lead to greater survival.

Analyzing Thorough QT Study 1 & 2 in the Telemetric and Holter ECG Warehouse (THEW) using Hannover ECG System HES : A validation study.

PubMed

Khawaja, A; Petrovic, R; Safer, A; Baas, T; Dössel, O; Fischer, R

2010-01-01

Following the ICH E14 clinical evaluation guideline [1], the measurement of QT/QTc interval prolongation has become the standard surrogate biomarker for cardiac drug safety assessment and the faith of a drug development. In Thorough QT (TQT) study, a so-called positive control is employed to assess the ability of this study to detect the endpoint of interest, i.e. the QT prolongation by about five milliseconds. In other words the lower bound of the one-sided 95% confidence interval (CI) must be above 0 [ms]. Fully automated detection of ECG fiducial points and measurement of the corresponding intervals including QT intervals and RR intervals vary between different computerized algorithms. In this work we demonstrate the ability and reliability of Hannover ECG System (HES(®)) to assess drug effects by detecting QT/QTc prolongation effects that meet the threshold of regulatory concern as mentioned by using THEW database studies namely TQT studies one and two.

[Effect of pazufloxacin mesilate, a new quinolone antibacterial agent, for intravenous use on QT interval].

PubMed

Fukuda, Hitoshi; Morita, Yukie; Shiotani, Norio; Mizuo, Midori; Komae, Norihisa

2004-08-01

The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies. Following results were obtained. In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD). Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter. In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg. These results suggest that PZFX mesilate has low potential for QT interval prolongation.

Gene-environment interaction between SCN5A-1103Y and hypokalemia influences QT interval prolongation in African Americans: the Jackson Heart Study.

PubMed

Akylbekova, Ermeg L; Payne, John P; Newton-Cheh, Christopher; May, Warren L; Fox, Ervin R; Wilson, James G; Sarpong, Daniel F; Taylor, Herman A; Maher, Joseph F

2014-01-01

African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established. We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval. The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P < .001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P < .001). Hypokalemia was associated with diuretic use (78%; P < .001). SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y. © 2014.

Atrioventricular junction (AVJ) motion tracking: a software tool with ITK/VTK/Qt.

PubMed

Pengdong Xiao; Shuang Leng; Xiaodan Zhao; Hua Zou; Ru San Tan; Wong, Philip; Liang Zhong

2016-08-01

The quantitative measurement of the Atrioventricular Junction (AVJ) motion is an important index for ventricular functions of one cardiac cycle including systole and diastole. In this paper, a software tool that can conduct AVJ motion tracking from cardiovascular magnetic resonance (CMR) images is presented by using Insight Segmentation and Registration Toolkit (ITK), The Visualization Toolkit (VTK) and Qt. The software tool is written in C++ by using Visual Studio Community 2013 integrated development environment (IDE) containing both an editor and a Microsoft complier. The software package has been successfully implemented. From the software engineering practice, it is concluded that ITK, VTK, and Qt are very handy software systems to implement automatic image analysis functions for CMR images such as quantitative measure of motion by visual tracking.

Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation.

PubMed

Malik, Marek; Hnatkova, Katerina; Batchvarov, Velislav; Gang, Yi; Smetana, Peter; Camm, A John

2004-12-01

Regulatory authorities require new drugs to be investigated using a so-called "thorough QT/QTc study" to identify compounds with a potential of influencing cardiac repolarization in man. Presently drafted regulatory consensus requires these studies to be powered for the statistical detection of QTc interval changes as small as 5 ms. Since this translates into a noticeable drug development burden, strategies need to be identified allowing the size and thus the cost of thorough QT/QTc studies to be minimized. This study investigated the influence of QT and RR interval data quality and the precision of heart rate correction on the sample sizes of thorough QT/QTc studies. In 57 healthy subjects (26 women, age range 19-42 years), a total of 4,195 drug-free digital electrocardiograms (ECG) were obtained (65-84 ECGs per subject). All ECG parameters were measured manually using the most accurate approach with reconciliation of measurement differences between different cardiologists and aligning the measurements of corresponding ECG patterns. From the data derived in this measurement process, seven different levels of QT/RR data quality were obtained, ranging from the simplest approach of measuring 3 beats in one ECG lead to the most exact approach. Each of these QT/RR data-sets was processed with eight different heart rate corrections ranging from Bazett and Fridericia corrections to the individual QT/RR regression modelling with optimization of QT/RR curvature. For each combination of data quality and heart rate correction, standard deviation of individual mean QTc values and mean of individual standard deviations of QTc values were calculated and used to derive the size of thorough QT/QTc studies with an 80% power to detect 5 ms QTc changes at the significance level of 0.05. Irrespective of data quality and heart rate corrections, the necessary sample sizes of studies based on between-subject comparisons (e.g., parallel studies) are very substantial requiring >140

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

PubMed Central

Taubel, Jorg; Naseem, Asif; Harada, Tomohiko; Wang, Duolao; Arezina, Radivoj; Lorch, Ulrike; Camm, A John

2010-01-01

AIMS To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. METHODS Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. RESULTS Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. CONCLUSIONS Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms. PMID:20406223

QT Interval Prolongation and QRS Voltage Reduction in Patients with Liver Cirrhosis.

PubMed

Cichoż-Lach, Halina; Tomaszewski, Michał; Kowalik, Agnieszka; Lis, Emilia; Tomaszewski, Andrzej; Lach, Tomasz; Boczkowska, Sylwia; Celiński, Krzysztof

2015-01-01

Liver cirrhosis is associated with functional abnormalities of the cardiovascular system with co-existing electrocardiographic (ECG) abnormalities. The aim was to analyze ECG changes in patients with cirrhosis, to evaluate whether alcoholic etiology of cirrhosis and ascites has an impact on ECG changes. The study involved 81 patients with previously untreated alcoholic cirrhosis (64 patients with ascites, classes B and C according to the Child-Pugh classification; and 17 without ascites, categorized as class A); 41 patients with previously untreated cirrhosis due to chronic hepatitis C (HCV--30 patients with ascites, classes B and C; and 11 without ascites, class A); 42 with alcoholic steatohepatitis and 46 with alcoholic steatosis. The control group consisted of 32 healthy volunteers. Twelve-lead ECG recordings were performed and selected parameters were measured. Significantly longer QT and QTc intervals and lower QRS voltage were found in patients with alcoholic and HCV cirrhosis compared to the controls. Significantly lower QRS voltage was found in subjects with ascites than in those without ascites. Removal of ascites significantly increased QRS voltage. In cirrhosis, irrespective of etiology, ECG changes involved prolonged QT and QTc intervals and reduced QRS voltage. Prolonged QT and QTc intervals were not related to the severity of cirrhosis or to the presence of ascites. However, low QRS voltage was associated with the presence of ascites. Removal of ascites reverses low QRS voltage.

T-wave alternans and dispersion of the QT interval as risk stratification markers in patients susceptible to sustained ventricular arrhythmias

NASA Technical Reports Server (NTRS)

Armoundas, A. A.; Osaka, M.; Mela, T.; Rosenbaum, D. S.; Ruskin, J. N.; Garan, H.; Cohen, R. J.

1998-01-01

T-wave alternans and QT dispersion were compared as predictors of the outcome of electrophysiologic study and arrhythmia-free survival in patients undergoing electrophysiologic evaluation. T-wave alternans was a highly significant predictor of these 2 outcome variables, whereas QT dispersion was not.

Prediction of Thorough QT study results using action potential simulations based on ion channel screens.

PubMed

Mirams, Gary R; Davies, Mark R; Brough, Stephen J; Bridgland-Taylor, Matthew H; Cui, Yi; Gavaghan, David J; Abi-Gerges, Najah

2014-01-01

Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development. Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms - IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration-effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration. Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1Hz and running to steady state, for a range of concentrations. We compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥5ms was predicted with up to 79% sensitivity and 100% specificity. This study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety

QT effect of semagacestat at therapeutic and supratherapeutic doses.

PubMed

Zhang, Wei; Ayan-Oshodi, Mosun; Willis, Brian A; Annes, William; Hall, Stephen D; Chiesa, Joseph; Seger, Mary

2012-04-01

This thorough QT/ QT interval corrected for heart rate (QTc) study was designed to assess the potential of semagacestat, a functional gamma-secretase inhibitor, to delay cardiac repolarization. In this Phase I, single-dose, randomized, 4-period crossover study, semagacestat was compared with placebo in 54 healthy male and female subjects between the ages of 19 and 63 years, inclusive. Each study period included single oral-dose administrations of semagacestat 140 mg, semagacestat 280 mg, moxifloxacin 400 mg, or placebo. Study subjects and the investigator were blinded to the identity of semagacestat and placebo; however, moxifloxacin was administered as open-label. Moxifloxacin was compared with placebo for assay sensitivity analysis. Pharmacokinetic parameters were also assessed. For each QTc, the upper bound of the 2-sided 90% confidence interval (CI) for the least squares mean difference between semagacestat (at both the 140- and 280-mg dose levels) and placebo was < 10 msec at all time points, and thus, within the limits set for clinical relevance in regulatory guidelines. The results of this study indicate that single doses of 140 and 280 mg semagacestat did not prolong QTc to a clinically significant degree.

ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies.

PubMed

Shah, Rashmi R; Morganroth, Joel

2013-04-01

The International Conference on Harmonization (ICH) guidance ICH E14 provides recommendations, focusing on a clinical 'thorough QT/QTc (TQT) study', to evaluate the QT liability of a drug during its development. An Implementation Working Group (IWG) was also established to assist the sponsors with any uncertainties and clarify any ambiguities. In April 2012, the IWG updated its June 2008 version of the Questions and Answers document to address additional issues. These include the gender of the study population, a reasonable approach to evaluating QTc changes in late stage clinical development and the recommended approach to correcting the measured QT interval. This commentary provides our observations and, when appropriate, recommendations, on these issues. We review briefly evidence that suggests that (i) the greater QT effect observed in females is not entirely related to differences in drug exposure and (ii) the Fridericia correction of measured QT interval is adequate for a majority of TQT studies. Until further evidence suggests otherwise, we recommend balanced gender representation in TQT studies, unless warranted otherwise, and for positive studies, subgroup analysis of key data by common demographic variables including the gender and ethnicity. We provide a general scheme for ECG monitoring in late phase clinical trials and consider that while intensive monitoring and centralized reading of ECGs in late phase clinical trials is the norm when a TQT study is positive, there are other circumstances that also call for high quality ECG reading. Therefore, locally read ECGs should only be acceptable as long as accurate high quality ECG data can be guaranteed. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects

PubMed Central

Shin, Jae-Gook; Kang, Won-ku; Shon, Ji-Hong; Arefayene, Million; Yoon, Young-Ran; Kim, Kyung-Ah; Kim, Doo-Il; Kim, Dong-Soo; Cho, Kwang-Hyun; Woosley, Raymond L; Flockhart, David A

2007-01-01

Aims The aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in healthy Caucasian and Korean subjects to investigate interethnic differences in susceptibility to drug-induced arrhythmia. Methods A randomized, double-blind crossover study was conducted in 24 (12 male and 12 female) Korean and 13 (seven male and six female) Caucasian subjects. After a 20 min infusion of quinidine (4 mg kg−1) or saline, the serum concentration of quinidine and the QT interval corrected by Bazett's formula (QTc) were monitored. The dynamic data were analyzed by means of a population modelling approach using NONMEM. Results There were no statistical differences in the pharmacokinetic profiles of quinidine between ethnic groups. The QTc values in Caucasians were higher than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations and in female subjects. According to an Emax model , the population modelling approach revealed that E0 (ms) was related to gender (408 + [34*(1 − Sex)]; 1 for male and 0 for female), ΔEmax (ms) was related to ethnicity ((136*fETHN) + Cfemale: fETHN = 1 for Koreans and 1.26 for Caucasians; Cfemale was 106 only for Caucasian females), and EC50 was estimated to be 3.13 µm. Conclusions These results suggest that Korean subjects were less sensitive to quinidine-induced QT prolongation than Caucasian subjects, and that this trend was particularly true for females. Further population-based studies are merited to characterize more completely the ethnic differences in drug-induced QT prolongation between Asians and other ethnic groups. PMID:17096683

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

PubMed

de Jong, Jan; Hellemans, Peter; Jiao, James Juhui; Huang, Yuhan; Mesens, Sofie; Sukbuntherng, Juthamas; Ouellet, Daniele

2017-12-01

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max . Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.

Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene

PubMed Central

Moss, Arthur J.; Shimizu, Wataru; Wilde, Arthur A.M.; Towbin, Jeffrey A.; Zareba, Wojciech; Robinson, Jennifer L.; Qi, Ming; Vincent, G. Michael; Ackerman, Michael J.; Kaufman, Elizabeth S.; Hofman, Nynke; Seth, Rahul; Kamakura, Shiro; Miyamoto, Yoshihiro; Goldenberg, Ilan; Andrews, Mark L.; McNitt, Scott

2012-01-01

Background Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. Methods and Results We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. Conclusions This genotype–phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder. PMID:17470695

Efficacy and safety of cell-associated vaccines against Marek's disease virus grown in QT35 cells or JBJ-1 cells.

PubMed

Geerligs, Harm; Spijkers, Ine; Rodenberg, Jeff

2013-06-01

The Marek's disease virus (MDV) vaccine strain CVI 988 usually is grown in primary chicken embryo fibroblasts (CEFs). We found that the strains could be grown also in the QT35 and JBJ-1 cell lines to titers in the same range as in the CEFs. Both cell lines are fibroblast-like cell lines, which can be grown in flat-bottomed tissue-culture flasks, roller bottles, and on microcarriers. For growth in QT35 cells it was necessary to adapt the virus to the cell line; for growth in JBJ-1 cells this was not necessary. We investigated the efficacy of experimental CVI 988 vaccines grown in QT35 cells and JBJ-1 cells. The efficacy studies were performed in accordance with European Pharmacopoeia (EP) monograph for live MDV disease vaccines. Groups of 1-day-old specific-pathogen-free chicks were vaccinated. Nonvaccinated control groups were included in the studies. Five to 7 days after vaccination all chickens were challenged with the very virulent MDV strain RB1B. After challenge the chickens were observed for a period of 70 days for signs of MD. The protection induced by CVI 988 grown in QT35 cells as well as JBJ-1 cells complied with the requirements of the EP that prescribe that the protection index should be at least 80%. The safety of the vaccines grown in QT35 cells and JBJ-1 cells was tested in a field study in commercial layer chickens. The vaccine virus was not safe after passaging in QT35 cells. This can be explained by the presence of fragments of the genome of MDV strains in the QT35 cell line. No signs of MD were noticed in the study in which CVI988 grown in JBJ-1 cells was tested. It is concluded that the JBJ-1 cell line is a suitable substrate for the current vaccines against MD.

Brugada syndrome: two decades of progress.

PubMed

Veerakul, Gumpanart; Nademanee, Koonlawee

2012-01-01

Two decades ago, a series of 8 idiopathic ventricular fibrillation patients who each had an abnormal ECG (right bundle branch block with coved-type ECG), but otherwise had normal hearts were described by Brugada and Brugada. Since then, the clinical entity has become known as Brugada syndrome (BS). Shortly thereafter, mutations of the SCN5A gene that encodes for the α-subunit of the sodium channel were found, galvanizing the field of ion channelopathies following in the footsteps of the breakthrough in long QT syndrome. Over the past 20 years, extensive research in this field has produced major progress toward better understanding of BS and the gaining of knowledge of the genetic background, pathophysiology and new management. Two consensus reports were published to help define the diagnostic criteria, risk stratification and management of BS patients. However, there are controversies. In this review, we will share our experiences of BS patients in Thailand and discuss advances in many aspects of the syndrome (ie, genetics and pathophysiology) and some of these pertinent controversies, as well as new treatment of the syndrome with catheter ablation.

[Effect of intermittent variable intensity exercise on QT variation and risk of sudden cardiac death among Cameroonian school adolescents].

PubMed

Bika Lele, E C; Pepouomi, M N; Temfemo, A; Mekoulou, J; Assomo Ndemba, P; Mandengue, S H

2018-02-01

Several cases of sudden deaths are observed among students practicing sport and physical activity (SPA). Just few studies have been carried out on the variation of the QT (interval) and risk of sudden death during sporting exercises. To determine the effect of variable intermittent stress intensity on the variation of QT and the risk of sudden cardiac death. Form 4, lower sixth and upper sixth students were recruited from a high school in Douala (Cameroon). Each subject was tested; starting with a 2-km walk followed by a sprint race or an endurance race, protocol I (P1) or the reverse; protocol II (P2). Two electrocardiograms were recorded; prior to the beginning of the SPA and 5minutes after the last race. QT was corrected using four formulas. Forty-one subjects (21 women and 20 men), mean age 18±2 years were recruited. At the end of the exercise, corrected QT increased with Bazzet's formula and decreased with Frahmingam's formula. The difference was not significant with Fridericia and Hodges formulas. The frequency of long QT was higher at the end of the exercise with Bazzet's formula (12.2% vs. 24.4%, P=0.009) while the difference was not significant for the other formulas. The risk of sudden cardiac death increases significantly after SPA. More studies on large samples are needed. Copyright © 2017. Published by Elsevier SAS.

A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data.

PubMed

Jonker, Daniël M; Kenna, Leslie A; Leishman, Derek; Wallis, Rob; Milligan, Peter A; Jonsson, E Niclas

2005-06-01

QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT prolongation in humans for the class III antiarrhythmic dofetilide. The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease). A population pharmacokinetic-pharmacodynamic analysis of the in vitro and in vivo data was performed in NONMEM by use of the operational model of pharmacologic agonism to estimate the efficiency of transduction from ion channel binding to Fridericia-corrected QT response. A 3-compartment pharmacokinetic model with first-order absorption characterized the time course of dofetilide concentrations. On the basis of an in vitro potency of 5.13 ng/mL for potassium current inhibition and predicted unbound dofetilide concentrations, the estimated transducer ratio (tau) of 6.2 suggests that the QT response plateaus before currents are fully blocked. In our study population, 10% hERG blockade corresponds to a QT prolongation of 20 ms (95% confidence interval, 12-32 ms). With long-term dofetilide administration, tolerance develops with a half-life of 4.7 days. The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties.

A new approach to correct the QT interval for changes in heart rate using a nonparametric regression model in beagle dogs.

PubMed

Watanabe, Hiroyuki; Miyazaki, Hiroyasu

2006-01-01

Over- and/or under-correction of QT intervals for changes in heart rate may lead to misleading conclusions and/or masking the potential of a drug to prolong the QT interval. This study examines a nonparametric regression model (Loess Smoother) to adjust the QT interval for differences in heart rate, with an improved fitness over a wide range of heart rates. 240 sets of (QT, RR) observations collected from each of 8 conscious and non-treated beagle dogs were used as the materials for investigation. The fitness of the nonparametric regression model to the QT-RR relationship was compared with four models (individual linear regression, common linear regression, and Bazett's and Fridericia's correlation models) with reference to Akaike's Information Criterion (AIC). Residuals were visually assessed. The bias-corrected AIC of the nonparametric regression model was the best of the models examined in this study. Although the parametric models did not fit, the nonparametric regression model improved the fitting at both fast and slow heart rates. The nonparametric regression model is the more flexible method compared with the parametric method. The mathematical fit for linear regression models was unsatisfactory at both fast and slow heart rates, while the nonparametric regression model showed significant improvement at all heart rates in beagle dogs.

High Resolution ECG for Evaluation of QT Interval Variability during Exposure to Acute Hypoxia

NASA Technical Reports Server (NTRS)

Zupet, P.; Finderle, Z.; Schlegel, Todd T.; Starc, V.

2010-01-01

Ventricular repolarization instability as quantified by the index of QT interval variability (QTVI) is one of the best predictors for risk of malignant ventricular arrhythmias and sudden cardiac death. Because it is difficult to appropriately monitor early signs of organ dysfunction at high altitude, we investigated whether high resolution advanced ECG (HR-ECG) analysis might be helpful as a non-invasive and easy-to-use tool for evaluating the risk of cardiac arrhythmias during exposure to acute hypoxia. 19 non-acclimatized healthy trained alpinists (age 37, 8 plus or minus 4,7 years) participated in the study. Five-minute high-resolution 12-lead electrocardiograms (ECGs) were recorded (Cardiosoft) in each subject at rest in the supine position breathing room air and then after breathing 12.5% oxygen for 30 min. For beat-to-beat RR and QT variability, the program of Starc was utilized to derive standard time domain measures such as root mean square of the successive interval difference (rMSSD) of RRV and QTV, the corrected QT interval (QTc) and the QTVI in lead II. Changes were evaluated with paired-samples t-test with p-values less than 0.05 considered statistically significant. As expected, the RR interval and its variability both decreased with increasing altitude, with p = 0.000 and p = 0.005, respectively. Significant increases were found in both the rMSSDQT and the QTVI in lead II, with p = 0.002 and p = 0.003, respectively. There was no change in QTc interval length (p = non significant). QT variability parameters may be useful for evaluating changes in ventricular repolarization caused by hypoxia. These changes might be driven by increases in sympathetic nervous system activity at ventricular level.

Increased risk of QT prolongation associated with atherosclerotic diseases in arseniasis-endemic area in southwestern coast of Taiwan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, C.-H.; Chen, C.-L.; Hsiao, C.K.

2009-09-15

Chronic arsenic exposure has been documented to be associated with various cardiovascular diseases. We aimed to investigate 1) the increased risk of QT prolongation in chronic arsenic exposure, and 2) the relationships of cardiac repolarization (QT interval duration) with ischemic heart disease and carotid atherosclerosis. We studied 280 men and 355 women living in the endemic area of arseniasis in southwestern Taiwan. QT intervals in electrocardiogram and carotid intima-media thickness (IMT) by ultrasonography were measured. Ischemic heart disease was diagnosed by history or abnormal electrocardiogram. Significant associations of the corrected QT interval (QTc) duration with ischemic heart disease and carotidmore » intima-medium thickness and plaque were observed after adjustment for various risk factors in the multiple linear regression analysis (all p values < 0.05). Three indices of chronic arsenic exposure were all significantly associated with the risk of QTc prolongation showing dose-response relationships (p < 0.001). Chronic arsenic exposure was dose-dependently associated with the risk of QTc prolongation. Ischemic heart disease and carotid atherosclerosis were significantly associated with QTc intervals in chronic arsenic exposure. QTc prolongation might be suggested as an early biomarker for ischemic heart disease or carotid atherosclerosis in population with previous exposure to arsenic.« less

Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin (CaM) Variants in Long QT Syndrome (LQTS) and Functional Characterization of a Novel LQTS-Associated CaM Missense Variant, E141G

PubMed Central

Calvert, Melissa L.; Tester, David J.; Kryshtal, Dmytro; Hwang, Hyun Seok; Johnson, Christopher N.; Chazin, Walter J.; Loporcaro, Christina G.; Shah, Maully; Papez, Andrew L.; Lau, Yung R.; Kanter, Ronald; Knollmann, Bjorn C.; Ackerman, Michael J.

2016-01-01

Background Calmodulin (CaM) is encoded by three genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca2+ and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All of these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. Methods and Results Thirty-nine genetically elusive LQTS cases underwent whole exome sequencing to identify CaM variants. Non-synonymous CaM variants were overrepresented significantly in this heretofore LQTS cohort (15.4%) compared to exome aggregation consortium (0.04%; p<0.0001). When the clinical sequelae of these 6 CaM-positive cases was compared to the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 8 months, an average QTc of 679 ms, and a high prevalence of cardiac arrest. Functional characterization of one novel variant, E141G-CaM, revealed an 11-fold reduction in Ca2+ binding affinity and a functionally-dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. Conclusions Overall, 15% of our genetically elusive LQTS cohort harbored non-synonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history. PMID:26969752

Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings.

PubMed

Noel, Gary J; Goodman, Daniel B; Chien, Shuchean; Solanki, Bhavna; Padmanabhan, Mukund; Natarajan, Jaya

2004-05-01

A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value

The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk

PubMed Central

Guns, P-J; Johnson, DM; Van Op den bosch, J; Weltens, E; Lissens, J

2012-01-01

BACKGROUND AND PURPOSE QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A negative electro-mechanical (E-M) window has recently been proposed as an alternative risk marker for TdP in a canine LQT1 model. Here, we evaluated the E-M window in anaesthetized guinea pigs as a screening marker for TdP in humans. EXPERIMENTAL APPROACH The effects of various reference drugs and changes in body temperature on the E-M window were assessed in instrumented guinea pigs. The E-M window was defined as the delay between the duration of the electrical (QT interval) and mechanical (QLVPend) systole. KEY RESULTS Drugs with known TdP liability (quinidine, haloperidol, domperidone, terfenadine, thioridazine and dofetilide), but not those with no TdP risk in humans (salbutamol and diltiazem) consistently decreased the E-M window. Interestingly, drugs with known clinical QT prolongation, but with low risk for TdP (amiodarone, moxifloxacin and ciprofloxacin) did not decrease the E-M window. Furthermore, the E-M window was minimally affected by changes in heart rate or body temperature. CONCLUSIONS AND IMPLICATIONS A decreased E-M window was consistently observed with drugs already known to have high TdP risk, but not with drugs with low or no TdP risk. These results suggest that the E-M window in anaesthetized guinea pigs is a risk marker for TdP in humans. PMID:22122450

The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study

PubMed Central

2013-01-01

Background Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters. Methods A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. Treatments: single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1–4 hours after dosing. Results Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18–52] years) were randomised. The placebo-corrected MCfB in QTcN 1–4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2–4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis. Conclusions/interpretation Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. Trial registration ClinicalTrials.gov: NCT01195675 PMID:23617452

F463L increases the potential of dofetilide on human ether-a-go-go-related gene (hERG) channels.

PubMed

Cheng, Gong; Wu, Jine; Han, Wenqi; Sun, Chaofeng

2018-06-01

Mutations in genes related to long QT syndrome (LQTS) is recognized as an independent risk of drug-induced LQTS. We previously screened a mutation F463L in a Chinese patient with LQT2, syncope, and epilepsy. Here, we planned to illustrate how F463L influences the action of dofetilide on hERG channels. F463L-hERG plasmids were transfected into the stable Human Embryonic Kidney 293 (HEK293) cells expressing WT-hERG to generate heterozygous mutant (WT + F463L-hERG). Whole-cell patch clamp and laser confocal scanning microscopy were used to evaluate electrophysiological consequences and the membrane distribution of hERG protein. In comparison of WT-hERG channels exposed to dofetilide, heterozygous F463L-hERG channels showed a reduction in the density of tail currents when exposed amidarone. F463L-hERG also altered the action of dofetilide on the gating properties of hERG channels. Images of dofetilide-treated cells expressing heterozygous F463L showed a severe retention and reduction of protein expression on the membrane compared to WT. In conclusion, dofetilide displays a powerful inhibitory effect on the currents from cells expressing heterozygous F463L, thus showing an additive suppression of currents by F463L with dofetilide. © 2018 Wiley Periodicals, Inc.

Noninvasive cardiac activation imaging of ventricular arrhythmias during drug-induced QT prolongation in the rabbit heart.

PubMed

Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R; Zhou, Zhaoye; He, Bin

2013-10-01

Imaging myocardial activation from noninvasive body surface potentials promises to aid in both cardiovascular research and clinical medicine. To investigate the ability of a noninvasive 3-dimensional cardiac electrical imaging technique for characterizing the activation patterns of dynamically changing ventricular arrhythmias during drug-induced QT prolongation in rabbits. Simultaneous body surface potential mapping and 3-dimensional intracardiac mapping were performed in a closed-chest condition in 8 rabbits. Data analysis was performed on premature ventricular complexes, couplets, and torsades de pointes (TdP) induced during intravenous administration of clofilium and phenylephrine with combinations of various infusion rates. The drug infusion led to a significant increase in the QT interval (from 175 ± 7 to 274 ± 31 ms) and rate-corrected QT interval (from 183 ± 5 to 262 ± 21 ms) during the first dose cycle. All the ectopic beats initiated by a focal activation pattern. The initial beat of TdPs arose at the focal site, whereas the subsequent beats were due to focal activity from different sites or 2 competing focal sites. The imaged results captured the dynamic shift of activation patterns and were in good correlation with the simultaneous measurements, with a correlation coefficient of 0.65 ± 0.02 averaged over 111 ectopic beats. Sites of initial activation were localized to be ~5 mm from the directly measured initiation sites. The 3-dimensional cardiac electrical imaging technique could localize the origin of activation and image activation sequence of TdP during QT prolongation induced by clofilium and phenylephrine in rabbits. It offers the potential to noninvasively investigate the proarrhythmic effects of drug infusion and assess the mechanisms of arrhythmias on a beat-to-beat basis. © 2013 Heart Rhythm Society. All rights reserved.

Long QT Syndrome

MedlinePlus

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Exposure to antibacterial agents with QT liability in 14 European countries: trends over an 8-year period

PubMed Central

Raschi, Emanuel; Poluzzi, Elisabetta; Zuliani, Chiara; Muller, Arno; Goossens, Herman; De Ponti, Fabrizio

2009-01-01

AIMS (i) To classify antibacterial agents with QT liability on the basis of the available evidence, and (ii) to assess trends in their consumption over an 8-year period (1998–2005) in 14 European countries. METHODS Current published evidence on QT liability of antibiotics was retrieved through MEDLINE search and joined to official warnings from regulatory agencies. Each drug was classified according to an already proposed algorithm based on the strength of evidence: from group A (any evidence) to group E (clinical reports of torsades de pointes and warnings on QT liability). Consumption data were provided by the European Surveillance of Antibacterial Consumption (ESAC) project and were expressed as defined daily doses per 1000 inhabitants per day (DID). RESULTS Among 21 detected compounds, nine [six fluoroquinolones (FQs) and three macrolides (MACs)] belonged to group E. Use of group E drugs ranged from 1.3 (Sweden) to 4.1 DID (Italy) in 1998 and from 1.2 (Sweden) to 6.5 DID (Italy) in 2005. Significant exposure was observed in Italy and Spain (6.5 and 3.8 DID, respectively, in 2005). Only Denmark, Sweden and UK showed a slight decrease in use. Exposure to clarithromycin increased in 10 out of 14 countries, with a marked increment in Italy (3 DID in 2005). CONCLUSIONS Notwithstanding regulatory measures, in 2005 there was still significant exposure to antibacterials with strong evidence of QT liability and, in most countries, it was even increased. This warrants further investigation of appropriateness of use and suggests closer monitoring of group E drugs. Physicians should be aware when prescribing them to susceptible patients. PMID:19076158

Pharmacogenomics Study of Thiazide Diuretics and QT Interval in Multi-Ethnic Populations: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)

PubMed Central

Seyerle, Amanda A; Sitlani, Colleen M; Noordam, Raymond; Gogarten, Stephanie M; Li, Jin; Li, Xiaohui; Evans, Daniel S; Sun, Fangui; Laaksonen, Maarit A; Isaacs, Aaron; Kristiansson, Kati; Highland, Heather M; Stewart, James D; Harris, Tamara B; Trompet, Stella; Bis, Joshua C; Peloso, Gina M; Brody, Jennifer A; Broer, Linda; Busch, Evan L; Duan, Qing; Stilp, Adrienne M; O’Donnell, Christopher J; Macfarlane, Peter W; Floyd, James S; Kors, Jan A; Lin, Henry J; Li-Gao, Ruifang; Sofer, Tamar; Méndez-Giráldez, Raúl; Cummings, Steven R; Heckbert, Susan R; Hofman, Albert; Ford, Ian; Li, Yun; Launer, Lenore J; Porthan, Kimmo; Newton-Cheh, Christopher; Napier, Melanie D; Kerr, Kathleen F; Reiner, Alexander P; Rice, Kenneth M; Roach, Jeffrey; Buckley, Brendan M; Soliman, Elsayed Z; de Mutsert, Renée; Sotoodehnia, Nona; Uitterlinden, André G; North, Kari E; Lee, Craig R; Gudnason, Vilmundur; Stürmer, Til; Rosendaal, Frits R; Taylor, Kent D; Wiggins, Kerri L; Wilson, James G; Chen, Yii-Der I; Kaplan, Robert C; Wilhelmsen, Kirk; Cupples, L Adrienne; Salomaa, Veikko; van Duijn, Cornelia; Jukema, J Wouter; Liu, Yongmei; Mook-Kanamori, Dennis O; Lange, Leslie A; Vasan, Ramachandran S; Smith, Albert V; Stricker, Bruno H; Laurie, Cathy C; Rotter, Jerome I; Whitsel, Eric A; Psaty, Bruce M; Avery, Christy L

2017-01-01

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common SNPs modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic, and cross-phenotype genome-wide analyses of European (66%), African American (15%), and Hispanic (19%) populations (N=78,199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5×10−8), we found suggestive evidence (P<5×10−6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (e.g. NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions. PMID:28719597

{sub qT} uncertainties for W and Z production.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berge, S.; Nadolsky, P. M.; Olness, F. I.

Analysis of semi-inclusive DIS hadroproduction suggests broadening of transverse momentum distributions at small x below 10-3 {approx} 10-2, which can be modeled in the Collins-Soper-Sterman formalism by a modification of impact parameter dependent parton densities. We investigate these consequences for the production of electroweak bosons at the Tevatron and the LHC. If substantial small-x broadening is observed in forward Z0 boson production in the Tevatron Run-2, it will strongly affect the predicted qT distributions for W{+-} and Z0 boson production at the LHC.

Elevation of QT dispersion after obesity drug sibutramine.

PubMed

Yalcin, Ahmet A; Yavuz, Bunyamin; Ertugrul, Derun T; Algul, Beyza; Yilmaz, Hamiyet; Deveci, Onur S; Kucukazman, Metin; Ata, Naim; Demirel, Gokhan; Dal, Kursat; Tutal, Emre

2010-11-01

QT dispersion (QTd) is an arrhythmia parameter that can be used to assess homogeneity of cardiac repolarization. An antiobesity drug sibutramine is linked with several cardiovascular adverse events, including arrhythmias. Previous studies showed that sibutramine may prolong the QT interval and may be associated with cardiac arrest. The aim of this study was to evaluate the effect of sibutramine on QTd. The study group consisted of 65 consecutive patients with obesity. All patients were to receive 15 mg of sibutramine once a day in addition to standard care for lifestyle change. Twelve-lead ECG was performed before the onset of the medication and after 16 weeks of treatment. QTd was calculated. Three individuals were withdrawn from the study because of the adverse effects of sibutramine. Sixty-two patients with obesity were recruited into the study. All patients were women (62, 100%). Body weight (106.3 ± 15.0 kg vs. 101.6 ± 16.9 kg, P < 0.001) and low-density lipoprotein cholesterol (128.4 ± 29.7 mg/dl vs. 111.6 ± 24.6 mg/dl, P < 0.001) levels were significantly decreased whereas QTd (46.1 ± 22.6 ms vs. 53.7 ± 16.7 ms, P = 0.026) was significantly increased after 16 weeks of sibutramine treatment. The increase in QTd was not correlated with the decrease in body weight. There was no correlation between QTd and any conditions such as diabetes or hypertension. This study has shown an elevation in QTd, which may lead to cardiac arrhythmias, after sibutramine treatment. Molecular mechanisms may play role in increasing QTd. Further randomized studies are needed to clarify cardiac adverse events of the sibutramine.

The effects of intravenous anesthetics on QT interval during anesthetic induction with sevoflurane.

PubMed

Terao, Yoshiaki; Higashijima, Ushio; Toyoda, Tomomi; Ichinomiya, Taiga; Fukusaki, Makoto; Hara, Tetsuya

2016-12-01

Sevoflurane is known to prolong the QT interval. This study aimed to determine the effect of the interaction between intravenous anesthetics and sevoflurane on the QT interval. The study included 48 patients who underwent lumbar spine surgery. Patients received 3 μg/kg fentanyl and were then randomly allocated to either Group T, in which they received 5 mg/kg thiamylal, or Group P, in which they received 1.5 mg/kg propofol, at 2 min after administration of fentanyl injection for anesthetic induction. Vecuronium (1.5 mg/kg) and sevoflurane (3 % inhaled concentration) were administered immediately after loss of consciousness and tracheal intubation was performed 3 min after vecuronium injection. Heart rate (HR), mean arterial pressure (MAP), bispectral index score (BIS), and the heart rate-corrected QT (QTc) interval on a 12-lead electrocardiogram were recorded immediately before fentanyl administration (T1), 2 min after fentanyl injection (T2), immediately before intubation (T3), and 2 min after intubation (T4). There were no significant differences between the two groups in baseline patient characteristics. BIS and MAP significantly decreased after anesthesia induction in both groups. At T3, MAP in Group T was higher than in Group P, while HR had reduced in both groups. The QTc interval was prolonged after anesthesia induction in Group T, but did not change at any time point in Group P. The QTc interval after anesthesia induction in Group T was longer than in Group P. We concluded that an injection of propofol could counteract QTc interval prolongation associated with sevoflurane anesthesia induction.

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

PubMed

Suzuki, Yutaro; Tajiri, Misuzu; Sugimoto, Atsunori; Orime, Naoki; Hayashi, Taketsugu; Egawa, Jun; Sugai, Takuro; Inoue, Yoshimasa; Someya, Toshiyuki

2017-02-01

The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

PubMed Central

2010-01-01

Background Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. Methods The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. Results Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine. Conclusions In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity. PMID:21067575

New age- and sex-specific criteria for QT prolongation based on rate correction formulas that minimize bias at the upper normal limits.

PubMed

Rautaharju, Pentti M; Mason, Jay W; Akiyama, Toshio

2014-07-01

Existing formulas for rate-corrected QT (QTc) commonly fail to properly adjust the upper normal limits which are more critical than the mean QTc for evaluation of prolonged QT. Age- and sex-related differences in QTc are also often overlooked. Our goal was to establish criteria for prolonged QTc using formulas that minimize QTc bias at the upper normal limits. Strict criteria were used in selecting a study group of 57,595 persons aged 5 to 89 years (54% women) and to exclude electrocardiograms (ECG) with possible disease-associated changes. Two QT rate adjustment formulas were identified which both minimized rate-dependency in the 98 th percentile limits: QTcmod, based on an electrophysiological model (QTcMod = QTx(120 + HR)/180)), and QTcLogLin, a power function of the RR interval with exponents 0.37 for men and 0.38 for women. QTc shortened in men during adolescence and QTcMod became 13 ms shorter than in women at age 20-29 years. The sex difference was maintained through adulthood although decreasing with age. The criteria established for prolonged QTc were: Age < 40 years, men 430 ms, women 440 ms; Age 40 to 69, men 440 ms, women 450 ms; Age ≥ 70 years, men 455 ms, and women 460 ms. Sex difference in QTc originates from shortened QT in adolescent males. Upper normal limits for QTc vary substantially by age and sex, and it is essential to use age- and sex-specific criteria for evaluation of QT prolongation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Short-term effect of percutaneous recanalization of chronic total occlusions on QT dispersion and heart rate variability parameters

PubMed Central

Erdogan, Ercan; Akkaya, Mehmet; Bacaksız, Ahmet; Tasal, Abdurrahman; Sönmez, Osman; Asoglu, Emin; Kul, Seref; Sahın, Musa; Turfan, Murat; Vatankulu, Mehmet Akif; Göktekin, Omer

2013-01-01

Background QT dispersion (QTd), which is a measure of inhomogeneity of myocardial repolarization, increases following impaired myocardial perfusion. Its prolongation may provide a suitable substrate for life-threatening ventricular arrhythmias. We investigated the changes in QTd and heart rate variability (HRV) parameters after successful coronary artery revascularization in a patient with chronic total occlusions (CTO). Material/Methods This study included 139 successfully revascularized CTO patients (118 men, 21 women, mean age 58.3±9.6 years). QTd was measured from a 12-lead electrocardiogram and was defined as the difference between maximum and minimum QT interval. HRV analyses of all subjects were obtained. Frequency domain (LF: HF) and time domain (SDNN, pNN50, and rMSSD) parameters were analyzed. QT intervals were also corrected for heart rate using Bazett’s formula, and the corrected QT interval dispersion (QTcd) was then calculated. All measurements were made before and after percutaneous coronary intervention (PCI). Results Both QTd and QTcd showed significant improvement following successful revascularization of CTO (55.83±14.79 to 38.87±11.69; p<0.001 and 61.02±16.28 to 42.92±13.41; p<0.001). The revascularization of LAD (n=38), Cx (n=28) and RCA (n=73) resulted in decrease in HRV indices, including SDDN, rMSSD, and pNN50, but none of the variables reached statistical significance. Conclusions Successful revascularization of CTO may result in improvement in regional heterogeneity of myocardial repolarization, evidenced as decreased QTcd after the PCI. The revascularization in CTO lesions does not seem to have a significant impact on HRV. PMID:23969577

QT prolongation caused by insulin-induced hypoglycaemia - An interventional study in 119 individuals.

PubMed

Kacheva, Stella; Karges, Beate; Göller, Katrin; Marx, Nikolaus; Mischke, Karl; Karges, Wolfram

2017-01-01

Hypoglycaemia is associated with increased risk of cardiovascular events and mortality in patients with diabetes, but the extent and mechanisms of this link are ill defined. We here prospectively studied cardiac repolarization abnormalities during insulin-induced hypoglycaemia in humans. 119 individuals (69 males, age 47.5±13.4years, range 18-82years) were assessed during hypoglycaemia after the injection of 0.1-0.25units/kg human insulin. Corrected QT intervals (QTc) and QT dispersion (QTd) were calculated from serially recorded twelve lead electrocardiograms, and plasma glucose and other endocrine markers were studied. QTc increased from 415.1±21.9ms (mean±standard deviation) at baseline to 444.9±26.5ms during hypoglycaemia (plasma glucose nadir, 1.6±0.5mmol/L, p=0.001), accompanied by an increase of QTd from 45.0±22.7ms to 64.1±40.0ms (p<0.001). Hypoglycaemia-induced abnormal QTc prolongation (defined as ⩾460ms in females and ⩾450ms in males) occurred in 17% (9/54) of females and 26% (17/65) of males. 97 of 119 of individuals (82%) developed transient hypokalaemia (K + ⩽3.6mmol/L), and plasma epinephrine increased from 220.4±169.5pmol/L at baseline to 2945.6±2421.4pmol/L during hypoglycaemia. Baseline QTc, but not age or gender, was a significant predictor of hypoglycaemia-induced QTc prolongation (p=0.001). Insulin-induced hypoglycaemia frequently causes abnormal QT prolongation and is associated with hypokalaemia and sympathoadrenal activation, thereby increasing the potential risk for ventricular arrhythmias, particularly in individuals with pre-existing high normal QTc. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Draft Genome Sequence of Pediococcus lolii NGRI 0510QT Isolated from Ryegrass Silage

PubMed Central

Mori, Kazuki; Tashiro, Kosuke; Fujino, Yasuhiro; Nagayoshi, Yuko; Hayashi, Yoshiharu; Kuhara, Satoru; Ohshima, Toshihisa

2013-01-01

Pediococcus lolii NGRI 0510QT was isolated from ryegrass silage produced on Ishigaki Island, Okinawa Prefecture, Japan. Here we present a draft genome sequence for this strain, consisting of 103 contigs for a total of 2,047,078 bp, 2,154 predicted coding sequences, and a G+C content of 42.1%. PMID:23405350

Xenon does not increase heart rate-corrected cardiac QT interval in volunteers and in patients free of cardiovascular disease.

PubMed

Neukirchen, Martin; Schaefer, Maximilian S; Kern, Carolin; Brett, Sarah; Werdehausen, Robert; Rellecke, Philipp; Reyle-Hahn, Matthias; Kienbaum, Peter

2015-09-01

Impaired cardiac repolarization, indicated by prolonged QT interval, may cause critical ventricular arrhythmias. Many anesthetics increase the QT interval by blockade of rapidly acting potassium rectifier channels. Although xenon does not affect these channels in isolated cardiomyocytes, the authors hypothesized that xenon increases the QT interval by direct and/or indirect sympathomimetic effects. Thus, the authors tested the hypothesis that xenon alters the heart rate-corrected cardiac QT (QTc) interval in anesthetic concentrations. The effect of xenon on the QTc interval was evaluated in eight healthy volunteers and in 35 patients undergoing abdominal or trauma surgery. The QTc interval was recorded on subjects in awake state, after their denitrogenation, and during xenon monoanesthesia (FetXe > 0.65). In patients, the QTc interval was recorded while awake, after anesthesia induction with propofol and remifentanil, and during steady state of xenon/remifentanil anesthesia (FetXe > 0.65). The QTc interval was determined from three consecutive cardiac intervals on electrocardiogram printouts in a blinded manner and corrected with Bazett formula. In healthy volunteers, xenon did not alter the QTc interval (mean difference: +0.11 ms [95% CI, -22.4 to 22.7]). In patients, after anesthesia induction with propofol/remifentanil, no alteration of QTc interval was noted. After propofol was replaced with xenon, the QTc interval remained unaffected (417 ± 32 ms vs. awake: 414 ± 25 ms) with a mean difference of 4.4 ms (95% CI, -4.6 to 13.5). Xenon monoanesthesia in healthy volunteers and xenon/remifentanil anesthesia in patients without clinically relevant cardiovascular disease do not increase QTc interval.

Intra-QT spectral coherence as a possible noninvasive marker of sustained ventricular tachycardia.

PubMed

Piccirillo, Gianfranco; Moscucci, Federica; Persi, Alessandro; Di Barba, Daniele; Pappadà, Maria Antonella; Rossi, Pietro; Quaglione, Raffaele; Nguyen, Bich Lien; Barillà, Francesco; Casenghi, Matteo; Magrì, Damiano

2014-01-01

Sudden cardiac death is the main cause of mortality in patients affected by chronic heart failure (CHF) and with history of myocardial infarction. No study yet investigated the intra-QT phase spectral coherence as a possible tool in stratifying the arrhythmic susceptibility in patients at risk of sudden cardiac death (SCD). We, therefore, assessed possible difference in spectral coherence between the ECG segment extending from the q wave to the T wave peak (QTp) and the one from T wave peak to the T wave end (Te) between patients with and without Holter ECG-documented sustained ventricular tachycardia (VT). None of the QT variability indexes as well as most of the coherences and RR power spectral variables significantly differed between the two groups except for the QTp-Te spectral coherence. The latter was significantly lower in patients with sustained VT than in those without (0.508 ± 0.150 versus 0.607 ± 0.150, P < 0.05). Although the responsible mechanism remains conjectural, the QTp-Te spectral coherence holds promise as a noninvasive marker predicting malignant ventricular arrhythmias.

QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.

PubMed

Wedam, Erich F; Bigelow, George E; Johnson, Rolley E; Nuzzo, Paul A; Haigney, Mark C P

2007-12-10

Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.

PubMed

Lahrouchi, Najim; Raju, Hariharan; Lodder, Elisabeth M; Papatheodorou, Efstathios; Ware, James S; Papadakis, Michael; Tadros, Rafik; Cole, Della; Skinner, Jonathan R; Crawford, Jackie; Love, Donald R; Pua, Chee J; Soh, Bee Y; Bhalshankar, Jaydutt D; Govind, Risha; Tfelt-Hansen, Jacob; Winkel, Bo G; van der Werf, Christian; Wijeyeratne, Yanushi D; Mellor, Greg; Till, Jan; Cohen, Marta C; Tome-Esteban, Maria; Sharma, Sanjay; Wilde, Arthur A M; Cook, Stuart A; Bezzina, Connie R; Sheppard, Mary N; Behr, Elijah R

2017-05-02

Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10 -5 ). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Medical toxicologists' practice patterns regarding drug-induced QT prolongation in overdose patients: a survey in the United States of America, Europe, and Asia Pacific region.

PubMed

Othong, Rittirak; Devlin, John J; Kazzi, Ziad N

2015-05-01

To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose. A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region. The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty

Genetics Home Reference: Romano-Ward syndrome

MedlinePlus

... part of the heartbeat known as the QT interval is abnormally long. Abnormalities in the time it ... those types that involve only a long QT interval without other abnormalities. Related Information What does it ...

Intra-QT Spectral Coherence as a Possible Noninvasive Marker of Sustained Ventricular Tachycardia

PubMed Central

Piccirillo, Gianfranco; Moscucci, Federica; Di Barba, Daniele; Pappadà, Maria Antonella; Rossi, Pietro; Quaglione, Raffaele; Barillà, Francesco; Magrì, Damiano

2014-01-01

Sudden cardiac death is the main cause of mortality in patients affected by chronic heart failure (CHF) and with history of myocardial infarction. No study yet investigated the intra-QT phase spectral coherence as a possible tool in stratifying the arrhythmic susceptibility in patients at risk of sudden cardiac death (SCD). We, therefore, assessed possible difference in spectral coherence between the ECG segment extending from the q wave to the T wave peak (QTp) and the one from T wave peak to the T wave end (T e) between patients with and without Holter ECG-documented sustained ventricular tachycardia (VT). None of the QT variability indexes as well as most of the coherences and RR power spectral variables significantly differed between the two groups except for the QTp-T e spectral coherence. The latter was significantly lower in patients with sustained VT than in those without (0.508 ± 0.150 versus 0.607 ± 0.150, P < 0.05). Although the responsible mechanism remains conjectural, the QTp-T e spectral coherence holds promise as a noninvasive marker predicting malignant ventricular arrhythmias. PMID:25133170

Massive Boson Production at Small qT in Soft-Collinear Effective Theory

NASA Astrophysics Data System (ADS)

Becher, Thomas; Neubert, Matthias; Wilhelm, Daniel

2013-01-01

We study the differential cross sections for electroweak gauge-boson and Higgs production at small and very small transverse-momentum qT. Large logarithms are resummed using soft-collinear effective theory. The collinear anomaly generates a non-perturbative scale q*, which protects the processes from receiving large long-distance hadronic contributions. A numerical comparison of our predictions with data on the transverse-momentum distribution in Z-boson production at the Tevatron and LHC is given.

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

PubMed Central

Du, Yi-mei; Xia, Cheng-kun; Zhao, Ning; Dong, Qian; Lei, Ming; Xia, Jia-hong

2012-01-01

Aim: To compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na+ current, HERG and Kv1.5 channel currents. Methods: Wild-type (WT) and long QT syndrome type 3 (LQT-3) mutant ΔKPQ Nav1.5 channels, as well as HERG and Kv1.5 channels were expressed in Xenopus oocytes. In addition, isolated human atrial myocytes were used. Two-microelectrode voltage-clamp technique was used to record the voltage-activated currents. Results: Superfusion of 18β-glycyrrhetinic acid (18β-GA, 1–100 μmol/L) blocked both the peak current (INa,P) and late current (INa,L) generated by WT and ΔKPQ Nav1.5 channels in a concentration-dependent manner, while 18α-glycyrrhetinic acid (18α-GA) at the same concentrations had no effects. 18β-GA preferentially blocked INa,L (IC50=37.2±14.4 μmol/L) to INa,P (IC50=100.4±11.2 μmol/L) generated by ΔKPQ Nav1.5 channels. In human atrial myocytes, 18β-GA (30 μmol/L) inhibited 47% of INa,P and 87% of INa,L induced by Anemonia sulcata toxin (ATX-II, 30 nmol/L). Superfusion of 18β-GA (100 μmol/L) had no effects on HERG and Kv1.5 channel currents. Conclusion: 18β-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels. PMID:22609834

QT interval correction for drug-induced changes in body temperature during integrated cardiovascular safety assessment in regulatory toxicology studies in dogs: A case study.

PubMed

El Amrani, Abdel-Ilah; El Amrani-Callens, Francine; Loriot, Stéphane; Singh, Pramila; Forster, Roy

2016-01-01

Cardiovascular safety assessment requires accurate evaluation of QT interval, which depends on the length of the cardiac cycle and also on core body temperature (BT). Increases in QT interval duration have been shown to be associated with decreases in BT in dogs. An example of altered QT interval duration associated with changes in body temperature observed during a 4-week regulatory toxicology study in dogs is presented. Four groups of Beagle dogs received the vehicle or test item once on Day 1, followed by a 4-week observation period. Electrocardiogram (ECG) parameters were continuously recorded on Days 1 and 26 by jacketed external telemetry (JET). Core body temperature (BT) was measured with a conventional rectal thermometer at appropriate time-points during the Day 1 recording period. Decreased BT was observed approximately 2h after treatment on Day 1, along with increased QT interval duration corrected according to the Van de Water formula (QTcV), but the effect was no longer observed after correction for changes in BT [QTcVcT=QTcV-14(37.5-BT)] according to the Van der Linde formula. No significant changes in QTcV were reported at the end of the observation period, on Day 26. The present study demonstrates that core body (rectal) temperature can easily be monitored at appropriate time-points during JET recording in regulatory toxicology studies in dogs, in order to correct QT interval duration values for treatment-related changes in BT. The successful application of the Van der Linde formula to correct QTc prolongation for changes in BT was demonstrated. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome

PubMed Central

Chen, Xian; Cass, Jessica D; Bradley, Jenifer A; Dahm, Corinn M; Sun, Zhuoqian; Kadyszewski, Edmund; Engwall, Michael J; Zhou, Jun

2005-01-01

Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study, we investigated effects of moxifloxacin on the hERG current in HEK-293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model. Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration-dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after-depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration-dependent, and 100 μM (∼18-fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP). Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well-behaved pharmacokinetic profile and other dose-limiting effects. PMID:16158069

Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: administration of interacting co-medication and QT prolongation.

PubMed

Niedrig, David; Maechler, Sarah; Hoppe, Liesa; Corti, Natascia; Kovari, Helen; Russmann, Stefan

2016-07-01

Some macrolide and quinolone antibiotics (MQABs) are associated with QT prolongation and life-threatening torsade de pointes (TdP) arrhythmia. MQAB may also inhibit cytochrome P450 isoenzymes and thereby cause pharmacokinetic drug interactions (DDIs). There is limited data on the frequency and management of such risks in clinical practice. We aimed to quantify co-administration of MQAB with interacting drugs and associated adverse drug reactions. We conducted an observational study within our pharmacoepidemiological database derived from electronic medical records of a tertiary care hospital. Among all users of MQAB associated with TdP, we determined the prevalence of additional QT-prolonging drugs and risk factors and identified contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine. Electrocardiographic (ECG) monitoring and associated adverse events were validated in medical records. Among 3444 administered courses of clarithromycin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, or moxifloxacin, there were 1332 (38.7 %) with concomitant use of additional QT-prolonging drugs. Among those, we identified seven cases of drug-related QT prolongation, but 49.1 % had no ECG monitoring. Of all MQAB users, 547 (15.9 %) had hypokalemia. Forty-four MQAB users had contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine and three of those related adverse drug reactions. In the studied real-life setting, we found a considerable number of MQAB users with additional risk factors for TdP but no ECG monitoring. However, adverse drug reactions were rarely found, and costs vs. benefits of ECG monitoring have to be weighted. In contrast, avoidable risk factors and selected contraindicated pharmacokinetic interactions are clear targets for implementation as automated alerts in electronic prescribing systems.

Continuous ECG Monitoring in Patients With Acute Coronary Syndrome or Heart Failure: EASI Versus Gold Standard.

PubMed

Lancia, Loreto; Toccaceli, Andrea; Petrucci, Cristina; Romano, Silvio; Penco, Maria

2018-05-01

The purpose of the study was to compare the EASI system with the standard 12-lead surface electrocardiogram (ECG) for the accuracy in detecting the main electrocardiographic parameters (J point, PR, QT, and QRS) commonly monitored in patients with acute coronary syndromes or heart failure. In this observational comparative study, 253 patients who were consecutively admitted to the coronary care unit with acute coronary syndrome or heart failure were evaluated. In all patients, two complete 12-lead ECGs were acquired simultaneously. A total of 6,072 electrocardiographic leads were compared (3,036 standard and 3,036 EASI). No significant differences were found between the investigate parameters of the two measurement methods, either in patients with acute coronary syndrome or in those with heart failure. This study confirmed the accuracy of the EASI system in monitoring the main ECG parameters in patients admitted to the coronary care unit with acute coronary syndrome or heart failure.

Graphical representation of QT rate correction formulae: an aid facilitating the use of a given formula and providing a visual comparison of the impact of different formulae.

PubMed

Rowlands, Derek J

2012-01-01

The QT interval on the electrocardiogram is an increasingly important measurement, especially in relation to drug action and interaction. The QT interval varies inversely as the heart rate and numerous rate correction formulae have been proposed. It is difficult to compare the effect of applying different formulae at different heart rates and for different measured QT intervals. A simple graphical display of the results from different formulae is proposed. This display is dependent on the concept of the absolute correction factor. This graphical presentation is useful (a) in comparing the effect of the application of different formulae and (b) in directly reading the correction produced by any individual formula. Copyright © 2012 Elsevier Inc. All rights reserved.

The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study

PubMed Central

Palmisano, Maria; Wu, Anfan; Assaf, Mahmoud; Liu, Liangang; Park, C. Hyung; Savant, Ishani; Liu, Yong; Zhou, Simon

2016-01-01

Objective: This study was conducted to evaluate the effect of apremilast and its major metabolites on the placebo-corrected change-from-baseline QTc interval of an electrocardiogram (ECG). Materials and methods: Healthy male subjects received each of 4 treatments in a randomized, crossover manner. In the 2 active treatment periods, apremilast 30 mg (therapeutic exposure) or 50 mg (supratherapeutic exposure) was administered twice daily for 9 doses. A placebo control was used to ensure double-blind treatment of apremilast, and an open-label, single dose of moxifloxacin 400 mg was administered as a positive control. ECGs were measured using 24-hour digital Holter monitoring. Results: The two-sided 98% confidence intervals (CIs) for ΔΔQTcI of moxifloxacin completely exceeded 5 ms 2 – 4 hours postdose. For both apremilast dose studies, the least-squares mean ΔΔQTcI was < 1 ms at all time points, and the upper limit of two-sided 90% CIs was < 10 ms. There were no QT/QTc values > 480 ms or a change from baseline > 60 ms. Exploratory evaluation of pharmacokinetic/pharmacodynamic data showed no trend between the changes in QT/QTc interval and the concentration of apremilast or its major metabolites M12 and M14. Conclusions: Apremilast did not prolong the QT interval and appears to be safe and well tolerated up to doses of 50 mg twice daily. PMID:27285466

Drug-induced Brugada syndrome: Clinical characteristics and risk factors.

PubMed

Konigstein, Maayan; Rosso, Raphael; Topaz, Guy; Postema, Pieter G; Friedensohn, Limor; Heller, Karin; Zeltser, David; Belhassen, Bernard; Adler, Arnon; Viskin, Sami

2016-05-01

Cardiac arrest may result from seemingly innocuous medications that do not necessarily have cardiac indications. The best-known example is the drug-induced long QT syndrome. A less known but not necessarily less important form of drug-induced proarrhythmia is the drug-induced Brugada syndrome. The purpose of this study was to identify clinical and ECG risk markers for drug-induced Brugada syndrome. Reports of drug-induced Brugada syndrome recounted by an international database (http://www.brugadadrugs.org) were reviewed to define characteristics that identify patients prone to developing this complication. For each patient with drug-induced Brugada syndrome who had an ECG recorded in the absence of drugs, we included 5 healthy controls matched by gender and age. All ECGs were evaluated for Brugada-like abnormalities. Seventy-four cases of drug-induced Brugada syndrome from noncardiac medications were identified: 77% were male, and drug toxicity was involved in 46%. Drug-induced Brugada syndrome from oral medications generally occurred weeks after the initiation of therapy. Mortality was 13%. By definition, all cases had a type I Brugada pattern during drug therapy. Nevertheless, their ECG in the absence of drugs was more frequently abnormal than the ECG of controls (56% vs 33%, P = .04). Drug-induced Brugada syndrome from noncardiac drugs occurs predominantly in adult males, is frequently due to drug toxicity, and occurs late after the onset of therapy. Minor changes are frequently noticeable on baseline ECG, but screening is impractical because of a prohibitive false-positive rate. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk.

PubMed

Romero, Lucia; Cano, Jordi; Gomis-Tena, Julio; Trenor, Beatriz; Sanz, Ferran; Pastor, Manuel; Saiz, Javier

2018-04-23

Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue. Multiple channel-drug interactions and state-of-the-art human ventricular action potential models ( O'Hara , T. , PLos Comput. Biol. 2011 , 7 , e1002061 ) were used in our simulations. Specifically, 206.766 cellular and 7072 tissue simulations were performed by blocking the slow and the fast components of the delayed rectifier current ( I Ks and I Kr , respectively) and the L-type calcium current ( I CaL ) at different levels. The performance of our system was validated by classifying the proarrhythmic risk of 84 compounds, 40 of which present torsadogenic properties. On the basis of these results, we propose the use of a new index (Tx) for discriminating torsadogenic compounds, defined as the ratio of the drug concentrations producing 10% prolongation of the cellular endocardial, midmyocardial, and epicardial APDs and the QT interval, over the maximum effective free therapeutic plasma concentration (EFTPC). Our results show that the Tx index outperforms standard methods for early identification of torsadogenic compounds. Indeed, for the analyzed compounds, the Tx tests accuracy was in the range of 87-88% compared with a 73% accuracy of the hERG IC 50 based test.

Lack of significant effect of bilastine administered at therapeutic and supratherapeutic doses and concomitantly with ketoconazole on ventricular repolarization: results of a thorough QT study (TQTS) with QT-concentration analysis.

PubMed

Tyl, Benoît; Kabbaj, Meriam; Azzam, Sara; Sologuren, Ander; Valiente, Román; Reinbolt, Elizabeth; Roupe, Kathryn; Blanco, Nathalie; Wheeler, William

2012-06-01

The effect of bilastine on cardiac repolarization was studied in 30 healthy participants during a multiple-dose, triple-dummy, crossover, thorough QT study that included 5 arms: placebo, active control (400 mg moxifloxacin), bilastine at therapeutic and supratherapeutic doses (20 mg and 100 mg once daily, respectively), and bilastine 20 mg administered with ketoconazole 400 mg. Time-matched, triplicate electrocardiograms (ECGs) were recorded with 13 time points extracted predose and 16 extracted over 72 hours post day 4 dosing. Four QT/RR corrections were implemented: QTcB; QTcF; a linear individual correction (QTcNi), the primary correction; and a nonlinear one (QTcNnl). Moxifloxacin was associated with a significant increase in QTcNi at all time points between 1 and 12 hours, inclusively. Bilastine administration at 20 mg and 100 mg had no clinically significant impact on QTc (maximum increase in QTcNi, 5.02 ms; upper confidence limit [UCL] of the 1-sided, 95% confidence interval, 7.87 ms). Concomitant administration of ketoconazole and bilastine 20 mg induced a clinically relevant increase in QTc (maximum increase in QTcNi, 9.3 ms; UCL, 12.16 ms). This result was most likely related to the cardiac effect of ketoconazole because for all time points, bilastine plasma concentrations were lower than those observed following the supratherapeutic dose.

Effect of dexmedetomidine on the QT interval in pediatric patients undergoing general anesthesia.

PubMed

Kako, Hiromi; Krishna, Senthil G; Sebastian, Roby; Smith, Kyle; Tobias, Joseph D

2015-12-01

Recent years have seen an increase in the use of dexmedetomidine in pediatric patients presenting for surgical procedures. However, only a limited number of studies have evaluated its effects on the QT interval in this patient group. To address this lack of knowledge, we have evaluated the effects of dexmedetomidine on the QT interval in children receiving sevoflurane anesthesia. This study was a prospective case-control study in which pediatric patients presenting for anesthetic care were divided into two groups--the dexmedetomidine (D) and control (C) groups. Three electrocardiograms (ECGs) were obtained on each patient, including a baseline ECG (T1) prior to anesthetic induction and an ECG after the induction of anesthesia with sevoflurane (T2). In group D, the third ECG was obtained 2 min after the administration of dexmedetomidine, which in turn was started immediately after the T2 ECG reading (T3D); in group C, it was obtained 2 min after the T2 reading (T3C). Statistical analysis was performed using analysis of variance to compare the QT intervals at the three time points outlined above. A total of 50 patients were recruited to the study, ranging in age from 1 to 16 [mean 7.9 ± 4.1 (SD) years]. There were 25 patients in group C and 25 in group D. There were no statistical differences in the demographics between the 2 groups. In group C, the QTc was noted to increase progressively with the administration of sevoflurane (T3C vs. T1; P = 0.006). In group D, following the administration of dexmedetomidine, there was a significant decrease in the QTc relative to the post-induction value [436 ± 25 (T2) vs. 418 ± 17 ms (T3D); P < 0.01]. A progressive lengthening of the QTc interval following the administration of sevoflurane was observed in the control group. In the dexmedetomidine group, there was a significant shortening of the QTc interval following the administration of dexmedetomidine compared to the length of the post-induction QTc interval and when

Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations.

PubMed

Perry, Matthew D; Ng, Chai Ann; Phan, Kevin; David, Erikka; Steer, Kieran; Hunter, Mark J; Mann, Stefan A; Imtiaz, Mohammad; Hill, Adam P; Ke, Ying; Vandenberg, Jamie I

2016-07-15

Most missense long QT syndrome type 2 (LQTS2) mutations result in Kv11.1 channels that show reduced levels of membrane expression. Pharmacological chaperones that rescue mutant channel expression could have therapeutic potential to reduce the risk of LQTS2-associated arrhythmias and sudden cardiac death, but only if the mutant Kv11.1 channels function normally (i.e. like WT channels) after membrane expression is restored. Fewer than half of mutant channels exhibit relatively normal function after rescue by low temperature. The remaining rescued missense mutant Kv11.1 channels have perturbed gating and/or ion selectivity characteristics. Co-expression of WT subunits with gating defective missense mutations ameliorates but does not eliminate the functional abnormalities observed for most mutant channels. For patients with mutations that affect gating in addition to expression, it may be necessary to use a combination therapy to restore both normal function and normal expression of the channel protein. In the heart, Kv11.1 channels pass the rapid delayed rectifier current (IKr ) which plays critical roles in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Over 500 inherited mutations in Kv11.1 are known to cause long QT syndrome type 2 (LQTS2), a cardiac electrical disorder associated with an increased risk of life threatening arrhythmias. Most missense mutations in Kv11.1 reduce the amount of channel protein expressed at the membrane and, as a consequence, there has been considerable interest in developing pharmacological agents to rescue the expression of these channels. However, pharmacological chaperones will only have clinical utility if the mutant Kv11.1 channels function normally after membrane expression is restored. The aim of this study was to characterize the gating phenotype for a subset of LQTS2 mutations to assess what proportion of mutations may be suitable for rescue. As an initial

Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

PubMed Central

Jehle, J; Ficker, E; Wan, X; Deschenes, I; Kisselbach, J; Wiedmann, F; Staudacher, I; Schmidt, C; Schweizer, PA; Becker, R; Katus, HA; Thomas, D

2013-01-01

Background and Purpose Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels. Experimental Approach Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. Key Results Zolpidem caused acute hERG channel blockade in oocytes (IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I–V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. Conclusions and Implications Zolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose. PMID:23061993

Design of MPPT Controller Monitoring Software Based on QT Framework

NASA Astrophysics Data System (ADS)

Meng, X. Z.; Lu, P. G.

2017-10-01

The MPPT controller was a hardware device for tracking the maximum power point of solar photovoltaic array. Multiple controllers could be working as networking mode by specific communicating protocol. In this article, based on C++ GUI programming with Qt frame, we designed one sort of desktop application for monitoring and analyzing operational parameter of MPPT controller. The type of communicating protocol for building network was Modbus protocol which using Remote Terminal Unit mode and The desktop application of host computer was connected with all the controllers in the network through RS485 communication or ZigBee wireless communication. Using this application, user could monitor the parameter of controller wherever they were by internet.

The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses

PubMed Central

Ring, Arne; Port, Andreas; Graefe-Mody, E Ulrike; Revollo, Ivette; Iovino, Mario; Dugi, Klaus A

2011-01-01

AIM To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QTc interval in healthy subjects. METHODS The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QTcI) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained. RESULTS Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QTcI, at any time point. The placebo-corrected MCfB of QTcI was −1.1 (90% CI −2.7, 0.5) ms and −2.5 (–4.1, –0.9) ms for linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were ∼24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QTcI with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. CONCLUSIONS Therapeutic and significantly supratherapeutic exposure to linagliptin is not associated with QT interval prolongation. PMID:21306414

Drug-physiology interaction and its influence on the QT prolongation-mechanistic modeling study.

PubMed

Wiśniowska, Barbara; Polak, Sebastian

2018-06-01

The current study is an example of drug-disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology-ten Tusscher ventricular cardiomyocyte cell model-was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Simulated and observed mean QTc values with standard deviation (SD) for each reported study point were compared and differences were analyzed with Student's t test (α = 0.05). The simulated results reflected the QTc interval changes measured in patients, as well as their clinically observed interindividual variability. The QTc interval changes were highly correlated with the change in plasma potassium both in clinical studies and in the simulations (Pearson's correlation coefficient > 0.55). The results suggest that the modeling and simulation approach could provide valuable quantitative insight into the cardiological effect of the potassium and heart rate changes caused by electrophysiologically inactive, non-cardiological drugs. This allows to simulate and predict the joint effect of several risk factors for QT prolongation, e.g., drug-dependent QT prolongation due to the ion channels inhibition and the current patient physiological conditions.

Cochlear implantation in children with Jervell and Lange-Nielsen syndrome - a cautionary tale.

PubMed

Broomfield, Stephen J; Bruce, Iain A; Henderson, Lise; Ramsden, Richard T; Green, Kevin M J

2012-08-01

Jervell and Lange-Nielsen (JLN) syndrome is a rare cause of congenital profound hearing loss associated with a prolonged QT interval on the electrocardiogram. Children presenting for cochlear implantation with this condition may be asymptomatic but are at risk of sudden death. SCREENING AND SUBSEQUENT: careful management is therefore required to ensure a successful outcome. We present our experience of cochlear implantation in children with JLN syndrome, including two who died unexpectedly, and suggest a protocol for management of such cases. Clinical presentation Four cases of cochlear implantation in JLN syndrome are described. None had any previous cardiological family history. Two were diagnosed pre-operatively but, despite appropriate management under a cardiologist, died from cardiac arrest; the first in the perioperative period following reimplantation for infection, and the second unrelated to his cochlear implant surgery. The other two patients were diagnosed only subsequent to their implantation and continue to use their implants successfully. These cases highlight the variation in presentation of JLN syndrome, and the spectrum of disease severity that exists. Our protocol stresses the importance of careful assessment and counselling of parents by an experienced implant team.

Convergence of models of human ventricular myocyte electrophysiology after global optimization to recapitulate clinical long QT phenotypes.

PubMed

Mann, Stefan A; Imtiaz, Mohammad; Winbo, Annika; Rydberg, Annika; Perry, Matthew D; Couderc, Jean-Philippe; Polonsky, Bronislava; McNitt, Scott; Zareba, Wojciech; Hill, Adam P; Vandenberg, Jamie I

2016-11-01

In-silico models of human cardiac electrophysiology are now being considered for prediction of cardiotoxicity as part of the preclinical assessment phase of all new drugs. We ask the question whether any of the available models are actually fit for this purpose. We tested three models of the human ventricular action potential, the O'hara-Rudy (ORD11), the Grandi-Bers (GB10) and the Ten Tusscher (TT06) models. We extracted clinical QT data for LQTS1 and LQTS2 patients with nonsense mutations that would be predicted to cause 50% loss of function in I Ks and I Kr respectively. We also obtained clinical QT data for LQTS3 patients. We then used a global optimization approach to improve the existing in silico models so that they reproduced all three clinical data sets more closely. We also examined the effects of adrenergic stimulation in the different LQTS subsets. All models, in their original form, produce markedly different and unrealistic predictions of QT prolongation for LQTS1, 2 and 3. After global optimization of the maximum conductances for membrane channels, all models have similar current densities during the action potential, despite differences in kinetic properties of the channels in the different models, and more closely reproduce the prolongation of repolarization seen in all LQTS subtypes. In-silico models of cardiac electrophysiology have the potential to be tremendously useful in complementing traditional preclinical drug testing studies. However, our results demonstrate they should be carefully validated and optimized to clinical data before they can be used for this purpose. Copyright © 2016 Elsevier Ltd. All rights reserved.

A comparison between lactose breath test and quick test on duodenal biopsies for diagnosing lactase deficiency in patients with self-reported lactose intolerance.

PubMed

Furnari, Manuele; Bonfanti, Daria; Parodi, Andrea; Franzè, Jolanda; Savarino, Edoardo; Bruzzone, Luca; Moscatelli, Alessandro; Di Mario, Francesco; Dulbecco, Pietro; Savarino, Vincenzo

2013-02-01

A lactose breath test (LBT) is usually used to diagnose lactase deficiency, and a lactose quick test (LQT) has been proposed as a new test on duodenal biopsies to detect this disorder. We aimed to assess the diagnostic accuracy of LBT and LQT and their ability to predict the clinical response to a lactose-free diet in patients with self-reported lactose intolerance. Fifty-five patients (age 47 ± 14 y; M/F 15/36) underwent upper gastrointestinal endoscopy and 25g-LBT. Two duodenal biopsies were taken to determine lactase deficiency (normal, mild, or severe) by LQT and to rule out other causes of secondary lactose malabsorption. Patients with a positive LBT and normal LQT also underwent a glucose breath test to exclude small intestinal bacterial overgrowth as a cause of the former result. The severity of gastrointestinal symptoms was measured with a GSS questionnaire, under basal condition and 1 month after a lactose-free diet. Lactose malabsorption was detected in 31/51 patients with LBT and in 37/51 patients with LQT (P = NS). Celiac disease was found in 2 patients. Two LBT+ patients showed a positive glucose breath test for small intestinal bacterial overgrowth. Eight patients had a mild hypolactasia by LQT and a negative LBT, but they had a significant improvement of symptoms after diet. LQT and LBT were concordant in 83% of cases and predicted the response to a lactose-free diet in 98% and 81% of the cases, respectively (P = 0.03). LQT is as sensitive as LBT in detecting lactase deficiency; however, it seems to be more accurate than LBT in predicting the clinical response to a lactose-free diet.

Brugada syndrome: More than 20 years of scientific excitement.

PubMed

Brugada, Pedro

2016-03-01

In 1992 we reported on eight patients with a particular electrocardiograph (ECG) showing ST segment elevation in the right precordial leads. All patients had a structurally normal heart and had survived one or multiple episodes of near sudden death caused by ventricular fibrillation. We showed 6 years later that this disease, known nowadays as Brugada syndrome, was caused by mutations in the SCN5A gene which encodes for the cardiac sodium channel. Other genes where mutations result in the same ECG have been also identified, with at present more than 17 different genes published. These data show that Brugada syndrome is a genetically heterogeneous disease as is also the case in the long QT syndrome. In Brugada syndrome, the clue to the initial clinical diagnosis remains the abnormal ECG. However, it was evident from the beginning that the ECG of Brugada syndrome is variable and sensitive to many autonomic, drug, exercise, emotions and other external influences such as a meal, fever, changes in heart rate from any cause, and even body position. When followed intensively, all patients with a Brugada ECG will show a completely normal ECG at one or another moment in their lives. The spontaneous normalization of the ECG represents a major diagnostic challenge, because a patient with Brugada syndrome seen during normalization of the ECG may fail to get the correct diagnosis. In these more than 20 years great challenges have been overcome but some remain, mainly the approach to the asymptomatic individual with a diagnosis of Brugada syndrome. In 30-50% of individuals who die suddenly because of documented or suspected Brugada syndrome, sudden death is the first manifestation of the disease. Thus, these individuals were fully asymptomatic until the first fatal event. Copyright © 2015. Published by Elsevier Ltd.

SCN5A (NaV1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance.

PubMed

Kroncke, Brett M; Glazer, Andrew M; Smith, Derek K; Blume, Jeffrey D; Roden, Dan M

2018-05-01

Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel SCN5A (protein Na V 1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare SCN5A variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance. From a comprehensive literature review, we quantified the number of carriers presenting with and without disease for 1712 reported SCN5A variants. For 356 variants, data were also available for 5 Na V 1.5 electrophysiological parameters: peak current, late/persistent current, steady-state V1/2 of activation and inactivation, and recovery from inactivation. We found that peak and late current significantly associate with Brugada syndrome ( P <0.001; ρ=-0.44; Spearman rank test) and long QT syndrome disease penetrance ( P <0.001; ρ=0.37). Steady-state V1/2 activation and recovery from inactivation associate significantly with Brugada syndrome and long QT syndrome penetrance, respectively. Continuous estimates of disease penetrance align with the current American College of Medical Genetics classification paradigm. Na V 1.5 in vitro electrophysiological parameters are correlated with Brugada syndrome and long QT syndrome disease risk. Our data emphasize the value of in vitro electrophysiological characterization and incorporating counts of affected and unaffected carriers to aid variant classification. This quantitative analysis of the electrophysiological literature should aid the interpretation of Na V 1.5 variant electrophysiological abnormalities and help improve Na V 1.5 variant classification. © 2018 American Heart Association, Inc.

Association of low-moderate urine arsenic and QT interval: Cross-sectional and longitudinal evidence from the Strong Heart Study.

PubMed

Moon, Katherine A; Zhang, Yiyi; Guallar, Eliseo; Francesconi, Kevin A; Goessler, Walter; Umans, Jason G; Best, Lyle G; Howard, Barbara V; Devereux, Richard B; Okin, Peter M; Navas-Acien, Ana

2018-05-21

Epidemiologic studies suggest that chronic exposure to arsenic is related to cardiovascular disease (CVD), but the pathophysiological link remains uncertain. We evaluated the association of chronic low-moderate arsenic exposure and arsenic metabolism with baseline difference and annual change in ECG measures (QT interval, JT interval, PR interval, QRS duration, and QT dispersion) using linear mixed models in the Strong Heart Study main cohort (N = 1174, median age 55 years) and family study (N = 1695 diabetes-free, median age 36 years). At baseline, arsenic exposure was measured as the sum of inorganic and methylated species in urine (ΣAs) and arsenic metabolism was measured as the relative percentage of arsenic species. Median ΣAs and Bazett heart rate-corrected QT interval (QTc) were 8.6 μg/g creatinine and 424 ms in the main cohort and 4.3 μg/g and 414 ms in the family study, respectively. In the main cohort, a comparison of the highest to lowest ΣAs quartile (>14.4 vs. <5.2 μg/g creatinine) was associated with a 5.3 (95% CI: 1.2, 9.5) ms higher mean baseline QTc interval but no difference in annual change in QTc interval. In the family study, a comparison of the highest to lowest quartile (>7.1 vs. <2.9 μg/g creatinine) was associated with a 3.2 (95% CI: 0.6, 5.7) ms higher baseline QTc interval and a 0.6 (95% CI: 0.04, 1.2) ms larger annual increase in QTc interval. Associations with JTc interval were similar but stronger in magnitude compared to QTc interval. Arsenic exposure was largely not associated with PR interval, QRS duration or QT dispersion. Similar to arsenic exposure, a pattern of lower %MMA and higher %DMA was associated with longer baseline QTc interval in both cohorts and with a larger annual change in QTc interval in the family study. Chronic low-moderate arsenic exposure and arsenic metabolism were associated with prolonged ventricular repolarization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Design of the arm-wrestling robot's force acquisition system based on Qt

NASA Astrophysics Data System (ADS)

Huo, Zhixiang; Chen, Feng; Wang, Yongtao

2017-03-01

As a collection of entertainment and medical rehabilitation in a robot, the research on the arm-wrestling robot is of great significance. In order to achieve the collection of the arm-wrestling robot's force signals, the design and implementation of arm-wrestling robot's force acquisition system is introduced in this paper. The system is based on MP4221 data acquisition card and is programmed by Qt. It runs successfully in collecting the analog signals on PC. The interface of the system is simple and the real-time performance is good. The result of the test shows the feasibility in arm-wrestling robot.

Usefulness of automatic QT dispersion measurement for detecting exercise-induced myocardial ischemia.

PubMed

Takase, Bonpei; Masaki, Nobuyuki; Hattori, Hidemi; Ishihara, Masayuki; Kurita, Akira

2009-06-01

The electrocardiographic index of QT dispersion (QTd) is related to the occurrence of arrhythmia. In patients with suspected or known coronary artery disease, QTd may be affected by exercise. We investigated whether QTd that is automatically calculated by a newly developed computer system could be used as a marker of exercise-induced myocardial ischemia. The design of this study was prospective and observational. Eighty-three consecutive patients were enrolled in this study. Their QTd was measured at rest and after 3 min of exercise during exercise-stress Thallium-201 scintigraphy and compared with conventional ST-segment changes. The patients were classified into 4 groups (normal group, redistribution group, fixed defect group, redistribution with fixed defect group) based on the result of single photon emission computed tomography. As statistical analysis, one-way ANOVA with post-hoc Scheffe's method, receiver-operating characteristics (ROC) and multiple logistic regression analysis were performed. At rest, QTd was significantly greater (p<0.05) in the fixed defect group (52+/-21 ms) and the redistribution with fixed defect group (53+/-20 ms) than in the normal group (32+/-14 ms) and the redistribution group (31+/-16 ms). However, QTd tended to increase after exercise in the redistribution group, while QTd tended to decrease in the normal group, the fixed defect group, and the redistribution with fixed defect group (QTd after exercise, normal group, 28+/-17 ms, redistribution group, 35+/-19 ms, fixed defect group, 43+/-25 ms, redistribution with fixed defect group, 49+/-27 ms). Exercise significantly increased QTcd (RR interval-corrected QT dispersion) in the redistribution group. The best cut-off values of QTd and QTcd obtained from ROC curves for exercise-induced myocardial ischemia were 41.6 ms and 40.4 ms, respectively (Qtd--AUC 0.68, 95%CI 0.53- 0.83 and QTcd--AUC 0.67, 95%CI 0.55-0.80). Using these values as cut-off ones, QTd, QTcd, and conventional ST

Is prolongation of corrected QT interval associated with seizures induced by electroconvulsive therapy reduced by atropine sulfate?

PubMed

Suzuki, Yoko; Miyajima, Miho; Ohta, Katsuya; Yoshida, Noriko; Omoya, Rie; Fujiwara, Mayo; Watanabe, Takafumi; Okumura, Masaki; Yamazaki, Hiroaki; Shintaku, Masayuki; Murata, Issei; Ozaki, Shigeru; Sasaki, Takeshi; Nakamura, Mitsuru; Suwa, Hiroshi; Sasano, Tetsuo; Kawara, Tokuhiro; Matsuura, Masato; Matsushima, Eisuke

2017-11-01

Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. We analyzed heart rate, QT interval, and QTc in 32 patients with depression who underwent ECT (25 women, 67.4 ± 8.7 years of age). The QTc from -30 to 0 seconds prestimulation was used as baseline, which was compared with QTc at 20-30 seconds and 140-150 seconds poststimulus onset. QTc was significantly prolonged at 20-30 seconds poststimulus, then significantly decreased at 140-150 seconds poststimulus, compared with baseline. QTc prolongation induced by ECT was significantly decreased by atropine sulfate. These data suggest that the risk of TdP may be enhanced by ECT. Further, the risk of cardiac ventricular arrhythmias, including TdP, may be reduced by administration of atropine sulfate. © 2017 Wiley Periodicals, Inc.

Testosterone-mediated upregulation of delayed rectifier potassium channel in cardiomyocytes causes abbreviation of QT intervals in rats.

PubMed

Masuda, Kimiko; Takanari, Hiroki; Morishima, Masaki; Ma, FangFang; Wang, Yan; Takahashi, Naohiko; Ono, Katsushige

2018-01-13

Men have shorter rate-corrected QT intervals (QTc) than women, especially at the period of adolescence or later. The aim of this study was to elucidate the long-term effects of testosterone on cardiac excitability parameters including electrocardiogram (ECG) and potassium channel current. Testosterone shortened QT intervals in ECG in castrated male rats, not immediately after, but on day 2 or later. Expression of Kv7.1 (KCNQ1) mRNA was significantly upregulated by testosterone in cardiomyocytes of male and female rats. Short-term application of testosterone was without effect on delayed rectifier potassium channel current (I Ks ), whereas I Ks was significantly increased in cardiomyocytes treated with dihydrotestosterone for 24 h, which was mimicked by isoproterenol (24 h). Gene-selective inhibitors of a transcription factor SP1, mithramycin, abolished the effects of testosterone on Kv7.1. Testosterone increases Kv7.1-I Ks possibly through a pathway related to a transcription factor SP1, suggesting a genomic effect of testosterone as an active factor for cardiac excitability.

Is there a new finding added to the fibromyalgia syndrome?

PubMed

Sarifakioglu, Banu; Guzelant, Aliye Yildirim; Alpsoy, Seref; Topcu, Birol; Unsal, Cuneyt; Sahin, Nilay

2014-01-01

The aim of this study is to examine depression and anxiety related arrhytmia risk in fibromyalgia syndrome (FMS). Fifty-nine patients with the diagnosis of FMS and 20 control participants were included in the study. Fibromyalgia Impact Questionnaire (FIQ), Visual Pain Scale (VPS) surveys were applied to determine the severity of the disease. Beck Anxiety (BAS) and Beck Depression scales (BDS) were applied to all participants. Electrocardiograms were obtained from all participants. P-wave dispersions (Pd) were estimated to determine the risk of the atrial arrhythmia, and QT wave dispersion (QTd) and corrected QT(QTdd) values were used to predict the risk of ventricular arrhythmia. BAS and BDS results were significantly higher in the patient group compared to the control group (p˂0001). In the patient group, Pd was significantly longer (p=0.034). Other clinical, and demographic data did not differ significantly between groups. In this study, the risk of arrhythmia in FMS was evaluated and increased Pd in patients with FMS compared to the control group was detected. This finding shows increased risk of atrial fibrilation (AF) in patients with FMS. If we consider that patients with fibromyalgia consist relatively of young patients together with the increased risk of AF with age, it is important to follow-up these patients in later ages for AF risk.

Sudden death in type 1 diabetes: the mystery of the 'dead in bed' syndrome.

PubMed

Tu, Emily; Twigg, Stephen M; Semsarian, Christopher

2010-01-07

Sudden cardiac death is an unpredictable and devastating event, particularly in the young. A significant proportion of sudden deaths in the young are unexplained-no cause is identified either during life or at post-mortem. This is seen in a subgroup of young patients with type 1 diabetes who have dead in bed syndrome, where these victims are in good health, retire to bed, only to be found dead the following morning in a bed which is undisturbed, suggesting no terminal struggle or seizure. The underlying cause of dead in bed syndrome remains unknown, but is likely to be due to a terminal malignant arrhythmia. A plausible hypothesis is that it may be secondary to QT interval prolongation (followed by a degenerate ventricular tachycardia), caused by a number of factors including acute hypoglycaemia, on a background of cardiac autonomic neuropathy, and possible genetic influences. It is envisaged that understanding the causes and triggers of dead in bed syndrome will allow appropriate therapeutic interventions to be initiated in high-risk patients with type 1 diabetes, with the ultimate goal to prevent sudden death.

Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

PubMed Central

Park, Eunjung; Gintant, Gary A; Bi, Daoqin; Kozeli, Devi; Pettit, Syril D; Skinner, Matthew; Willard, James; Wisialowski, Todd; Koerner, John; Valentin, Jean‐Pierre

2018-01-01

Background and Purpose Translation of non‐clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non‐clinical in vitro IKr current human ether‐à‐go‐go‐related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. Experimental Approach The predictive performance of three non‐clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). Key Results Non‐clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low‐intermediate (1×–30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post‐test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. Conclusions and Implications The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay. PMID:29181850

Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers.

PubMed

Kropeit, D; Johnson, M; Cawello, W; Rudd, G D; Horstmann, R

2015-11-01

To determine whether lacosamide prolongs the corrected QT interval (QTc). In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. Lacosamide (≤ 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

ShelXle: a Qt graphical user interface for SHELXL.

PubMed

Hübschle, Christian B; Sheldrick, George M; Dittrich, Birger

2011-12-01

ShelXle is a graphical user interface for SHELXL [Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122], currently the most widely used program for small-molecule structure refinement. It combines an editor with syntax highlighting for the SHELXL-associated .ins (input) and .res (output) files with an interactive graphical display for visualization of a three-dimensional structure including the electron density (F(o)) and difference density (F(o)-F(c)) maps. Special features of ShelXle include intuitive atom (re-)naming, a strongly coupled editor, structure visualization in various mono and stereo modes, and a novel way of displaying disorder extending over special positions. ShelXle is completely compatible with all features of SHELXL and is written entirely in C++ using the Qt4 and FFTW libraries. It is available at no cost for Windows, Linux and Mac-OS X and as source code.

Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias

ClinicalTrials.gov

2017-08-10

Inherited Cardiac Arrythmias; Long QT Syndrome (LQTS); Brugada Syndrome (BrS); Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT); Early Repolarization Syndrome (ERS); Arrhythmogenic Cardiomyopathy (AC, ARVD/C); Hypertrophic Cardiomyopathy (HCM); Dilated Cardiomyopathy (DCM); Muscular Dystrophies (Duchenne, Becker, Myotonic Dystrophy); Normal Control Subjects

The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction.

PubMed

van der Linde, H J; Van Deuren, B; Teisman, A; Towart, R; Gallacher, D J

2008-08-01

Body core temperature (Tc) changes affect the QT interval, but correction for this has not been systematically investigated. It may be important to correct QT intervals for drug-induced changes in Tc. Anaesthetized beagle dogs were artificially cooled (34.2 degrees C) or warmed (42.1 degrees C). The relationship between corrected QT intervals (QTcV; QT interval corrected according to the Van de Water formula) and Tc was analysed. This relationship was also examined in conscious dogs where Tc was increased by exercise. When QTcV intervals were plotted against changes in Tc, linear correlations were observed in all individual dogs. The slopes did not significantly differ between cooling (-14.85+/-2.08) or heating (-13.12+/-3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 degrees C: QTcVcT (QTcV corrected for changes in core temperature)=QTcV-14 (37.5 - Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 degrees C) and marked QTcV shortening (-29%) was induced. After Tc correction, using the above formula, this decrease was abolished. In these re-warmed dogs, we observed significant increases in T-wave amplitude and in serum [K(+)] levels. No arrhythmias or increase in pro-arrhythmic biomarkers were observed. In exercising dogs, the above formula completely compensated QTcV for the temperature increase. This study shows the importance of correcting QTcV intervals for changes in Tc, to avoid misleading interpretations of apparent QTcV interval changes. We recommend that all ICH S7A, conscious animal safety studies should routinely measure core body temperature and correct QTcV appropriately, if body temperature and heart rate changes are observed.

A genome-wide interaction analysis of tri/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium

PubMed Central

Noordam, Raymond; Sitlani, Colleen M; Avery, Christy L; Stewart, James D; Gogarten, Stephanie M; Wiggins, Kerri L; Trompet, Stella; Warren, Helen R; Sun, Fangui; Evans, Daniel S; Li, Xiaohui; Li, Jin; Smith, Albert V; Bis, Joshua C; Brody, Jennifer A; Busch, Evan L; Caulfield, Mark J; Chen, Yii-Der I; Cummings, Steven R; Cupples, L Adrienne; Duan, Qing; Franco, Oscar H; Méndez-Giráldez, Rául; Harris, Tamara B; Heckbert, Susan R; van Heemst, Diana; Hofman, Albert; Floyd, James S; Kors, Jan A; Launer, Lenore J; Li, Yun; Li-Gao, Ruifang; Lange, Leslie A; Lin, Henry J; de Mutsert, Renée; Napier, Melanie D; Newton-Cheh, Christopher; Poulter, Neil; Reiner, Alexander P; Rice, Kenneth M; Roach, Jeffrey; Rodriguez, Carlos J; Rosendaal, Frits R; Sattar, Naveed; Sever, Peter; Seyerle, Amanda A; Slagboom, P Eline; Soliman, Elsayed Z; Sotoodehnia, Nona; Stott, David J; Stürmer, Til; Taylor, Kent D; Thornton, Timothy A; Uitterlinden, André G; Wilhelmsen, Kirk C; Wilson, James G; Gudnason, Vilmundur; Jukema, J Wouter; Laurie, Cathy C; Liu, Yongmei; Mook-Kanamori, Dennis O; Munroe, Patricia B; Rotter, Jerome I; Vasan, Ramachandran S; Psaty, Bruce M; Stricker, Bruno H; Whitsel, Eric A

2017-01-01

Background Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tri/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. Methods and Results We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap Phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45,706; n=1,417 TCA users), African (n=10,235; n=296 TCA users) and Hispanic/Latino (n=13,808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β = 56.3, Pinteraction = 3.9e−9) and rs9830388 in UBE2E2 (β = 25.2, Pinteraction = 1.7e−8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β = 9.3, Pinteraction = 2.55e−8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (Pinteraction > 0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. Conclusion Among Europeans, TCA interactions with variants in BRE and UBE2E2, were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results. PMID:28039329

Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs.

PubMed

Singh, Bramah N; Wadhani, Nitin

2004-09-01

In recent years there has been a major reorientation of drug therapy for cardiac arrhythmias, its changing role, and above all, a radical change in the class of arrhythmia drugs because of their impact on mortality. The decline in the use of sodium-channel blockers has led to an ex panding use of beta-blockers and simple or complex class III agents for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion-channel blocking properties that have less complex adverse reactions. The resulting so-called pure class III agents, such as dofetilide or ibutilide, were found to have antifibrillatory effects in atrial fibrillation and flutter and in ventricular tachyarrhythmias. Such agents are effective and have diversity, but they have come into therapeutics with a price: the sometimes-fatal torsades de pointes. The drug amiodarone, a complex compound that was synthesized as an antianginal agent, has been an exception in this regard. Its therapeutic use is associated with a negligibly low incidence of torsades de pointes, even though the drug produces significant bradycardia and QT lengthening to 500 to 700 msec. Recent electrophysiologic studies suggest that this paradox is likely due to the differential block of ion channels in endocardium, epicardium, midmyocardial (M) cells, and Purkinje fibers in the ventricular myocardium. There is also clinical evidence suggesting that amiodarone reduces the "torsadogenic" effects of pure class III agents. Ranolazine was also synthesized for the development of antianginal properties that stem from a partial inhibition of fatty acid oxidation; it too has been found to have electrophysioloigic properties. These are somewhat similar to those of amiodarone on ion channels in endocardium, epicardium, M cells, and Purkinje fibers in the ventricular myocardium, but the drug does not prolong the QT interval to the same extent as amiodarone does

Risk Factors and Causes of Syncope

MedlinePlus

... Risk Factors & Causes of Syncope Risk Factors for Cardiovascular Syncope The risk of cardiovascular syncope increases with ... Long QT syndrome and Brugada Syndrome Signs of Cardiovascular Syncope Cardiovascular syncope usually is sudden. There may ...

Predictive Value of Beat-to-Beat QT Variability Index across the Continuum of Left Ventricular Dysfunction: Competing Risks of Non-cardiac or Cardiovascular Death, and Sudden or Non-Sudden Cardiac Death

PubMed Central

Tereshchenko, Larisa G.; Cygankiewicz, Iwona; McNitt, Scott; Vazquez, Rafael; Bayes-Genis, Antoni; Han, Lichy; Sur, Sanjoli; Couderc, Jean-Philippe; Berger, Ronald D.; de Luna, Antoni Bayes; Zareba, Wojciech

2012-01-01

Background The goal of this study was to determine the predictive value of beat-to-beat QT variability in heart failure (HF) patients across the continuum of left ventricular dysfunction. Methods and Results Beat-to-beat QT variability index (QTVI), heart rate variance (LogHRV), normalized QT variance (QTVN), and coherence between heart rate variability and QT variability have been measured at rest during sinus rhythm in 533 participants of the Muerte Subita en Insuficiencia Cardiaca (MUSIC) HF study (mean age 63.1±11.7; males 70.6%; LVEF >35% in 254 [48%]) and in 181 healthy participants from the Intercity Digital Electrocardiogram Alliance (IDEAL) database. During a median of 3.7 years of follow-up, 116 patients died, 52 from sudden cardiac death (SCD). In multivariate competing risk analyses, the highest QTVI quartile was associated with cardiovascular death [hazard ratio (HR) 1.67(95%CI 1.14-2.47), P=0.009] and in particular with non-sudden cardiac death [HR 2.91(1.69-5.01), P<0.001]. Elevated QTVI separated 97.5% of healthy individuals from subjects at risk for cardiovascular [HR 1.57(1.04-2.35), P=0.031], and non-sudden cardiac death in multivariate competing risk model [HR 2.58(1.13-3.78), P=0.001]. No interaction between QTVI and LVEF was found. QTVI predicted neither non-cardiac death (P=0.546) nor SCD (P=0.945). Decreased heart rate variability (HRV) rather than increased QT variability was the reason for increased QTVI in this study. Conclusions Increased QTVI due to depressed HRV predicts cardiovascular mortality and non-sudden cardiac death, but neither SCD nor excracardiac mortality in HF across the continuum of left ventricular dysfunction. Abnormally augmented QTVI separates 97.5% of healthy individuals from HF patients at risk. PMID:22730411

ELECTROCARDIOGRAPHIC ABNORMALITIES AMONG MEXICAN AMERICANS: CORRELATIONS WITH DIABETES, OBESITY, AND THE METABOLIC SYNDROME.

PubMed

Queen, Saulette R; Smulevitz, Beverly; Rentfro, Anne R; Vatcheva, Kristina P; Kim, Hyunggun; McPherson, David D; Hanis, Craig L; Fisher-Hoch, Susan P; McCormick, Joseph B; Laing, Susan T

2012-04-01

Resting ischemic electrocardiographic abnormalities have been associated with cardiovascular mortality. Simple markers of abnormal autonomic tone have also been associated with diabetes, obesity, and the metabolic syndrome in some populations. Data on these electrocardiographic abnormalities and correlations with coronary risk factors are lacking among Mexican Americans wherein these conditions are prevalent. This study aimed to evaluate the prevalent resting electrocardiographic abnormalities among community-dwelling Mexican Americans, and correlate these findings with coronary risk factors, particularly diabetes, obesity, and the metabolic syndrome. Study subjects (n=1280) were drawn from the Cameron County Hispanic Cohort comprised of community-dwelling Mexican Americans living in Brownsville, Texas at the United States-Mexico border. Ischemic electrocardiographic abnormalities were defined as presence of ST/T wave abnormalities suggestive of ischemia, abnormal Q waves, and left bundle branch block. Parameters that reflect autonomic tone, such as heart rate-corrected QT interval and resting heart rate, were also measured. Ischemic electrocardiographic abnormalities were more prevalent among older persons and those with hypertension, diabetes, obesity, and the metabolic syndrome. Subjects in the highest quartiles of QTc interval and resting heart rate were also more likely to be diabetic, hypertensive, obese, or have the metabolic syndrome. Among Mexican Americans, persons with diabetes, obesity, and the metabolic syndrome were more likely to have ischemic electrocardiographic abnormalities, longer QTc intervals, and higher resting heart rates. A resting electrocardiogram can play a complementary role in the comprehensive evaluation of cardiovascular risk in this minority population.

Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale?

PubMed

Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C

2013-12-01

Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes.

Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse

PubMed Central

Park, Man Young; Kim, Eun Yeob; Lee, Young Ho; Kim, Woojae; Kim, Ku Sang; Sheen, Seung Soo; Lim, Hong Seok

2011-01-01

Objective The aim of this study was to examine whether or not levofloxacin has any relationship with QT prolongation in a real clinical setting by analyzing a clinical data warehouse of data collected from different hospital information systems. Methods Electronic prescription data and medical charts from 3 different hospitals spanning the past 9 years were reviewed, and a clinical data warehouse was constructed. Patients who were both administrated levofloxacin and given electrocardiograms (ECG) were selected. The correlations between various patient characteristics, concomitant drugs, corrected QT (QTc) prolongation, and the interval difference in QTc before and after levofloxacin administration were analyzed. Results A total of 2,176 patients from 3 different hospitals were included in the study. QTc prolongation was found in 364 patients (16.7%). The study revealed that age (OR 1.026, p < 0.001), gender (OR 0.676, p = 0.007), body temperature (OR 1.267, p = 0.024), and cigarette smoking (OR 1.641, p = 0.022) were related with QTc prolongation. After adjusting for related factors, 12 drugs concomitant with levofloxacin were associated with QTc prolongation. For patients who took ECGs before and after administration of levofloxacin during their hospitalization (n = 112), there was no significant difference in QTc prolongation. Conclusions The age, gender, body temperature, cigarette smoking and various concomitant drugs might be related with QTc prolongation. However, there was no definite causal relationship or interaction between levofloxacin and QTc prolongation. Alternative surveillance methods utilizing the massive accumulation of electronic medical data seem to be essential to adverse drug reaction surveillance in future. PMID:21818458

Changes in ST, QT and RR ECG intervals during acute stress in firefighters: a pilot study.

PubMed

Paiva, Joana S; Rodrigues, Susana; Cunha, Joao Paulo Silva

2016-08-01

Firefighting is a stressful occupation. The monitoring of psychophysiological measures in those professionals can be a way to prevent and early detect cardiac diseases and other stress-related problems. The current study aimed to assess morphological changes in the ECG signal induced by acute stress. A laboratory protocol was conducted among 6 firefighters, including a laboratory stress-inducer task - the Trier Social Stress Task (TSST) - and a 2-choice reaction time task (CRTT) that was performed before (CRTT1) and after (CRTT2) the stress condition. ECG signals were continuously acquired using the VitalJacket®, a wearable t-shirt that acts as a medical certified ECG monitor. Results showed that ECG morphological features such as QT and ST intervals are able to differentiate stressful from non stressful events in first responders. Group mean Visual Analogue Scale (VAS) for stress assessment significantly increased after the stress task (TSST), relatively to the end of CRTT2 (after TSST: 4.67±1.63; after CRTT2: 3.17±0.75), a change that was accompanied by a significant increase in group mean QT and ST segments corrected for heart rate during TSST. These encouraging results will be followed by larger studies in order to explore those measures and its physiological impact under realistic environments in a higher scalability.

The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction

PubMed Central

van der Linde, H J; Van Deuren, B; Teisman, A; Towart, R; Gallacher, D J

2008-01-01

Background and purpose: Body core temperature (Tc) changes affect the QT interval, but correction for this has not been systematically investigated. It may be important to correct QT intervals for drug-induced changes in Tc. Experimental approach: Anaesthetized beagle dogs were artificially cooled (34.2 °C) or warmed (42.1 °C). The relationship between corrected QT intervals (QTcV; QT interval corrected according to the Van de Water formula) and Tc was analysed. This relationship was also examined in conscious dogs where Tc was increased by exercise. Key results: When QTcV intervals were plotted against changes in Tc, linear correlations were observed in all individual dogs. The slopes did not significantly differ between cooling (−14.85±2.08) or heating (−13.12±3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 °C: QTcVcT (QTcV corrected for changes in core temperature)=QTcV–14 (37.5 – Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 °C) and marked QTcV shortening (−29%) was induced. After Tc correction, using the above formula, this decrease was abolished. In these re-warmed dogs, we observed significant increases in T-wave amplitude and in serum [K+] levels. No arrhythmias or increase in pro-arrhythmic biomarkers were observed. In exercising dogs, the above formula completely compensated QTcV for the temperature increase. Conclusions and implications: This study shows the importance of correcting QTcV intervals for changes in Tc, to avoid misleading interpretations of apparent QTcV interval changes. We recommend that all ICH S7A, conscious animal safety studies should routinely measure core body temperature and correct QTcV appropriately, if body temperature and heart rate changes are observed. PMID:18574451

Jervell and Lange-Nielsen Syndrome (Long QT Syndrome).

ERIC Educational Resources Information Center

Hulbert, T. P.

1994-01-01

Clinical features, pathogenetic hypotheses, and symptoms of the cardio-auditory or surdo-cardiac disorder first reported by Jervell and Lange-Nielsen are described, and methods of diagnosis and treatment are presented, to alert teachers and other professionals to potentially life-threatening symptoms they may observe when working with deaf and…

A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers.

PubMed

Kim, Anhye; Lim, Kyoung Soo; Lee, Howard; Chung, Hyewon; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Jang, In-Jin; Chung, Jae-Yong

2016-07-01

Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4×4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for ΔΔQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the ΔΔQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on ΔΔQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-ΔΔQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose-response manner.

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study.

PubMed

Mehta, Puja K; Johnson, B Delia; Kenkre, Tanya S; Eteiba, Wafia; Sharaf, Barry; Pepine, Carl J; Reis, Steven E; Rogers, William J; Kelsey, Sheryl F; Thompson, Diane V; Bittner, Vera; Sopko, George; Shaw, Leslee J; Bairey Merz, C Noel

2017-08-21

Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study. Overall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non-SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person-hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P <0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively ( P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression ( P =0.018) and longer corrected QT interval ( P =0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD ( P =0.033). SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Realtime Multichannel System for Beat to Beat QT Interval Variability

NASA Technical Reports Server (NTRS)

Starc, Vito; Schlegel, Todd T.

2006-01-01

The measurement of beat-to-beat QT interval variability (QTV) shows clinical promise for identifying several types of cardiac pathology. However, until now, there has been no device capable of displaying, in real time on a beattobeat basis, changes in QTV in all 12 conventional leads in a continuously monitored patient. While several software programs have been designed to analyze QTV, heretofore, such programs have all involved only a few channels (at most) and/or have required laborious user interaction or offline calculations and postprocessing, limiting their clinical utility. This paper describes a PC-based ECG software program that in real time, acquires, analyzes and displays QTV and also PQ interval variability (PQV) in each of the eight independent channels that constitute the 12lead conventional ECG. The system also processes certain related signals that are derived from singular value decomposition and that help to reduce the overall effects of noise on the realtime QTV and PQV results.

Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale?

PubMed Central

Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C.

2013-01-01

Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes. PMID:24653586

Effect of intravenous amiodarone on QT and T peak-T end dispersions in patients with nonischemic heart failure treated with cardiac resynchronization-defibrillator therapy and electrical storm.

PubMed

Ogiso, Masataka; Suzuki, Atsushi; Shiga, Tsuyoshi; Nakai, Kenji; Shoda, Morio; Hagiwara, Nobuhisa

2015-02-01

The effect of intravenous amiodarone on spatial and transmural dispersion of ventricular repolarization in patients receiving cardiac resynchronization therapy (CRT) remains unclear. We studied 14 patients with nonischemic heart failure who received CRT with a defibrillator, experienced electrical storm and were treated with intravenous amiodarone. Each patient underwent 12-lead electrocardiography (ECG) and 187-channel repolarization interval-difference mapping electrocardiography (187-ch RIDM-ECG) before and during the intravenous administration of amiodarone infusion. A recurrence of ventricular tachyarrhythmia was observed in 2 patients during the early period of intravenous amiodarone therapy. Intravenous amiodarone increased the corrected QT interval (from 470±52 ms to 508±55 ms, P=0.003), but it significantly decreased the QT dispersion (from 107±35 ms to 49±27 ms, P=0.001), T peak-T end (Tp-e) dispersion (from 86±17 ms to 28±28 ms, P=0.001), and maximum inter-lead difference between corrected Tp-e intervals as measured by using the 187-ch RIDM-ECG (from 83±13 ms to 50±19 ms, P=0.001). Intravenous amiodarone suppressed the electrical storm and decreased the QT and Tp-e dispersions in patients treated by using CRT with a defibrillator.

In vivo effects of the IKr agonist NS3623 on cardiac electrophysiology of the guinea pig.

PubMed

Hansen, Rie Schultz; Olesen, Søren-Peter; Rønn, Lars Christian B; Grunnet, Morten

2008-07-01

The long QT syndrome is characterized by a prolongation of the QT interval measured on the surface electrocardiogram. Prolonging the QT interval increases the risk of dangerous ventricular fibrillations, eventually leading to sudden cardiac death. Pharmacologically induced QT interval prolongations are most often caused by antagonizing effects on the repolarizing cardiac current called IKr. In humans IKr is mediated by the human ether-a-go-go related gene (hERG) potassium channel. We recently presented NS3623, a compound that selectively activates this channel. The present study was dedicated to examining the in vivo effects of NS3623. Injection of 30 mg/kg NS3623 shortened the corrected QT interval by 25 +/- 4% in anaesthetized guinea pigs. Accordingly, 50 mg/kg of NS3623 shortened the QT interval by 30 +/- 6% in conscious guinea pigs. Finally, pharmacologically induced QT prolongation by a hERG channel antagonist (0.15 mg/kg E-4031) could be reverted by injection of NS3623 (50 mg/kg) in conscious guinea pigs. In conclusion, the present in vivo study demonstrates that injection of the hERG channel agonist NS3623 results in shortening of the QTc interval as well as reversal of a pharmacologically induced QT prolongation in both anaesthetized and conscious guinea pigs.

Optimisation of Embryonic and Larval ECG Measurement in Zebrafish for Quantifying the Effect of QT Prolonging Drugs

PubMed Central

Dhillon, Sundeep Singh; Dóró, Éva; Magyary, István; Egginton, Stuart; Sík, Attila; Müller, Ferenc

2013-01-01

Effective chemical compound toxicity screening is of paramount importance for safe cardiac drug development. Using mammals in preliminary screening for detection of cardiac dysfunction by electrocardiography (ECG) is costly and requires a large number of animals. Alternatively, zebrafish embryos can be used as the ECG waveform is similar to mammals, a minimal amount of chemical is necessary for drug testing, while embryos are abundant, inexpensive and represent replacement in animal research with reduced bioethical concerns. We demonstrate here the utility of pre-feeding stage zebrafish larvae in detection of cardiac dysfunction by electrocardiography. We have optimised an ECG recording system by addressing key parameters such as the form of immobilization, recording temperature, electrode positioning and developmental age. Furthermore, analysis of 3 days post fertilization (dpf) zebrafish embryos treated with known QT prolonging drugs such as terfenadine, verapamil and haloperidol led to reproducible detection of QT prolongation as previously shown for adult zebrafish. In addition, calculation of Z-factor scores revealed that the assay was sensitive and specific enough to detect large drug-induced changes in QTc intervals. Thus, the ECG recording system is a useful drug-screening tool to detect alteration to cardiac cycle components and secondary effects such as heart block and arrhythmias in zebrafish larvae before free feeding stage, and thus provides a suitable replacement for mammalian experimentation. PMID:23579446

Cardiac Delayed Rectifier Potassium Channels in Health and Disease.

PubMed

Chen, Lei; Sampson, Kevin J; Kass, Robert S

2016-06-01

Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this article, we will review their molecular identities and biophysical properties. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiac Delayed Rectifier Potassium Channels in Health and Disease

PubMed Central

Chen, Lei; Sampson, Kevin J.; Kass, Robert S.

2016-01-01

Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this chapter, we will review the molecular identities and biophysical properties of these channels. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the possibility and prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. PMID:27261823

Linear quadratic tracking problems in Hilbert space - Application to optimal active noise suppression

NASA Technical Reports Server (NTRS)

Banks, H. T.; Silcox, R. J.; Keeling, S. L.; Wang, C.

1989-01-01

A unified treatment of the linear quadratic tracking (LQT) problem, in which a control system's dynamics are modeled by a linear evolution equation with a nonhomogeneous component that is linearly dependent on the control function u, is presented; the treatment proceeds from the theoretical formulation to a numerical approximation framework. Attention is given to two categories of LQT problems in an infinite time interval: the finite energy and the finite average energy. The behavior of the optimal solution for finite time-interval problems as the length of the interval tends to infinity is discussed. Also presented are the formulations and properties of LQT problems in a finite time interval.

The effect of Si-contents on the impact properties and dynamic graphite growth for cast iron QT400-18L

NASA Astrophysics Data System (ADS)

Lipeng, Jiang; Yingdong, Qu; Rongde, Li

2018-03-01

Low temperature impact test of QT400-18L ductile iron was investigated. The microstructure and fracture morphology were analyzed by the optical microscope and scanning electron microscope. The effect of different Si content on the graphite growth by liquid quenching method was discussed. There are the highest impact energies for the cast iron with 2.1% of Si over the whole investigated temperature range (‑60 to 20 °C). With the Si element addition increased from 1.9% to 2.1%, the graphite nodulizing grade of QT400 18L is increased from 5 to 7. However the graphite nodulizing grade is reduced from 7 to 6 with Si content increasing from 2.1% to 2.3%. When the Si element addition is exceed 2.1%, the excess of Si content also leads to abnormal graphite. The large size of the abnormal graphite is equivalent to a larger microcrack in the ferrite matrix, and it is helpful for the crack propagation. Large size of abnormal graphite not only destroyed the continuity of ferritic matrix, but also it creates the stress concentration in the surrounding.

QT interval and dispersion in drug-free anorexia nervosa adolescents: a case control study.

PubMed

Bomba, Monica; Tremolizzo, Lucio; Corbetta, Fabiola; Nicosia, Franco; Lanfranconi, Francesca; Poggioli, Gianni; Goulene, Karine; Stramba-Badiale, Marco; Conti, Elisa; Neri, Francesca; Nacinovich, Renata

2017-11-16

Long QT values have been reported in patients with anorexia nervosa of the restricting type (ANr) potentially increasing the risk of fatal arrhythmia, especially if psychotropic drug treatment is required. Nevertheless, the previous studies on this topic are biased by drug exposure, long disease durations, and small sample sizes. This study is aimed at assessing QTc and QTcd values in ANr adolescents with recent onset and drug free, as compared to subjects affected by psychiatric disorders other than ANr. We evaluated QTc and its dispersion (QTcd) in a population of 77 drug-free ANr female adolescents and compared to an equal number of healthy controls (H-CTRL) and pathological controls (P-CTRL, mixed psychiatric disorders). The QT determination was performed on a standard simultaneous 12-lead ECG in blind by a single experienced investigator. QTc was calculated by the Bazett's formula and QTcd was determined as the difference between the maximum and minimum QTc intervals in different leads. Only for ANr patients, clinico-demographic data, hormones, and electrolytes were obtained. QTc was slightly reduced in ANr patients (27.7 ms, < 10%, p < 0.0003) vs. controls, while QTcd was increased in P-CTRL (30%, p < 0.0003). Heart rate was significantly lower in ANr patients vs. controls (25%; p < 0.003). Tyroid hormones and serum potassium showed weak although significant positive correlations with QTc in ANr patients. QTcd displayed a weak negative correlation with the BMI percentile (r = - 0.262, p = 0.03). We reject the hypothesis that QTc and QTcd are increased in drug-free ANr adolescents with a relatively short-disease duration. Further studies are needed to understand if the previously reported increase might be related to other associated chronic disorders, such as hormonal or electrolyte imbalance.

Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride.

PubMed

Matsunaga, Yugo; Tanaka, Takao; Yoshinaga, Koji; Ueki, Shigeru; Hori, Yuko; Eta, Runa; Kawabata, Yoshihiro; Yoshii, Kazuyoshi; Yoshida, Kenji; Matsumura, Toshihiro; Furuta, Shigeru; Takei, Mineo; Tack, Jan; Itoh, Zen

2011-03-01

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.

Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.

PubMed

Bowles, Neil E; Jou, Chuanchau J; Arrington, Cammon B; Kennedy, Brett J; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L; Etheridge, Susan P; Saarel, Elizabeth V; Bleyl, Steven B; Yost, H Joseph; Yandell, Mark; Leppert, Mark F; Tristani-Firouzi, Martin; Gruber, Peter J

2015-12-01

Wolff-Parkinson-White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5'-AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. © 2015 Wiley Periodicals, Inc.

Exome Analysis of a Family with Wolff–Parkinson–White Syndrome Identifies a Novel Disease Locus

PubMed Central

Bowles, Neil E.; Jou, Chuanchau J.; Arrington, Cammon B.; Kennedy, Brett J.; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L.; Etheridge, Susan P.; Saarel, Elizabeth V.; Bleyl, Steven B.; Yost, H. Joseph; Yandell, Mark; Leppert, Mark F.; Tristani-Firouzi, Martin; Gruber, Peter J.

2016-01-01

Wolff–Parkinson–White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5’ -AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. PMID:26284702

Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.

PubMed

Murphy, Patricia J; Yasuda, Sanae; Nakai, Kenya; Yoshinaga, Takashi; Hall, Nancy; Zhou, Meijian; Aluri, Jagadeesh; Rege, Bhaskar; Moline, Margaret; Ferry, Jim; Darpo, Borje

2017-01-01

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed C max was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies. © 2016, The American College of Clinical Pharmacology.

Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study

PubMed Central

Morganroth, Joel; Wang, Yaning; Thorn, Michael; Kumagai, Yuji; Harris, Stuart; Stockbridge, Norman; Kleiman, Robert; Shah, Rashmi

2015-01-01

Aim We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. Methods A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTcF) and concentration–effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTcF for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration–effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQTcF was contained within −5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. Results There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml–1), ΔΔQTcF (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml–1) and concentration–response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml–1). The difference in the two ΔΔQTcF of −1.8 (90% CI −4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits. Conclusions Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study. PMID:26011050

Effect of Loss of Heart Rate Variability on T-Wave Heterogeneity and QT Variability in Heart Failure Patients: Implications in Ventricular Arrhythmogenesis.

PubMed

Nayyar, Sachin; Hasan, Muhammad A; Roberts-Thomson, Kurt C; Sullivan, Thomas; Baumert, Mathias

2017-06-01

Heart rate variability (HRV) modulates dynamics of ventricular repolarization. A diminishing value of HRV is associated with increased vulnerability to life-threatening ventricular arrhythmias, however the causal relationship is not well-defined. We evaluated if fixed-rate atrial pacing that abolishes the effect of physiological HRV, will alter ventricular repolarization wavefronts and is relevant to ventricular arrhythmogenesis. The study was performed in 16 subjects: 8 heart failure patients with spontaneous ventricular tachycardia [HFVT], and 8 subjects with structurally normal hearts (H Norm ). The T-wave heterogeneity descriptors [total cosine angle between QRS and T-wave loop vectors (TCRT, negative value corresponds to large difference in the 2 loops), T-wave morphology dispersion, T-wave loop dispersion] and QT intervals were analyzed in a beat-to-beat manner on 3-min records of 12-lead surface ECG at baseline and during atrial pacing at 80 and 100 bpm. The global T-wave heterogeneity was expressed as mean values of each of the T-wave morphology descriptors and variability in QT intervals (QTV) as standard deviation of QT intervals. Baseline T-wave morphology dispersion and QTV were higher in HFVT compared to H Norm subjects (p ≤ 0.02). While group differences in T-wave morphology dispersion and T-wave loop dispersion remained unaltered with atrial pacing, TCRT tended to fall more in HFVT patients compared to H Norm subjects (interaction p value = 0.086). Atrial pacing failed to reduce QTV in both groups, however group differences were augmented (p < 0.0001). Atrial pacing and consequent loss of HRV appears to introduce unfavorable changes in ventricular repolarization in HFVT subjects. It widens the spatial relationship between wavefronts of ventricular depolarization and repolarization. This may partly explain the concerning relation between poorer HRV and the risk of ventricular arrhythmias.

Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death

PubMed Central

Crotti, Lia; Tester, David J.; White, Wendy M.; Bartos, Daniel C.; Insolia, Roberto; Besana, Alessandra; Kunic, Jennifer D.; Will, Melissa L.; Velasco, Ellyn J.; Bair, Jennifer J.; Ghidoni, Alice; Cetin, Irene; Van Dyke, Daniel L.; Wick, Myra J.; Brost, Brian; Delisle, Brian P.; Facchinetti, Fabio; George, Alfred L.; Schwartz, Peter J.; Ackerman, Michael J.

2013-01-01

Importance Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. Objective To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. Design, Setting, and Patients In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. Main Outcomes and Measures Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. Results The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation

Hypoglycaemia and QT interval prolongation in type 1 diabetes--bridging the gap between clamp studies and spontaneous episodes.

PubMed

Christensen, T F; Cichosz, S L; Tarnow, L; Randløv, J; Kristensen, L E; Struijk, J J; Eldrup, E; Hejlesen, O K

2014-01-01

We propose a study design with controlled hypoglycaemia induced by subcutaneous injection of insulin and matched control episodes to bridge the gap between clamp studies and studies of spontaneous hypoglycaemia. The observed prolongation of the heart rate corrected QT interval (QTc) during hypoglycaemia varies greatly between studies. We studied ten adults with type 1 diabetes (age 41±15years) without cardiovascular disease or neuropathy. Single-blinded hypoglycaemia was induced by a subcutaneous insulin bolus followed by a control episode on two occasions separated by 4weeks. QT intervals were measured using the semi-automatic tangent approach, and QTc was derived by Bazett's (QTcB) and Fridericia's (QTcF) formulas. QTcB increased from baseline to hypoglycaemia (403±20 vs. 433±39ms, p<0.001). On the euglycaemia day, QTcB also increased (398±20 vs. 410±27ms, p<0.01), but the increase was less than during hypoglycaemia (p<0.001). The same pattern was seen for QTcF. Plasma adrenaline levels increased significantly during hypoglycaemia compared to euglycaemia (p<0.01). Serum potassium levels decreased similarly after insulin injection during both hypoglycaemia and euglycaemia. Hypoglycaemia as experienced after a subcutaneous injection of insulin may cause QTc prolongation in type 1 diabetes. However, the magnitude of prolongation is less than typically reported during glucose clamp studies, possible because of the study design with focus on minimizing unwanted study effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Trafficking-deficient long QT syndrome mutation KCNQ1-T587M confers severe clinical phenotype by impairment of KCNH2 membrane localization: evidence for clinically significant IKr-IKs alpha-subunit interaction.

PubMed

Biliczki, Peter; Girmatsion, Zenawit; Brandes, Ralf P; Harenkamp, Sabine; Pitard, Bruno; Charpentier, Flavien; Hébert, Terence E; Hohnloser, Stefan H; Baró, Isabelle; Nattel, Stanley; Ehrlich, Joachim R

2009-12-01

KCNQ1-T587M is a trafficking-deficient long QT syndrome (LQTS) missense mutation. Affected patients exhibit severe clinical phenotypes that are not explained by the mutant's effects on I(Ks). Previous work showed a KCNH2 and KCNQ1 alpha-subunit interaction that increases KCNH2 membrane localization and function. We hypothesized that failure of trafficking-deficient KCNQ1-T587M to enhance KCNH2 membrane expression could reduce KCNH2 current versus wild-type KCNQ1 (KCNQ1-WT), contributing to the LQTS phenotype of KCNQ1-T587M carriers. Patch-clamp, protein biochemical studies, confocal imaging, and in vivo transfection of guinea pig cardiomyocytes were performed. KCNQ1-T587M failed to generate functional current when coexpressed with KCNE1 and caused haploinsufficiency when coexpressed with KCNQ1-WT/KCNE1. Coexpression of KCNQ1-WT with KCNH2 increased I(KCNH2) versus KCNH2 alone (P <.05). Immunoblots and confocal microscopy indicated increased plasma membrane localization of KCNH2 alpha-subunits in cells cotransfected with KCNQ1-WT plasmid, while total KCNH2 protein synthesis and KCNH2 glycosylation remained unaffected, which suggests a chaperone effect of KCNQ1-WT to enhance the membrane localization of KCNH2. KCNH2 also coimmunoprecipitated with KCNQ1-WT. Although KCNQ1-T587M coprecipitated with KCNH2, the mutant was retained intracellularly and failed to increase KCNH2 membrane localization, abolishing the KCNQ1-WT chaperone function and reducing I(KCNH2) upon coexpression substantially compared with coexpression with KCNQ1-WT (P <.05). In vivo transfection of KCNQ1-T587M in guinea pigs suppressed I(Kr) in isolated cardiomyocytes. The trafficking-deficient LQTS mutation KCNQ1-T587M fails to show the chaperoning function that enhances KCNH2 membrane localization with KCNQ1-WT. This novel mechanism results in reduced I(KCNH2), which would be expected to decrease repolarization reserve and synergize with reduced I(KCNQ1) caused directly by the mutation, potentially

Sudden arrhythmic death syndrome: diagnostic yield of comprehensive clinical evaluation of pediatric first-degree relatives.

PubMed

Giudici, Valentina; Spanaki, Adriani; Hendry, Jennifer; Mead-Regan, Sarah; Field, Ella; Zuccotti, Gian Vincenzo; Abrams, Dominic; Lowe, Martin; Kaski, Juan Pablo

2014-12-01

Sudden arrhythmic death syndrome (SADS) is most often caused by heritable cardiac diseases. Studies in adults have identified evidence of inherited cardiovascular diseases in up to 53% of families, but data on the prevalence of familial disease in children are scarce. The aim of this study was to evaluate the yield of clinical screening in pediatric first-degree relatives of victims of SADS using a systematic and comprehensive protocol. Patients referred for family screening after sudden cardiac death (SCD) of a family member were, retrospectively, enrolled into the study. Systematic evaluation of the children included clinical examination, family history, electrocardiogram (ECG), echocardiogram, 24-hour tape, and signal-averaged ECG. Older patients also underwent exercise testing, cardiac magnetic resonance imaging, and ajmaline provocation testing. A total of 90 children from 52 consecutive families were included in the study. An inherited cardiac disease was identified in seven first-degree children from seven (13.5%) families (five children were diagnosed with Brugada syndrome, one with long QT syndrome, and one with catecholaminergic polymorphic ventricular tachycardia). Two further children had late potentials on signal-averaged ECGs with no other abnormalities. These data show a high prevalence of inherited heart disease in pediatric first-degree relatives of SADS victims. The results highlight the importance of a systematic, comprehensive approach and ongoing screening of pediatric family members. ©2014 Wiley Periodicals, Inc.

Detection of QT prolongation using a novel electrocardiographic analysis algorithm applying intelligent automation: prospective blinded evaluation using the Cardiac Safety Research Consortium electrocardiographic database.

PubMed

Green, Cynthia L; Kligfield, Paul; George, Samuel; Gussak, Ihor; Vajdic, Branislav; Sager, Philip; Krucoff, Mitchell W

2012-03-01

The Cardiac Safety Research Consortium (CSRC) provides both "learning" and blinded "testing" digital electrocardiographic (ECG) data sets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This article reports the first results from a blinded testing data set that examines developer reanalysis of original sponsor-reported core laboratory data. A total of 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel-group TQT in 181 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer-measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. Developer and sponsor-reported baseline-adjusted data were similar with average differences <1 ms for all intervals. Both developer- and sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject SD for triplicate QTcF measurements was significantly lower for developer- than sponsor-reported data (5.4 and 7.2 ms, respectively; P < .001). The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared with the sponsor-reported study, without the use of a manual core laboratory. These findings indicate that CSRC ECG data sets can be useful for evaluating novel methods and algorithms for determining drug-induced QT/QTc prolongation. Although the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to provide prospective, blinded comparisons of ECG

Detection of QT prolongation using a novel ECG analysis algorithm applying intelligent automation: Prospective blinded evaluation using the Cardiac Safety Research Consortium ECG database

PubMed Central

Green, Cynthia L.; Kligfield, Paul; George, Samuel; Gussak, Ihor; Vajdic, Branislav; Sager, Philip; Krucoff, Mitchell W.

2013-01-01

Background The Cardiac Safety Research Consortium (CSRC) provides both “learning” and blinded “testing” digital ECG datasets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This manuscript reports the first results from a blinded “testing” dataset that examines Developer re-analysis of original Sponsor-reported core laboratory data. Methods 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel-group TQT in 191 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. Results Developer and Sponsor-reported baseline-adjusted data were similar with average differences less than 1 millisecond (ms) for all intervals. Both Developer and Sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject standard deviation for triplicate QTcF measurements was significantly lower for Developer than Sponsor-reported data (5.4 ms and 7.2 ms, respectively; p<0.001). Conclusion The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared to the Sponsor-reported study, without the use of a manual core laboratory. These findings indicate CSRC ECG datasets can be useful for evaluating novel methods and algorithms for determining QT/QTc prolongation by drugs. While the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to

Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

PubMed Central

Hu, Zhaoyang; Kant, Ritu; Anand, Marie; King, Elizabeth C.; Krogh-Madsen, Trine; Christini, David J.; Abbott, Geoffrey W.

2014-01-01

Background Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in diabetics. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia susceptibility genes - including the KCNE2 K+ channel β subunit - are expressed in multiple tissues, suggesting potential multiplex SCD substrates. Methods and Results Using “whole transcript” transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2−/− mouse pups, and adrenal remodeling consistent with metabolic syndrome in adult Kcne2−/− mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes, hypercholesterolemia, hyperkalemia, anemia and elevated angiotensin II. Kcne2 deletion was also prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately following transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia and atrioventricular block. Conclusions Disruption of a single, widely expressed arrhythmia susceptibility gene can generate a multisystem syndrome comprising manifold electrical and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins. PMID:24403551

Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome

PubMed Central

McCauley, Mark D.; Wang, Tiannan; Mike, Elise; Herrera, Jose; Beavers, David L.; Huang, Teng-Wei; Ward, Christopher S.; Skinner, Steven; Percy, Alan K.; Glaze, Daniel G.; Wehrens, Xander H. T.; Neul, Jeffrey L.

2013-01-01

Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in Methyl-CpG-Binding Protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms (ECGs) in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), indicating a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally-mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current in order to prevent lethal cardiac arrhythmias. PMID:22174313

Why are we prolonging QT interval monitoring?

PubMed

Barrett, Trina

2015-01-01

At present, monitoring of the QT interval (QTI) is not a standard practice in the medical intensive care unit setting, where many drugs that prolong the QTI are administered. This literature review looked at the current research for evidence-based standards to support QTI monitoring of patients with risk factors for QTI prolongation, which can result in life-threatening arrhythmias such as torsade de pointes. The objective of this article is to establish the existence of evidence-based standards for monitoring of the QTI and to raise awareness in the nursing profession of the need for such monitoring among patients who are at high risk for prolonged QTI. To determine whether published standards for QTI monitoring exist, a search was conducted of the bibliographic databases CINAHL, EBSCOhost, Medline, PubMed, Google Scholar, and the Cochrane Library for the years 2013 and 2014. Also, a survey was conducted to determine whether practice standards for QTI monitoring are being implemented at 4 major hospitals in the Memphis area, including a level 1 trauma center. The database search established the existence of published guidelines that support the need for QTI monitoring. Results of the hospital survey indicated that direct care nurses were not aware of the need to identify high-risk patients, drugs with the potential to prolong QTI that were being administered to their patients, or evidence-based standards for QTI monitoring. Review of the research literature underscored the need for QTI monitoring among high-risk patients, that is, those with genetic conditions that predispose them to QTI prolongation, those with existing cardiac conditions being treated with antiarrhythmic medications, or those who are prescribed any new medication classified as high risk on the basis of clinical research. This need is especially crucial in intensive care unit settings, where many antiarrhythmic medications are administered.

Prevalence of Electrocardiographic Patterns Associated With Sudden Cardiac Death in the Spanish Population Aged 40 Years or Older. Results of the OFRECE Study.

PubMed

Awamleh García, Paula; Alonso Martín, Joaquín Jesús; Graupner Abad, Catherine; Jiménez Hernández, Rosa María; Curcio Ruigómez, Alejandro; Talavera Calle, Pedro; Cristóbal Varela, Carmen; Serrano Antolín, José; Muñiz, Javier; Gómez Doblas, Juan José; Roig, Eulalia

2017-10-01

Some electrocardiographic patterns are associated with an increased risk of sudden cardiac death due to ventricular arrhythmias. There is no information on the prevalence of these patterns in the general population in Spain. The objective of this study was to analyze the prevalence of these patterns and associated clinical and epidemiological factors. This subanalysis of the OFRECE study selected a representative sample of the Spanish population aged ≥ 40 years. We studied the presence or absence of electrocardiographic patterns of Brugada syndrome and QT interval abnormalities. Clinical data and electrocardiograms were available in all participants. Electrocardiograms were evaluated by 2 cardiologists and a third cardiologist was consulted if there was disagreement in the diagnosis. We calculated the weighted prevalence and clinical factors associated with the presence of Brugada-type patterns or QT segment abnormalities. Overall, 8343 individuals were evaluated (59.2 years, 52.4% female). There were 12 Brugada cases (type 1, 2 cases; type 2, 10 cases; weighted prevalence, 0.13%). For corrected QT (QTc) analysis, we excluded participants with left bundle branch block or without sinus rhythm. Weighted prevalences were as follows: short QTc (< 340ms) 0.18%, borderline QTc (441-469ms) 8.33%, long QTc (≥ 470ms criterion) 1.01% and long QTc (≥ 480 criterion) 0.42%. A total of 0.6% to 1.1% of the Spanish population aged ≥ 40 years has an electrocardiographic pattern associated with a higher risk of sudden death (Brugada syndrome, long QT, or short QT). Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Channelopathies.

PubMed

Kim, June-Bum

2014-01-01

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.

Channelopathies

PubMed Central

Kim, June-Bum

2014-01-01

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases. PMID:24578711

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances.

PubMed

Fernández-Falgueras, Anna; Sarquella-Brugada, Georgia; Brugada, Josep; Brugada, Ramon; Campuzano, Oscar

2017-01-29

Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). This review focuses on cardiac channelopathies, which are characterized by lethal arrhythmias in the structurally normal heart, incomplete penetrance, and variable expressivity. Arrhythmias in these diseases result from pathogenic variants in genes encoding cardiac ion channels or associated proteins. Due to a lack of gross structural changes in the heart, channelopathies are often considered as potential causes of death in otherwise unexplained forensic autopsies. The asymptomatic nature of channelopathies is cause for concern in family members who may be carrying genetic risk factors, making the identification of these genetic factors of significant clinical importance.

Increased Short-Term Variability of the QT Interval in Professional Soccer Players: Possible Implications for Arrhythmia Prediction

PubMed Central

Lengyel, Csaba; Orosz, Andrea; Hegyi, Péter; Komka, Zsolt; Udvardy, Anna; Bosnyák, Edit; Trájer, Emese; Pavlik, Gábor; Tóth, Miklós; Wittmann, Tibor; Papp, Julius Gy.; Varró, András; Baczkó, István

2011-01-01

Background Sudden cardiac death in competitive athletes is rare but it is significantly more frequent than in the normal population. The exact cause is seldom established and is mostly attributed to ventricular fibrillation. Myocardial hypertrophy and slow heart rate, both characteristic changes in top athletes in response to physical conditioning, could be associated with increased propensity for ventricular arrhythmias. We investigated conventional ECG parameters and temporal short-term beat-to-beat variability of repolarization (STVQT), a presumptive novel parameter for arrhythmia prediction, in professional soccer players. Methods Five-minute 12-lead electrocardiograms were recorded from professional soccer players (n = 76, all males, age 22.0±0.61 years) and age-matched healthy volunteers who do not participate in competitive sports (n = 76, all males, age 22.0±0.54 years). The ECGs were digitized and evaluated off-line. The temporal instability of beat-to-beat heart rate and repolarization were characterized by the calculation of short-term variability of the RR and QT intervals. Results Heart rate was significantly lower in professional soccer players at rest (61±1.2 vs. 72±1.5/min in controls). The QT interval was prolonged in players at rest (419±3.1 vs. 390±3.6 in controls, p<0.001). QTc was significantly longer in players compared to controls calculated with Fridericia and Hodges correction formulas. Importantly, STVQT was significantly higher in players both at rest and immediately after the game compared to controls (4.8±0.14 and 4.3±0.14 vs. 3.5±0.10 ms, both p<0.001, respectively). Conclusions STVQT is significantly higher in professional soccer players compared to age-matched controls, however, further studies are needed to relate this finding to increased arrhythmia propensity in this population. PMID:21526208

Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations

PubMed Central

Champeroux, P; Thireau, J; Judé, S; Laigot-Barbé, C; Maurin, A; Sola, M L; Fowler, J S L; Richard, S; Le Guennec, J Y

2015-01-01

Background and Purpose The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K+ channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency. Experimental Approach The short-term variability of beat-to-beat QT interval (STVQT), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium. Key Results Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans. Conclusions and Implications These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals. PMID:25625756

Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations.

PubMed

Champeroux, P; Thireau, J; Judé, S; Laigot-Barbé, C; Maurin, A; Sola, M L; Fowler, J S L; Richard, S; Le Guennec, J Y

2015-06-01

The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K(+) channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency. The short-term variability of beat-to-beat QT interval (STVQT ), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium. Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans. These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals. © 2015 The British Pharmacological Society.

A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

PubMed Central

Benedict, Michael S.; Thorn, Michael D.; Lawrence, Laura E.; Cammarata, Sue K.; Sun, Eugene

2015-01-01

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug. PMID:25845864

[Association of cardiovascular autonomic neuropathy and prolonged QT interval with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus].

PubMed

Ticse Aguirre, Ray; Villena, Jaime E

2011-03-01

In order to evaluate the relationship between cardiovascular autonomic neuropathy and corrected QT interval (QTc) with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus, we followed up for 5 years 67 patients attending the outpatient Endocrinology Service. 82% completed follow-up and cardiovascular events occurred in 16 patients. We found that long QTc interval was the only variable significantly associated with cardiovascular morbidity and mortality in the multiple logistic regression analysis (RR: 13.56, 95% CI: 2.01-91.36) (p = 0.0074).

Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report.

PubMed

Santosh, P J; Bell, L; Lievesley, K; Singh, J; Fiori, F

2016-11-29

Rett Syndrome (RTT), caused by a loss-of-function in the epigenetic modulator: X-linked methyl-CpG binding protein 2 (MeCP2), is a pervasive neurological disorder characterized by compromised brain functions, anxiety, severe mental retardation, language and learning disabilities, repetitive stereotyped hand movements and developmental regression. An imbalance in the sympathetic and the parasympathetic nervous system (dysautonomia) and the resulting autonomic storms is a frequent occurrence in patients with RTT. The prototypical beta blocker propranolol has been used to manage sympathetic hyperactivity in patients with RTT. A 13 year old girl with RTT was referred to the Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust. Her clinical picture included disordered breathing with concomitant hyperventilation and apnoea, epilepsy, scoliosis, no QT prolongation (QT/QTc [372/467 ms on automated electrocardiogram [ECG], but manually calculated to be 440 ms]), no cardiac abnormalities (PR interval: 104 ms, QRS duration: 78 ms), and generalised anxiety disorder (ICD-10-CM Diagnosis Code F41.1). She was also constipated and was fed via percutaneous endoscopic gastrostomy (PEG). To manage the dysautonomia, propranolol was given (5 mg and 10 mg) and in parallel her physiological parameters, including heart rate, skin temperature and skin transpiration, were monitored continuously for 24 h as she went about her activities of daily living. Whilst her skin temperature increased and skin transpiration decreased, unexpectedly there was a significant paradoxical increase in the patient's average heart rate following propranolol treatment. Here, we present a unique case of a paradoxical increase in heart rate response following propranolol treatment for managing dysautonomia in a child with RTT. Further studies are warranted to better understand the underlying dysautonomia in patients with RTT and

Motivation to Pursue Genetic Testing in Individuals with a Personal or Family History of Cardiac Events or Sudden Cardiac Death

PubMed Central

Erskine, Kathleen E.; Hidayatallah, Nadia Z.; Walsh, Christine A.; McDonald, Thomas V.; Cohen, Lilian; Marion, Robert W.; Dolan, Siobhan M.

2014-01-01

Genetic testing is becoming increasingly available for cardiac channelopathies, such as long QT syndrome and Brugada syndrome, which can lead to sudden cardiac death. Test results can be used to shape an individual’s medical management and to identify at-risk family members. In our qualitative study, all participants had a personal or family history of a diagnosed cardiac arrhythmia syndrome or sudden cardiac death. Open-ended interviews were conducted individually and in focus groups. Interviews were audio recorded, transcribed verbatim, and analyzed using a qualitative grounded-theory approach. Of 50 participants, 37 described their motivations for pursuing genetic testing for long QT syndrome or another cardiac channelopathy. Participants’ motivations included: to find an explanation for a family member’s sudden death, to relieve uncertainty regarding a diagnosis, to guide future medical management, to allay concern about children or other family members, and to comply with recommendations of physicians or family members. Perceived reasons not to pursue genetic testing included denial, fear, and lack of information. The genetic counseling and informed consent process can be enhanced by understanding and addressing an individual’s internal and external motivations either for or against pursuing genetic testing. PMID:24664857

Towards a Structural View of Drug Binding to hERG K+ Channels.

PubMed

Vandenberg, Jamie I; Perozo, Eduardo; Allen, Toby W

2017-10-01

The human ether-a-go-go-related gene (hERG) K + channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long-QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K + channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. The recent determination of the near-atomic resolution structure of the hERG K + channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding. Copyright © 2017 Elsevier Ltd. All rights reserved.

Association of functional genetic variants of A-kinase anchoring protein 10 with QT interval length in full-term Polish newborns.

PubMed

Łoniewska, Beata; Kaczmarczyk, Mariusz; Clark, Jeremy Simon; Gorący, Iwona; Horodnicka-Józwa, Anita; Ciechanowicz, Andrzej

2015-03-16

A-Kinase Anchoring Proteins (AKAPs) coordinate the specificity of protein kinase A signaling by localizing the kinase to subcellular sites. The 1936G (V646) AKAP10 allele has been associated in adults with low cholinergic/vagus nerve sensitivity, shortened PR intervals in ECG recording and in newborns with increased blood pressure and higher cholesterol cord blood concentration. The aim of the study was to answer the question of whether 1936A > G AKAP10 polymorphism is associated with the newborn electrocardiographic variables. Electrocardiograms were recorded from 114 consecutive healthy Polish newborns (55 females, 59 males), born after 37 gestational weeks to healthy women with uncomplicated pregnancies. All recordings were made between 3(rd) and 7(th) day of life to avoid QT variability. The heart rate per minute and duration of PR, QRS, RR and QT intervals were usually measured. The ECGs were evaluated independently by three observers. At birth, cord blood of neonates was obtained for isolation of genomic DNA. The distribution of anthropometric and electrocardiographic variables in our cohort approached normality (skewness < 2 for all variables). No significant differences in anthropometric variables and electrocardiographic traits with respect to AKAP10 genotype were found. Multiple regression analysis with adjustment for gender, gestational age and birth mass revealed that QTc interval in GG AKAP10 homozygotes was significantly longer, but in range, when compared with A alleles carriers (AA + AG, recessive mode of inheritance). No rhythm disturbances were observed. Results demonstrate possible association between AKAP10 1936A > G variant and QTc interval in Polish newborns.

A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization.

PubMed

Litwin, Jeffrey S; Benedict, Michael S; Thorn, Michael D; Lawrence, Laura E; Cammarata, Sue K; Sun, Eugene

2015-01-01

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Temporal patterns of radiographic infiltration in severely traumatized patients with and without adult respiratory distress syndrome.

PubMed

Johnson, K S; Bishop, M H; Stephen, C M; Jorgens, J; Shoemaker, W C; Shori, S K; Ordog, G; Thadepalli, H; Appel, P L; Kram, H B

1994-05-01

We prospectively evaluated the patterns of pulmonary structural and functional changes in 100 consecutive surgical intensive care unit trauma patients who had (1) emergent major surgery, (2) a pelvic fracture, or (3) two or more major long bone fractures. For each patient, arterial blood gas measurements (ABGs), central venous pressure (CVP), pulmonary capillary occlusion pressure (PAOP), thoracic compliance, arterial oxygen tension/fraction of inspired oxygen (PAO2/FIO2), pulmonary venous admixture (Qs/Qt), and portable chest roentgenograms were sequentially tracked. The senior staff radiologist interpreted all chest roentgenograms. Pulmonary infiltration was quantitated in each of six fields using a scale ranging from 0 to 4, with 0 being no infiltration and 4 being the maximum. Adult respiratory distress syndrome (ARDS) was defined as follows: Qs/Qt > or = 20%, PAO2/FIO2 < 250 or both; dependence on mechanical ventilation for life support for > or = 24 hours; PAOP or CVP or both < 20 mm Hg; and thoracic compliance < 50 mL/cm H2O. Time zero (T0) the time of onset of ARDS, was defined as the time these criteria were met. Eighty-three of 100 study group patients had penetrating injuries, and 17 were admitted with blunt trauma. Fifty-one of 100 patients developed ARDS: 36 of 51 died. Only 4 of 49 (8%) patients without ARDS died. The injured lungs of patients with and without ARDS had similar amounts of infiltration over most measured time intervals. The noninjured lungs of the ARDS patients, however, had significantly greater infiltration than those without ARDS at T0 and over subsequent time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of automated measurements of electrocardiographic intervals and durations by computer-based algorithms of digital electrocardiographs.

PubMed

Kligfield, Paul; Badilini, Fabio; Rowlandson, Ian; Xue, Joel; Clark, Elaine; Devine, Brian; Macfarlane, Peter; de Bie, Johan; Mortara, David; Babaeizadeh, Saeed; Gregg, Richard; Helfenbein, Eric D; Green, Cynthia L

2014-02-01

Automated measurements of electrocardiographic (ECG) intervals are widely used by clinicians for individual patient diagnosis and by investigators in population studies. We examined whether clinically significant systematic differences exist in ECG intervals measured by current generation digital electrocardiographs from different manufacturers and whether differences, if present, are dependent on the degree of abnormality of the selected ECGs. Measurements of RR interval, PR interval, QRS duration, and QT interval were made blindly by 4 major manufacturers of digital electrocardiographs used in the United States from 600 XML files of ECG tracings stored in the US FDA ECG warehouse and released for the purpose of this study by the Cardiac Safety Research Consortium. Included were 3 groups based on expected QT interval and degree of repolarization abnormality, comprising 200 ECGs each from (1) placebo or baseline study period in normal subjects during thorough QT studies, (2) peak moxifloxacin effect in otherwise normal subjects during thorough QT studies, and (3) patients with genotyped variants of congenital long QT syndrome (LQTS). Differences of means between manufacturers were generally small in the normal and moxifloxacin subjects, but in the LQTS patients, differences of means ranged from 2.0 to 14.0 ms for QRS duration and from 0.8 to 18.1 ms for the QT interval. Mean absolute differences between algorithms were similar for QRS duration and QT intervals in the normal and in the moxifloxacin subjects (mean ≤6 ms) but were significantly larger in patients with LQTS. Small but statistically significant group differences in mean interval and duration measurements and means of individual absolute differences exist among automated algorithms of widely used, current generation digital electrocardiographs. Measurement differences, including QRS duration and the QT interval, are greatest for the most abnormal ECGs. © 2014.

Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias.

PubMed

Spoonamore, Katherine G; Ware, Stephanie M

2016-03-01

Sudden cardiac death due to heritable ventricular arrhythmias is an important cause of mortality, especially in young healthy individuals. The identification of the genetic basis of Mendelian diseases associated with arrhythmia has allowed the integration of this information into the diagnosis and clinical management of patients and at-risk family members. The rapid expansion of genetic testing options and the increasing complexity involved in the interpretation of results creates unique opportunities and challenges. There is a need for competency to incorporate genetics into clinical management and to provide appropriate family-based risk assessment and information. In addition, disease-specific genetic knowledge is required to order and correctly interpret and apply genetic testing results. Importantly, genetic diagnosis has a critical role in the risk stratification and clinical management of family members. This review summarizes the approach to genetic counseling and genetic testing for inherited arrhythmias and highlights specific genetic principles that apply to long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Genetic causes of sudden cardiac death in children: inherited arrhythmogenic diseases.

PubMed

Vacanti, Gaetano; Maragna, Riccardo; Priori, Silvia G; Mazzanti, Andrea

2017-10-01

In this chapter we will discuss the most recent and relevant evidences published in the field of inherited arrhythmogenic disorders, focusing on the so called 'channelopathies' that are associated with sudden cardiac death (SCD) in children: long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). We will discuss the latest diagnostic criteria for channelopathies released by the European Society of Cardiology, the new data on BrS in children and the recent evidence supporting a genotype-specific therapy for LQTS type 3. Moreover, we will present further insights into the risk stratification of the children affected by LQTS, analyzing the role of imaging for the prediction of life-threatening arrhythmias. In addition, we will offer a perspective on how to deal with genetic results in families affected by SCD at very young ages. The selected publications will aid pediatricians in their clinical work when managing little patients with inherited arrhythmias, providing the most recent information for diagnosis, risk stratification, and management.

Obstructive sleep apnea is associated with increased QT corrected interval dispersion: the effects of continuous positive airway pressure.

PubMed

Bilal, Nagihan; Dikmen, Nursel; Bozkus, Fulsen; Sungur, Aylin; Sarica, Selman; Orhan, Israfil; Samur, Anil

2017-03-31

Severe obstructive sleep apnea (OSA) is associated with increased QT corrected interval dispersion (QTcd) and continuous positive airway pressure (CPAP) is thought to improve this arrhythmogenic marker. The aim of the study was to determine the decrease of ratio of cardiovascular risk in patients with obstructive sleep apnea. The study included 65 patients with severe OSA who had an apnea-hypopnea index (AHI) score of >30. Each patient underwent 12-channel electrocardiogram (ECG) monitoring and polysomnography. Patients with an AHI score of <5 were used as the control group. The control group also underwent ECG monitoring and polysomnography testing. The QTcd levels of both groups were calculated. Three months after CPAP treatment, ECG recordings were obtained from the 65 patients with severe OSA again, and their QTcd values were calculated. There were 44 male and 21 female patients with severe OSA syndrome. The age, gender, body mass index, initial saturation, minimum saturation, average saturation, and desaturation index were determined in both groups. The QTc intervals of the OSA patients (62.48±16.29ms) were significantly higher (p=0.001) than those of the control group (29.72±6.30ms). There were statistically significant differences between the QTc values before and after the CPAP treatment, with pretreatment QTc intervals of 62.48±16.29ms and 3-month post-treatment values of 41.42±16.96ms (p=0.001). There was a positive and significant correlation between QTcd periods and the AHI and hypopnea index (HI) in OSA patients (p=0.001; r=0.71; p=0.001; r=0.679, respectively). CPAP treatment reduced the QTcd in patients with severe OSA. In addition, shortening the QTcd periods in patients with severe OSA may reduce their risk of arrhythmias and cardiovascular disease. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray.

PubMed

Sellers, Edward M; Schoedel, Kerri; Bartlett, Cindy; Romach, Myroslava; Russo, Ethan B; Stott, Colin G; Wright, Stephen; White, Linda; Duncombe, Paul; Chen, Chien-Feng

2013-07-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain. A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers. The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed. Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day. In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies. © The Author(s) 2013.

Prolongation of the corrected QT complex--a cause of sudden cardiac death in the mountain environment?

PubMed

Windsor, J S; Rodway, G W; Mukherjee, R; Firth, P G; Shattock, M; Montgomery, H E

2011-03-01

In the mountain environment sudden cardiac death (SCD) has been shown to be responsible for the deaths of up to 52% of downhill skiers and 30% of hikers. The majority of SCD's are precipitated by a ventricular arrhythmia. Although most are likely to result from structural abnormalities associated with conditions such as ischaemic heart disease, a small but significant number may be due to abnormalities in ion channel activity, commonly known as, "channelopathies". Channelopathies have the potential to lengthen the time between ventricular depolarisation and repolarisation that can result in prolongation of the corrected QT interval (QTc) and episodes of polymorphic ventricular tachycardia (PVT) and eventually, ventricular fibrillation. This review examines the factors that prolong the QTc interval in the mountain environment and outlines a practical framework for preventing the life threatening arrhythmias that are associated with this condition.

Long-Term Haloperidol Treatment Prolongs QT Interval and Increases Expression of Sigma 1 and IP3 Receptors in Guinea Pig Hearts.

PubMed

Stracina, Tibor; Slaninova, Iva; Polanska, Hana; Axmanova, Martina; Olejnickova, Veronika; Konecny, Petr; Masarik, Michal; Krizanova, Olga; Novakova, Marie

2015-07-01

Haloperidol is a neuroleptic drug used for a medication of various psychoses and deliria. Its administration is frequently accompanied by cardiovascular side effects, expressed as QT interval prolongation and occurrence of even lethal arrhythmias. Despite these side effects, haloperidol is still prescribed in Europe in clinical practice. Haloperidol binds to sigma receptors that are coupled with inositol 1,4,5-trisphosphate (IP3) receptors. Sigma receptors are expressed in various tissues, including heart muscle, and they modulate potassium channels. Together with IP3 receptors, sigma receptors are also involved in calcium handling in various tissues. Therefore, the present work aimed to study the effects of long-term haloperidol administration on the cardiac function. Haloperidol (2 mg/kg once a day) or vehiculum was administered by intraperitoneal injection to guinea pigs for 21 consecutive days. We measured the responsiveness of the hearts isolated from the haloperidol-treated animals to additional application of haloperidol. Expression of the sigma 1 receptor and IP3 receptors was studied by real time-PCR and immunohistochemical analyses. Haloperidol treatment caused the significant decrease in the relative heart rate and the prolongation of QT interval of the isolated hearts from the haloperidol-treated animals, compared to the hearts isolated from control animals. The expression of sigma 1 and IP3 type 1 and type 2 receptors was increased in both atria of the haloperidol-treated animals but not in ventricles. The modulation of sigma 1 and IP3 receptors may lead to altered calcium handling in cardiomyocytes and thus contribute to changed sensitivity of cardiac cells to arrhythmias.

Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats.

PubMed

Erbas, Oytun; Yilmaz, Mustafa

2015-12-01

Ziprasidone, an atypical antipsychotic agent, has been shown to increase the corrected QT (QTc) interval in some patients. The aim of this study was to reveal the effects of metoprolol and diltiazem on ziprasidone drug-induced prolonged QTc interval. A total of 24 rats were equally divided into the following four groups: the first group was used as the control and received 1 mL/kg saline; 3 mg/kg ziprasidone and saline were administered to the second group; 3 mg/kg ziprasidone and 1 mg/kg metoprolol were administered to the third group and 3 mg/kg ziprasidone and 2 mg/kg diltiazem were administered to the fourth group. Two hours following application of the drugs, the QTc was calculated by performing electrocardiography in derivation (D)I. The duration of QTc interval was compared among the four groups. The mean QTc intervals were significantly increased in the third and fourth groups compared with the second group (p < 0.0005 and p < 0.0001, respectively). The study demonstrated the effectiveness of metoprolol and diltiazem in the prevention of ziprasidone-induced elongation in the QTc interval. Both metoprolol and diltiazem may be considered in the prophylactic therapy of high-risk patients who are using ziprasidone. © The Author(s) 2013.

Naval Air Development Center Medical Standards for Research Subjects Exposed to Hazardous Aerospace Environments

DTIC Science & Technology

1991-02-01

evidence of isolated hypertrophy compatible with athletic training. c. Left or right bundle branch block. d. Wolff - Parkinson - White or other pre-excitation... syndrome . e. Second or third-degree heart block. (Atrio-ventricular dissociation post-stress is not necessarily disqualifying.) f. QT-prolongation (QTc

The Cardiac Safety Research Consortium ECG database.

PubMed

Kligfield, Paul; Green, Cynthia L

2012-01-01

The Cardiac Safety Research Consortium (CSRC) ECG database was initiated to foster research using anonymized, XML-formatted, digitized ECGs with corresponding descriptive variables from placebo- and positive-control arms of thorough QT studies submitted to the US Food and Drug Administration (FDA) by pharmaceutical sponsors. The database can be expanded to other data that are submitted directly to CSRC from other sources, and currently includes digitized ECGs from patients with genotyped varieties of congenital long-QT syndrome; this congenital long-QT database is also linked to ambulatory electrocardiograms stored in the Telemetric and Holter ECG Warehouse (THEW). Thorough QT data sets are available from CSRC for unblinded development of algorithms for analysis of repolarization and for blinded comparative testing of algorithms developed for the identification of moxifloxacin, as used as a positive control in thorough QT studies. Policies and procedures for access to these data sets are available from CSRC, which has developed tools for statistical analysis of blinded new algorithm performance. A recently approved CSRC project will create a data set for blinded analysis of automated ECG interval measurements, whose initial focus will include comparison of four of the major manufacturers of automated electrocardiographs in the United States. CSRC welcomes application for use of the ECG database for clinical investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients.

PubMed

Tsujimoto, Tetsuro; Yamamoto-Honda, Ritsuko; Kajio, Hiroshi; Kishimoto, Miyako; Noto, Hiroshi; Hachiya, Remi; Kimura, Akio; Kakei, Masafumi; Noda, Mitsuhiko

2014-01-01

OBJECTIVE To assess vital signs, QT intervals, and newly diagnosed cardiovascular disease during severe hypoglycemia in diabetic patients. RESEARCH DESIGN AND METHODS From January 2006 to March 2012, we conducted a retrospective cohort study to assess type 1 and type 2 diabetic patients with severe hypoglycemia at a national center in Japan. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that could not be resolved by the patients themselves in prehospital settings. RESULTS A total of 59,602 cases that visited the emergency room by ambulance were screened, and 414 cases of severe hypoglycemia were analyzed. The median (interquartile range) blood glucose levels were not significantly different between the type 1 diabetes mellitus (T1DM) (n = 88) and type 2 diabetes mellitus (T2DM) (n = 326) groups (32 [24-42] vs. 31 [24-39] mg/dL, P = 0.59). During severe hypoglycemia, the incidences of severe hypertension (≥180/120 mmHg), hypokalemia (<3.5 mEq/L), and QT prolongation were 19.8 and 38.8% (P = 0.001), 42.4 and 36.3% (P = 0.30), and 50.0 and 59.9% (P = 0.29) in the T1DM and T2DM groups, respectively. Newly diagnosed cardiovascular disease during severe hypoglycemia and death were only observed in the T2DM group (1.5 and 1.8%, respectively). Blood glucose levels between the deceased and surviving patients in the T2DM group were significantly different (18 [14-33] vs. 31 [24-39] mg/dL, P = 0.02). CONCLUSIONS T1DM and T2DM patients with severe hypoglycemia experienced many critical problems that could lead to cardiovascular disease, fatal arrhythmia, and death.

Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects.

PubMed

Choi, Hyang-Ki; Jung, Jin Ah; Fujita, Tomoe; Amano, Hideki; Ghim, Jong-Lyul; Lee, Dong-Hwan; Tabata, Kenichi; Song, Il-Dae; Maeda, Mika; Kumagai, Yuji; Mendzelevski, Boaz; Shin, Jae-Gook

2016-12-01

The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic-pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration-effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An E max model (E[C]=[E max ⋅C]/[EC 50 +C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic-pharmacodynamic link model. The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Cardiac arrhythmia and thyroid dysfunction: a novel genetic link

PubMed Central

Purtell, Kerry; Roepke, Torsten K.; Abbott, Geoffrey W.

2010-01-01

Inherited Long QT Syndrome, a cardiac arrhythmia that predisposes to the often lethal ventricular fibrillation, is commonly linked to mutations in KCNQ1. The KCNQ1 voltage-gated K+ channel α subunit passes ventricular myocyte K+ current that helps bring a timely end to each heart-beat. KCNQ1, like many K+ channel α subunits, is regulated by KCNE β subunits, inherited mutations in which also associate with Long QT Syndrome. KCNQ1 and KCNE mutations are also associated with atrial fibrillation. It has long been known that thyroid status strongly influences cardiac function, and that thyroid dysfunction causes abnormal cardiac structure and rhythm. We recently discovered that KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated K+ channel in the thyroid that is required for normal thyroid hormone biosynthesis. Here, we review this novel genetic link between cardiac and thyroid physiology and pathology, and its potential influence upon future therapeutic strategies in cardiac and thyroid disease. PMID:20688187

The C-allele of tissue inhibitor of metalloproteinases 2 is associated with increased magnitude of QT dispersion prolongation in elderly Chinese - 4-year follow-up study.

PubMed

Lin, Tsung-Hsien; Chiu, Herng-Chia; Lee, Ya-Ting; Su, Ho-Ming; Juo, Suh-Hang Hank; Voon, Wen-Chol; Lai, Wen-Ter; Sheu, Sheng-Hsiung

2007-01-01

Matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) trigger the signal cascade instigating cardiac remodeling and fibrosis, which lead to changes of repolarization variables. We investigate the influence of MMP9-1562 C/T and TIMP2-418 G/C gene polymorphisms on repolarization parameters including QT dispersion (QTd) and the peak and the end of the T wave interval (Tpe) in a prospective cohort. Of 1500 people screened, 106 elderly Chinese without organic heart disease were recruited and received electrocardiography at the baseline, second and 4th year follow-ups. The QTc (corrected QT), QTd, QTc dispersion (QTcd) and Tpe were manually calculated. Age was 72.7+/-4.1 y (range 62-81 y). QTd, QTcd and Tpe were significantly prolonged (all p <0.001 at the 2nd and 4th year). At the 4th year the magnitude of QTd prolongation but not Tpe was significantly higher in subjects carrying the TIMP2 C-allele than non C-allele carriers (p=0.033) as well as QTcd (p=0.010). This association was still significant in multivariate analyses (p=0.012 and p=0.003 for QTd and QTcd, respectively) but not in MMP9 genotype. The elderly Chinese with TIMP2 C-allele have higher magnitude of QTd and QTcd prolongation.

Ventricular arrhythmias in the absence of structural heart disease.

PubMed

Prystowsky, Eric N; Padanilam, Benzy J; Joshi, Sandeep; Fogel, Richard I

2012-05-15

Ventricular arrhythmia (VA) in structurally normal hearts can be broadly considered under non-life-threatening monomorphic and life-threatening polymorphic rhythms. Monomorphic VA is classified on the basis of site of origin in the heart, and the most common areas are the ventricular outflow tracts and left ventricular fascicles. The morphology of the QRS complexes on electrocardiogram is an excellent tool to identify the site of origin of the rhythm. Although these arrhythmias are common and generally carry an excellent prognosis, rare sudden death events have been reported. Very frequent ventricular ectopy may also result in a cardiomyopathy in a minority of patients. Suppression of VA may be achieved using calcium-channel blockers, beta-adrenergic blockers, and class I or III antiarrhythmic drugs. Radiofrequency ablation has emerged as an excellent option to eliminate these arrhythmias, although certain foci including aortic cusps and epicardium may be technically challenging. Polymorphic ventricular tachycardia (VT) is rare and generally occurs in patients with genetic ion channel disorders including long QT syndrome, Brugada syndrome, catecholaminergic polymorphic VT, and short QT syndrome. Unlike monomorphic VT, these arrhythmic syndromes are associated with sudden death. While the cardiac gross morphology is normal, suggesting a structurally normal heart, abnormalities exist at the molecular level and predispose them to arrhythmias. Another fascinating area, idiopathic ventricular fibrillation and early repolarization syndrome, are undergoing research for a genetic basis. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Electrocardiography cannot reliably differentiate transient left ventricular apical ballooning syndrome from anterior ST-segment elevation myocardial infarction.

PubMed

Bybee, Kevin A; Motiei, Arashk; Syed, Imran S; Kara, Tomas; Prasad, Abhiram; Lennon, Ryan J; Murphy, Joseph G; Hammill, Stephen C; Rihal, Charanjit S; Wright, R Scott

2007-01-01

The presentation and electrocardiographic (ECG) characteristics of transient left ventricular apical ballooning syndrome (TLVABS) can be similar to that of anterior ST-segment elevation myocardial infarction (STEMI). We tested the hypothesis that the ECG on presentation could reliably differentiate these syndromes. Between January 1, 2002 and July 31, 2004, we identified 18 consecutive patients with TLVABS who were matched with 36 subjects presenting with acute anterior STEMI due to atherothrombotic left anterior descending coronary artery occlusion. All patients with TLVABS were women (mean age, 72.0 +/- 13.1 years). The heart rate, PR interval, QRS duration, and corrected QT interval were similar between groups. Distribution of ST elevation was similar, but patients with anterior STEMI exhibited greater ST elevation. Regressive partitioning analysis indicated that the combination of ST elevation in lead V2 of less than 1.75 mm and ST-segment elevation in lead V3 of less than 2.5 mm was a suggestive predictor of TLVABS (sensitivity, 67%; specificity, 94%). Conditional logistic regression indicated that the formula: (3 x ST-elevation lead V2) + (ST-elevation V3) + (2 x ST-elevation V5) allowed possible discrimination between TLVABS and anterior STEMI with an optimal cutoff level of less than 11.5 mm for TLVABS (sensitivity, 94%; specificity, 72%). Patients with TLVABS were less likely to have concurrent ST-segment depression (6% vs 44%; P = .003). Women presenting with TLVABS have similar ECG findings to patients with anterior infarct but with less-prominent ST-segment elevation in the anterior precordial ECG leads. These ECG findings are relatively subtle and do not have sufficient predictive value to allow reliable emergency differentiation of these syndromes.

Sudden cardiac death secondary to antidepressant and antipsychotic drugs

PubMed Central

Sicouri, Serge; Antzelevitch, Charles

2008-01-01

A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use. PMID:18324881

Familial Kleine-Levin Syndrome: A Specific Entity?

PubMed Central

Nguyen, Quang Tuan Remy; Groos, Elisabeth; Leclair-Visonneau, Laurène; Monaca-Charley, Christelle; Rico, Tom; Farber, Neal; Mignot, Emmanuel; Arnulf, Isabelle

2016-01-01

Study Objectives: Kleine-Levin syndrome (KLS) is a rare, mostly sporadic disorder, characterized by intermittent episodes of hypersomnia plus cognitive and behavior disorders. Although its cause is unknown, multiplex families have been described. We contrasted the clinical and biological features of familial versus sporadic KLS. Methods: Two samples of patients with KLS from the United States and France (n = 260) were studied using clinical interviews and human leukocyte antigen (HLA) genotyping. A multiplex family contained two or more first- or second-degree affected relatives (familial cases). Results: Twenty-one patients from 10 multiplex families (siblings: n = 12, including two pairs of monozygotic twins; parent-child: n = 4; cousins: n = 2; uncle-nephews: n = 3) and 239 patients with sporadic KLS were identified, yielding to 4% multiplex families and 8% familial cases. The simplex and multiplex families did not differ for autoimmune, neurological, and psychiatric disorders. Age, sex ratio, ethnicity, HLA typing, karyotyping, disease course, frequency, and duration of KLS episodes did not differ between groups. Episodes were less frequent in familial versus sporadic KLS (2.3 ± 1.8/y versus 3.8 ± 3.7/y, P = 0.004). Menses triggered more frequently KLS onset in the nine girls with familial KLS (relative risk, RR = 4.12, P = 0.03), but not subsequent episodes. Familial cases had less disinhibited speech (RR = 3.44, P = 0.049), less combined hypophagia/hyperphagia (RR = 4.38, P = 0.006), more abrupt termination of episodes (RR = 1.45, P = 0.04) and less postepisode insomnia (RR = 2.16, P = 0.008). There was similar HLA DQB1 distribution in familial versus sporadic cases and no abnormal karyotypes. Conclusion: Familial KLS is mostly present in the same generation, and is clinically similar to but slightly less severe than sporadic KLS. Citation: Nguyen QT, Groos E, Leclair-Visonneau L, Monaca-Charley C, Rico T, Farber N, Mignot E, Arnulf I. Familial Kleine

Effect of Acute Mental Stress on Heart Rate and QT Variability in Postmyocardial Infarction Patients.

PubMed

Magrì, Damiano; Piccirillo, Gianfranco; Quaglione, Raffaele; Dell'armi, Annalaura; Mitra, Marilena; Velitti, Stefania; Di Barba, Daniele; Lizio, Andrea; Maisto, Damiana; Barillà, Francesco

2012-01-01

Emotionally charged events are associated with an increased risk of sudden cardiac death (SCD). In this study we assessed RR and QT variability index (QTVI) at baseline during anger recall test (AR). We calculated QTVI from a 5-min ECG recording and from a 10-beats segment around the presumed maximum sympathetic activation in thirty post-myocardial infarction patients under β-blocker therapy and 10 controls underwent. In all groups, the low-frequency component of RR and SBP increased during AR. In all recordings, the QTVI calculated on a 5-min ECG recording and the QTVI(10 beats) were higher in patients than in controls (P < 0.05). The QTVI during AR remained unchanged from baseline within each group. Conversely, during AR, the QTVI(10 beats) in controls diminished significantly (P < 0.05) from baseline whereas in patients remained unchanged. The inability to buffer an acute stress-induced increase in sympathetic activity could explain why events charged with acute stress are associated with an increased risk of ventricular arrhythmias in this setting of patients and support the role of cognitive behavior stress management strategies.

Effect of Acute Mental Stress on Heart Rate and QT Variability in Postmyocardial Infarction Patients

PubMed Central

Magrì, Damiano; Piccirillo, Gianfranco; Quaglione, Raffaele; Dell'Armi, Annalaura; Mitra, Marilena; Velitti, Stefania; Di Barba, Daniele; Lizio, Andrea; Maisto, Damiana; Barillà, Francesco

2012-01-01

Emotionally charged events are associated with an increased risk of sudden cardiac death (SCD). In this study we assessed RR and QT variability index (QTVI) at baseline during anger recall test (AR). We calculated QTVI from a 5-min ECG recording and from a 10-beats segment around the presumed maximum sympathetic activation in thirty post-myocardial infarction patients under β-blocker therapy and 10 controls underwent. In all groups, the low-frequency component of RR and SBP increased during AR. In all recordings, the QTVI calculated on a 5-min ECG recording and the QTVI10 beats were higher in patients than in controls (P < 0.05). The QTVI during AR remained unchanged from baseline within each group. Conversely, during AR, the QTVI10 beats in controls diminished significantly (P < 0.05) from baseline whereas in patients remained unchanged. The inability to buffer an acute stress-induced increase in sympathetic activity could explain why events charged with acute stress are associated with an increased risk of ventricular arrhythmias in this setting of patients and support the role of cognitive behavior stress management strategies. PMID:22844616

Long QT molecular autopsy in sudden unexplained death in the young (1-40 years old): Lessons learnt from an eight year experience in New Zealand.

PubMed

Marcondes, Luciana; Crawford, Jackie; Earle, Nikki; Smith, Warren; Hayes, Ian; Morrow, Paul; Donoghue, Tom; Graham, Amanda; Love, Donald; Skinner, Jonathan R

2018-01-01

To review long QT syndrome molecular autopsy results in sudden unexplained death in young (SUDY) between 2006 and 2013 in New Zealand. Audit of the LQTS molecular autopsy results, cardiac investigations and family screening data from gene-positive families. During the study period, 365 SUDY cases were referred for molecular autopsy. 128 cases (35%) underwent LQTS genetic testing. 31 likely pathogenic variants were identified in 27 cases (21%); SCN5A (14/31, 45%), KCNH2 (7/31, 22%), KCNQ1 (4/31, 13%), KCNE2 (3/31, 10%), KCNE1 (2/31, 7%), KCNJ2 (1/31, 3%). Thirteen variants (13/128, 10%) were ultimately classified as pathogenic. Most deaths (63%) occurred during sleep. Gene variant carriage was more likely with a positive medical history (mostly seizures, 63% vs 36%, p = 0.01), amongst females (36% vs 12%, p = 0.001) and whites more than Maori (31% vs 0, p = 0.0009). Children 1-12 years were more likely to be gene-positive (33% vs 14%, p = 0.02). Family screening identified 42 gene-positive relatives, 18 with definitive phenotypic expression of LQTS/Brugada. 76% of the variants were maternally inherited (p = 0.007). Further family investigations and research now support pathogenicity of the variant in 13/27 (48%) of gene-positive cases. In New Zealand, variants in SCN5A and KCNH2, with maternal inheritance, predominate. A rare variant in LQTS genes is more likely in whites rather than Maori, females, children 1-12 years and those with a positive personal and family history of seizures, syncope or SUDY. Family screening supported the diagnosis in a third of the cases. The changing classification of variants creates a significant challenge.

Clinical utility of T-wave alternans

NASA Technical Reports Server (NTRS)

Armoundas, A. A.; Cohen, R. J.

1997-01-01

Electrical alternans represents a variation in the morphology of electrocardiographic complexes on an every-other-beat basis in an ABABAB... pattern. Apparent electrical alternans associated with pericardial effusion results from rotation of the heart in the pericardial sac, and not true alternation in electrical conduction patterns. In contrast, true electrical alternans results from an alternation in electrical conduction patterns in the heart itself. Repolarization alternans is true electrical alternans associated with the ST segment and T wave of the electrocardiogram (ECG). Here we will focus on T-wave alternans (TWA) and its association with susceptibility to ventricular tachyarrhythmias. Electrical alternans was reported in the literature as early as 1909. Historically, electrical alternans has been regarded as a fairly rare electrocardiographic abnormality. Case reports of electrical alternans have been associated with a variety of disease states, including acute ischemia, Prinzmetal's angina, a variety of electrolyte abnormalities, and the long QT syndrome. Interestingly, patients born with the prolonged QT syndrome have a very high incidence of sudden cardiac death at an early age. Schwartz and Malliani showed that patients with the prolonged QT syndrome who do not demonstrate alternans at rest, may evidence alternans during stress such as emotional excitement. Thus, over the years electrical alternans has been associated anecdotally with conditions associated with an increased risk of ventricular arrhythmias. In 1948, Kalter reviewed the world literature on electrical alternans and found a total of 41 reported cases. In addition, he reviewed clinical ectrocardiograms from 6059 patients and found five new cases (incidence of less than 1 in 1000 patients). Interestingly, he found a very high mortality, 62%, associated with this condition. Despite the clinical associations reported in the literature, the consensus view of electrical alternans until recent

Electrocardiogram Screening in Children with Congenital Sensorineural Hearing Loss: Prevalence and Follow-up of Abnormalities.

PubMed

Farzal, Zainab; Walsh, Jonathan; Ahmad, Faisal I; Roberts, Jason; Ferns, Sunita J; Zdanski, Carlton J

2018-03-01

Objective The purpose is to determine the prevalence of electrocardiogram (ECG) abnormalities, including borderline and prolonged QT, among screened children with sensorineural hearing loss (SNHL) and to analyze their subsequent medical workup. Study Design Institutional Review Board-approved case series with chart review. Setting Tertiary academic center. Subjects and Methods Cases from 1996 to 2014 involving pediatric patients (N = 1994) with SNHL were analyzed. Abnormal ECGs were categorized as borderline/prolonged QT or other. A board-certified pediatric cardiologist retrospectively determined the clinical significance of ECG changes. For follow-up analysis, children with heart disease, known syndromes, or inaccessible records were excluded. Results Among 772 children who had ECGs, 215 (27.8%) had abnormal results: 35 (4.5%) with QT abnormalities and 180 (23.3%) with other abnormalities. For children with QT abnormalities meeting inclusion criteria (n = 30), follow-up measures included cardiology referral (46.6%), repeat ECG by ear, nose, and throat (ENT) specialist (20%), clearance by ENT specialist with clinical correlation and/or comparison with old ECGs (20%), and pediatrician follow-up (6.7%). Documentation of further workup by ENT or referral was absent for 6.7%. For children with other ECG changes meeting inclusion criteria (n = 136), abnormalities were documented for 57 (41.9%); normal QT without other abnormality was documented for 18 (13.2%). The most common follow-up referrals were to pediatricians (16.9%) and cardiologists (10.3%). Among patients with clinically significant non-QT abnormalities mandating further evaluation (n = 122), 38 (31.1%) had documented follow-up in medical records. Conclusion There is a high prevalence of ECG abnormalities among children with congenital SNHL. If findings are confirmed by future studies, screening should be considered for congenital unilateral or bilateral SNHL, regardless of severity. We describe a

High prevalence of risk factors in elderly patients using drugs associated with acquired torsades de pointes chronically in Colombia.

PubMed

Moreno-Gutiérrez, Paula Andrea; Gaviria-Mendoza, Andrés; Cañón, Mauricio Montoya; Machado-Alba, Jorge Enrique

2016-08-01

Medication is one of the main causes of long QT syndrome (LQTS) and torsades de pointes (TdP), and the older adult population is at particularly high risk. The aim of the present study was to describe the prescription patterns of drugs with a risk of TdP in the Colombian older adult population. Patients older than 65 years who received medication with a risk of TdP during three consecutive months were selected. The medication was obtained and classified according to the QT Drug List from Crediblemeds.org. The data were analysed using SPSS-22. A total of 55 932 patients were chronically receiving QT-prolonging drugs; 61.9% (n = 34 ,632) were women and the mean age of the sample was 75.6 years. Drugs with a conditional risk were consumed by 95.2% of patients, 5.3% received drugs with a known risk and 2.9% received drugs with a possible risk. Two or more QT-prolonging drugs were consumed by 10.3% of the patients (n = 5786). Most of the sample (96.8%, n = 54 170) had at least one additional risk factor for LQTS, with a mean of 3.1 ± 0.9 risk factors. Patients receiving QT-prolonging drugs for psychiatric and neurological disease were at a higher risk of major polypharmacy [odds ratio (OR) 3.0; 95% confidence interval (CI) 2.80, 3.22) and of receiving high doses of QT-prolonging drugs (OR 3.8; 95% CI 3.52, 4.05). The widespread use of medication that causes TdP and the high prevalence of additional risks in the older adult population raise the need for accurate prediction of risk and constant patient monitoring. Patients taking psychiatric drugs are at a higher risk of TdP. © 2016 The British Pharmacological Society.

P-wave and QT dispersion in patients with conversion disorder.

PubMed

Izci, Filiz; Hocagil, Hilal; Izci, Servet; Izci, Vedat; Koc, Merve Iris; Acar, Rezzan Deniz

2015-01-01

The aim of this study was to investigate QT dispersion (QTd), which is the noninvasive marker of ventricular arrhythmia and sudden cardiac death, and P-wave dispersion, which is the noninvasive marker of atrial arrhythmia, in patients with conversion disorder (CD). A total of 60 patients with no known organic disease who were admitted to outpatient emergency clinic and were diagnosed with CD after psychiatric consultation were included in this study along with 60 healthy control subjects. Beck Anxiety Inventory and Beck Depression Scale were administered to patients and 12-lead electrocardiogram measurements were obtained. Pd and QTd were calculated by a single blinded cardiologist. There was no statistically significant difference in terms of age, sex, education level, socioeconomic status, weight, height, and body mass index between CD patients and controls. Beck Anxiety Inventory scores (25.2±10.8 and 3.8±3.2, respectively, P<0.001) and Beck Depression Scale scores (11.24±6.15 and 6.58±5.69, respectively, P<0.01) were significantly higher in CD patients. P-wave dispersion measurements did not show any significant differences between conversion patients and control group (46±5.7 vs 44±5.5, respectively, P=0.156). Regarding QTc and QTd, there was a statistically significant increase in all intervals in conversion patients (416±10 vs 398±12, P<0.001, and 47±4.8 vs 20±6.1, P<0.001, respectively). A similar relation to that in literature between QTd and anxiety and somatoform disorders was also observed in CD patients. QTc and QTd were significantly increased compared to the control group in patients with CD. These results suggest a possibility of increased risk of ventricular arrhythmia resulting from QTd in CD patients. Larger samples are needed to evaluate the clinical course and prognosis in terms of arrhythmia risk in CD patients.

Concomitant presentation of Anderson-Tawil syndrome and myasthenia gravis in an adult patient: A case report.

PubMed

Fan, Rui; Ji, Ruirui; Zou, Wenxin; Wang, Guoliang; Wang, Hu; Penney, Daniel James; Luo, Jin Jun; Fan, Yuxin

2016-10-01

Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies. Laboratory results revealed hypokalemia and an elevated anti-AChR antibody expression levels. Electrocardiography demonstrated prolonged QT-interval, ST-elevation, and subsequent third-degree atrioventricular block. Neurological examination revealed bilateral ptosis, horizontal diplopia, dysarthria and generalized weakness. No mutations in the potassium channel inwardly rectifying subfamily J member 2 gene were detected in the present case. The patient was treated with oral potassium supplementation and an acetylcholinesterase inhibitor (pyridostigmine), after which the symptoms were improved. To the best of our knowledge, the present case report was the first to describe concomitant presentation of both ATS and MG, which represents a diagnostic and therapeutic challenge.

Association between the physical activity and heart rate corrected-QT interval in older adults.

PubMed

Michishita, Ryoma; Fukae, Chika; Mihara, Rikako; Ikenaga, Masahiro; Morimura, Kazuhiro; Takeda, Noriko; Yamada, Yosuke; Higaki, Yasuki; Tanaka, Hiroaki; Kiyonaga, Akira

2015-07-01

Increased physical activity can reduce the incidence of cardiovascular disease and the mortality rate. In contrast, a prolonged heart rate corrected-QT (QTc) interval is associated with an increased risk of arrhythmias, sudden cardiac death and coronary artery disease. The present cross-sectional study was designed to clarify the association between the physical activity level and the QTc interval in older adults. The participants included 586 older adults (267 men and 319 women, age 71.2 ± 4.7 years) without a history of cardiovascular disease, who were taking cardioactive drugs. Electrocardiography was recorded with a standard resting 12-lead electrocardiograph, while the QTc interval was calculated according to Hodges' formula. The physical activity level was assessed using a triaxial accelerometer. The participants were divided into four categories, which were defined equally quartile distributions of the QTc interval. After adjusting for age, body mass index, waist circumference and the number of steps, the time spent in inactivity was higher and the time spent in light physical activity was significantly lower in the longest QTc interval group than in the shortest QTc interval group in both sexes (P < 0.05, respectively). However, there were no significant differences in the time spent in moderate and vigorous physical activities among the four groups in either sex. These results suggest that a decreased physical activity level, especially inactivity and light intensity physical activity, were associated with QTc interval in older adults. © 2014 Japan Geriatrics Society.

QT dispersion increases with low glomerular filtration rate in patients with coronary artery disease

PubMed Central

Celik, Murat; Yuksel, UygarCagdas; Gokoglan, Yalcin; Bugan, Baris; Yalcinkaya, Emre; Unal, HilmiUmut; Celik, Turgay; Iyisoy, Atila; Kilic, Selim

2014-01-01

Objective: We aimed to evaluate the relationship between estimated glomerular filtration rate (eGFR) and QT dispersion (QTd) in patients with coronary artery disease (CAD). Methods: Sixty patients(mean age 62.72 ± 12.48 years) included 46 male, (mean age 60.89 ± 12.70 years)and 14 female (mean age 68.71± 9.86 years) were enrolled in this study. Patients were divided into 2 groups according to their eGFR using the 6 variable MDRD equation. Group 1 consisted of patients with estimated eGFR<60 ml/min/1.73m2 and Group 2 consisted of patients witheGFR ≥ 60 ml/min/1.73m2. Results: Baseline patient characteristics were homogeneous in both groups except for age, gender and smoking.Also, the extent of CAD was similar in both groups (p > 0.05) QTd values were found higher in group 1 than those of group 2 (57.23 ± 40.65 ms vs. 31.23 ± 14.47 ms, p = 0.002). After adjustment for age, gender and smoking using one-way ANCOVA test, statistically significant difference in QTd still existedbetween the groups (p=0.038). Conclusion:QTd tends to be higher in patients with poor renal function independent of severity of angiographical CAD. QTd may be a potentially useful non-invasive test in the management of patients with poor renal function, especially those with CAD. PMID:24772124

Multi-channel System for Beat to Beat QT Interval Variability and its Use in Screening for Coronary Artery Disease and Cardiomyopathy

NASA Technical Reports Server (NTRS)

Starc, V.; Schlegel, T. T.; Arenare, B.; Greco, E. C.; DePalma, J. L.; Nunez, T.; Medina, R.; Jugo, D.; Rahman, M. A.; Delgado, R.

2007-01-01

We investigated the ability of beat-to-beat QT interval variability (QTV) and related parameters to differentiate healthy individuals from patients with obstructive coronary artery disease (CAD) and cardiomyopathy (CM). For this purpose we developed a PC-based ECG software program that in real time, acquires, analyzes and displays QTV in each of the eight independent channels that constitute the 12-lead conventional ECG. The system also analyzes and displays the QTV from QT interval signals that are derived from multiple channels and from singular value decomposition (SVD) to substantially reduce the effect of noise and other artifacts on the QTV results. It also provides other useful SVD-related parameters such as the normalized 3-dimensional volume of the T wave (nTV) = 100*(rho(sub 2)*rho(sub 3)rho(sub 1^2). Advanced high-fidelity 12-lead ECG tests (approx. 5-min supine) were first performed on a "training set" of 99 individuals: 33 with ischemic or dilated CM and low ejection fraction (EF less than 40%); 33 with catheterization-proven obstructive CAD but normal EF; and 33 age-/gender-matched healthy controls. All QTV parameters that were studied for their accuracy in detecting CM and CAD significantly differentiated both CM and CAD from controls (p less than 0.0001). Retrospective areas under the ROC curve (AUC) of SDNN-QTV, rmsSD-QTV, and QTV Index (QTVI) for CM vs. controls in the lead V5 were 0.85, 0.90, and 0.99, respectively, and those for CAD vs. controls in the lead II were 0.82, 0.82, and 0.89. Other advanced ECG parameters, such as HFQRS RAZ score, LF Lomb of RRV or QRS-T angle, differentiated both CM and CAD from controls less significantly, with the respective AUC values of 0.89, 0.88 and 0.98 for CM vs. controls, and 0.73, 0.71 and 0.80 for CAD vs. controls. QTV parameters (especially QTVI, which is QTV as indexed to RRV) were, diagnostically speaking, amongst the best performing of the advanced ECG techniques studied thus far.

Understanding Bartter syndrome and Gitelman syndrome.

PubMed

Fremont, Oliver T; Chan, James C M

2012-02-01

We aim to review the clinical features of two renal tubular disorders characterized by sodium and potassium wasting: Bartter syndrome and Gitelman syndrome. Selected key references concerning these syndromes were analyzed, together with a PubMed search of the literature from 2000 to 2011. The clinical features common to both conditions and those which are distinct to each syndrome were presented. The new findings on the genetics of the five types of Bartter syndrome and the discrete mutations in Gitelman syndrome were reviewed, together with the diagnostic workup and treatment for each condition. Patients with Bartter syndrome types 1, 2 and 4 present at a younger age than classic Bartter syndrome type 3. They present with symptoms, often quite severe in the neonatal period. Patients with classic Bartter syndrome type 3 present later in life and may be sporadically asymptomatic or mildly symptomatic. The severe, steady-state hypokalemia in Bartter syndrome and Gitelman syndrome may abruptly become life-threatening under certain aggravating conditions. Clinicians need to be cognizant of such renal tubular disorders, and promptly treat at-risk patients.

Defective calcium inactivation causes long QT in obese insulin-resistant rat.

PubMed

Lin, Yen-Chang; Huang, Jianying; Kan, Hong; Castranova, Vincent; Frisbee, Jefferson C; Yu, Han-Gang

2012-02-15

insulin resistance, enhancing our understanding of long QT associated with obese type 2 diabetic patients.

Jervell and Lange-Nielsen syndrome in cochlear implanted patients: our experience and a review of literature.

PubMed

Eftekharian, Ali; Mahani, Mozhgan Hosseinerezai

2015-09-01

To share our experience in cochlear implanted patients with Jervell and Lange-Nielsen syndrome (JLNS), to review the literature results and to disclose precautions which have to be taken dealing with these patients. Electrocardiograms (ECG) of 503 children with congenital bilateral profound hearing loss which were cochlear implanted in cochlear implant center of a tertiary hospital were evaluated for long QT syndrome. Clinical reports of the patients with JLNS were evaluated and a review of literature performed. The prevalence of disease was 0.79% (four cases) in our center which is in the range of literature reports (0-2.6%). None of our patients had a history of syncopal attack. Two patients (50%) were born from parents with consanguineous marriage. Considering all precautions their cochlear implant surgeries were done uneventfully. A review of the literature has identified sixteen reports on cochlear implantation in a total of 38 children with JLNS. Similar to our cases none of the authors reported cardiac events during device switch-on. Nine available reports about the outcome of cochlear implantation in these patients indicated good auditory outcome. It is recommended that all congenitally deaf patients have an ECG taken as a part of the evaluation. As auditory stimuli is reported to be a specific trigger, it is prudent to activate the processor with continuous heart monitoring even though there is no reported cardiac event during device switch-on. Cochlear implantation can be performed relatively safely in these patients if necessary precautions have been taken appropriately and their auditory outcome is good. Triggers of the cardiac events should be avoided throughout their life. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism.

PubMed

Danielsson, Christian; Brask, Johan; Sköld, Anna-Carin; Genead, Rami; Andersson, Agneta; Andersson, Ulf; Stockling, Kenneth; Pehrson, Rickard; Grinnemo, Karl-Henrik; Salari, Sajjad; Hellmold, Heike; Danielsson, Bengt; Sylvén, Christer; Elinder, Fredrik

2013-01-01

Several drugs blocking the rapidly activating potassium (K(r)) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species. Patch-clamp and quantitative-mRNA measurements of K(r) and slowly activating K (K(s)) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K(r) channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K(r)-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K(r)-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K(s) channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit. This first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K(r)-channel blocker in human, rat, and rabbit embryos provides evidence of K(r)-channel inhibition as a common mechanism for embryonic malformations and death.

Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing.

PubMed

Baurand, Amandine; Falcon-Eicher, Sylvie; Laurent, Gabriel; Villain, Elisabeth; Bonnet, Caroline; Thauvin-Robinet, Christel; Jacquot, Caroline; Eicher, Jean-Christophe; Gourraud, Jean-Baptiste; Schmitt, Sébastien; Bézieau, Stéphane; Giraud, Mathilde; Dumont, Solenne; Kuentz, Paul; Probst, Vincent; Burguet, Antoine; Kyndt, Florence; Faivre, Laurence

2017-02-01

Autosomal dominant genetic diseases can occur de novo and in the form of somatic mosaicism, which can give rise to a less severe phenotype, and make diagnosis more difficult given the sensitivity limits of the methods used. We report the case of female child with a history of surgery for syndactyly of the hands and feet, who was admitted at 6 years of age to a pediatric intensive care unit following cardiac arrest. The electrocardiogram (ECG) showed a long QT interval that on occasions reached 500 ms. Despite the absence of facial dysmorphism and the presence of normal psychomotor development, a diagnosis of Timothy syndrome was made given the association of syndactyly and the ECG features. Sanger sequencing of the CACNA1C gene, followed by sequencing of the genes KCNQ1, KCNH2, KCNE1, KCNE2, were negative. The subsequent analysis of a panel of genes responsible for hereditary cardiac rhythm disorders using Haloplex technology revealed a recurrent mosaic p.Gly406Arg missense mutation of the CACNA1C gene in 18% of the cells. This mosaicism can explain the negative Sanger analysis and the less complete phenotype in this patient. Given the other cases in the literature, mosaic mutations in Timothy syndrome appear more common than previously thought. This case demonstrates the importance of using next-generation sequencing to identify mosaic mutations when the clinical picture supports a specific mutation that is not identified using conventional testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Tafenoquine at therapeutic concentrations does not prolong fridericia-corrected QT interval in healthy subjects

PubMed Central

Green, Justin A; Patel, Apurva K; Patel, Bela R; Hussaini, Azra; Harrell, Emma J; McDonald, Mirna J; Carter, Nick; Mohamed, Khadeeja; Duparc, Stephan; Miller, Ann K

2014-01-01

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18–65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine–QTcF concentration–effect relationship demonstrated a shallow slope (0.5 ms/μg mL–1) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization. PMID:24700490

Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects.

PubMed

Green, Justin A; Patel, Apurva K; Patel, Bela R; Hussaini, Azra; Harrell, Emma J; McDonald, Mirna J; Carter, Nick; Mohamed, Khadeeja; Duparc, Stephan; Miller, Ann K

2014-09-01

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18-65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine-QTcF concentration-effect relationship demonstrated a shallow slope (0.5 ms/μg mL(-1) ) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization. © 2014, The American College of Clinical Pharmacology.

Neurological Complications of Cardiac Disease.

PubMed

Madan, Nandini; Carvalho, Karen S

2017-02-01

This article focuses on the complex interactions between the cardiovascular and neurologic systems. Initially, we focus on neurological complications in children with congenital heart disease both secondary to the underlying cardiac disease and complications of interventions. We later discuss diagnosis and management of common syncope syndromes with emphasis on vasovagal syncope. We also review the diagnosis, classification, and management of children and adolescents with postural orthostatic tachycardia syndrome. Lastly, we discuss long QT syndrome and sudden unexpected death in epilepsy (SUDEP), reviewing advances in genetics and current knowledge of pathophysiology of these conditions. This article attempts to provide an overview of these disorders with focus on pathophysiology, advances in molecular genetics, and current medical interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of QT and RR interval series during acute myocardial ischemia by means of recurrence quantification analysis.

PubMed

Peng, Yi; Sun, Zhongwei

2011-01-01

This study is aimed to investigate the nonlinear dynamic properties of the fluctuations in ventricular repolarization, heart rate and their correlation during acute myocardial ischemia. From 13 ECG records in long-term ST-T database, 170 ischemic episodes were selected with the duration of 34 s to 23 min 18 s, and two 5-min episodes immediately before and after each ischemic episode as non-ischemic ones for comparison. QT interval (QTI) and RR interval (RRI) were extracted and the ectopic beats were removed. Recurrence quantification analysis (RQA) was performed on QTI and RRI series, respectively, and cross recurrence quantification analysis (CRQA) on paired normalized QTI and RRI series. Wilcoxon signed-rank test was used for statistical analysis. Results revealed that the RQA indexes for QTI and HRI series had the same changing trend during ischemia with more significantly changed indexes in QTI series. In the CRQA, indexes related to the vertical and horizontal structures in recurrence plot significantly increased, representing decreased dependency of QTI on RRI. Both QTI and RRI series showed reduced complexity during ischemia with higher sensitivity in ventricular repolarization. The weakened coupling between QTI and RRI suggests the decreased influence of sinoatrial node on QTI modulation during ischemia.

The developmental trajectory of disruptive behavior in Down syndrome, fragile X syndrome, Prader-Willi syndrome and Williams syndrome.

PubMed

Rice, Lauren J; Gray, Kylie M; Howlin, Patricia; Taffe, John; Tonge, Bruce J; Einfeld, Stewart L

2015-06-01

The aim of this study was to investigate the developmental trajectories of verbal aggression, physical aggression, and temper tantrums in four genetic syndrome groups. Participants were part of the Australian Child to Adult Development Study (ACAD), which collected information from a cohort of individuals with an intellectual disability at five time points over 18 years. Data were examined from a total of 248 people with one of the four following syndromes: Down syndrome, Fragile X syndrome, Prader-Willi syndrome, or Williams syndrome. Changes in behaviors were measured using validated items from the Developmental Behavior Checklist (DBC). The results indicate that, while verbal aggression shows no evidence of diminishing with age, physical aggression, and temper tantrums decline with age before 19 years for people with Down syndrome, Fragile X syndrome, and William syndrome; and after 19 years for people with Prader-Willi syndrome. These findings offer a somewhat more optimistic outlook for people with an intellectual disability than has previously been suggested. Research is needed to investigate the mechanisms predisposing people with PWS to persistence of temper tantrums and physical aggression into adulthood. © 2015 Wiley Periodicals, Inc.

The metabolic syndrome in polycystic ovary syndrome.

PubMed

Essah, P A; Nestler, J E

2006-03-01

Much overlap is present between the polycystic ovary syndrome (PCOS) and the metabolic syndrome. This article reviews the existing data regarding the prevalence, characteristics, and treatment of the metabolic syndrome in women with PCOS. The prevalence of the metabolic syndrome in PCOS is approximately 43-47%, a rate 2-fold higher than that for women in the general population. High body mass index and low serum HDL cholesterol are the most frequently occurring components of the metabolic syndrome in PCOS. The pathogenic link between the metabolic syndrome and PCOS is most likely insulin resistance. Therefore, the presence of the metabolic syndrome in PCOS suggests a greater degree of insulin resistance compared to PCOS without the metabolic syndrome. Obesity, atherogenic dyslipidemia, hypertension, impaired fasting glucose/impaired glucose tolerance, and vascular abnormalities are all common metabolic abnormalities present in PCOS. Lifestyle modification has proven benefit and pharmacological therapy with insulin-sensitizing agents has potential benefit in the treatment of the metabolic syndrome in women with PCOS.

Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish.

PubMed

Pott, Alexander; Bock, Sarah; Berger, Ina M; Frese, Karen; Dahme, Tillman; Keßler, Mirjam; Rinné, Susanne; Decher, Niels; Just, Steffen; Rottbauer, Wolfgang

2018-05-08

The genetic underpinnings that orchestrate the vertebrate heart rate are not fully understood yet, but of high clinical importance, since diseases of cardiac impulse formation and propagation are common and severe human arrhythmias. To identify novel regulators of the vertebrate heart rate, we deciphered the pathogenesis of the bradycardia in the homozygous zebrafish mutant hiphop (hip) and identified a missense-mutation (N851K) in Na + /K + -ATPase α1-subunit (atp1a1a.1). N851K affects zebrafish Na + /K + -ATPase ion transport capacity, as revealed by in vitro pump current measurements. Inhibition of the Na + /K + -ATPase in vivo indicates that hip rather acts as a hypomorph than being a null allele. Consequently, reduced Na + /K + -ATPase function leads to prolonged QT interval and refractoriness in the hip mutant heart, as shown by electrocardiogram and in vivo electrical stimulation experiments. We here demonstrate for the first time that Na + /K + -ATPase plays an essential role in heart rate regulation by prolonging myocardial repolarization. Copyright © 2018. Published by Elsevier Ltd.

Functional characterization of a novel hERG variant in a family with recurrent sudden infant death syndrome: Retracting a genetic diagnosis.

PubMed

Sergeev, Valentine; Perry, Frances; Roston, Thomas M; Sanatani, Shubhayan; Tibbits, Glen F; Claydon, Thomas W

2018-03-01

Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2. Functional characterization was undertaken due to the variable phenotype in carriers, the discrepancy with published cases, and the importance of identifying a cause for recurrent deaths in a single family. Studies of the mutated ion channel in in vitro heterologous expression systems revealed that the mutation has no detectable impact on membrane surface expression, biophysical gating properties such as activation, deactivation and inactivation, or the amplitude of the protective current conducted by hERG channels during early repolarization. These observations suggest that the p.Pro963Thr mutation is not a monogenic disease-causing LQTS mutation despite evidence of co-segregation in two siblings affected by SIDS. Our findings demonstrate some of the potential pitfalls in post-mortem molecular testing and the importance of functional testing of gene variants in determining disease-causation, especially where the impacts of cascade screening can affect multiple generations. Copyright © 2017 Elsevier B.V. All rights reserved.

hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.

PubMed

Nogawa, Hisashi; Kawai, Tomoyuki

2014-10-15

Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. Copyright © 2014 Elsevier B.V. All rights reserved.

Quinidine revisited.

PubMed

Yang, Felix; Hanon, Sam; Lam, Patrick; Schweitzer, Paul

2009-04-01

One of the earliest antiarrhythmic drugs developed, quinidine had a significant role in the treatment of many arrhythmias. After concerns for increased risk of ventricular arrhythmia and death with quinidine emerged, the use of quinidine fell dramatically in favor of newer antiarrhythmic medications. However, recent trials have generated renewed interest in the use of quinidine. In particular, quinidine appears to be safe and efficacious in combination with verapamil for the treatment of atrial fibrillation. Quinidine has also been used successfully to treat idiopathic ventricular fibrillation, Brugada syndrome, and Short QT syndrome. Although it is one of the oldest drugs in our armamentarium, quinidine continues to have a role in modern cardiology.

A Rare Variant of Wallenberg’s Syndrome: Opalski syndrome

PubMed Central

KK, Parathan; P, Chitrambalam; Aiyappan, Senthil Kumar; N, Deepthi

2014-01-01

Lateral Medullary Syndrome (LMS) is a well-documented vascular syndrome of the posterior circulation territory. This syndrome is easily localised because of characteristic presentation, unique territory of blood supply and very small area of involvement. We present a case of Wallenberg’s syndrome which did not have all the classical components of the syndrome, like Horner’s syndrome. Opalski syndrome is a rare variant of Wallenberg syndrome, where lateral medullary syndrome is associated with ipsilateral hemiparesis. This case report highlights how differential involvement of the lateral part of medulla can result in varied presentation. PMID:25177595

Relationship between QT Interval Dispersion in acute stroke and stroke prognosis: A Systematic Review

PubMed Central

Lederman, Yitzchok S.; Balucani, Clotilde; Lazar, Jason; Steinberg, Leah; Gugger, James; Levine, Steven R.

2014-01-01

Background QT dispersion (QTd) has been proposed as an indirect ECG measure of heterogeneity of ventricular repolarization. The predictive value of QTd in acute stroke remains controversial. We aimed to clarify the relationship between QTd and acute stroke and stroke prognosis. Methods A systematic review of the literature was performed using pre-specified medical subjects heading (MeSH) terms, Boolean logic and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Eligible studies (a) included ischemic or hemorrhagic stroke and (b) provided QTd measurements. Results Two independent reviewers identified 553 publications. Sixteen articles were included in the final analysis. There were a total of 888 stroke patients: 59% ischemic and 41% hemorrhagic. There was considerable heterogeneity in study design, stroke subtypes, ECG assessment-time, control groups and comparison groups. Nine studies reported a significant association between acute stroke and baseline QTd. Two studies reported that QTd increases are specifically related to hemorrhagic strokes, involvement of the insular cortex, right-side lesions, larger strokes, and increases in 3, 4-dihydroxyphenylethylene glycol in hemorrhagic stroke. Three studies reported QTd to be an independent predictor of stroke mortality. One study each reported increases in QTd in stroke patients who developed ventricular arrhythmias and cardiorespiratory compromise. Conclusions There are few well-designed studies and considerable variability in study design in addressing the significance of QTd in acute stroke. Available data suggest that stroke is likely to be associated with increased QTd. While some evidence suggests a possible prognostic role of QTd in stroke, larger and well-designed studies need to confirm these findings. PMID:25282188

Duane Syndrome

MedlinePlus

... is Duane Syndrome? Duane syndrome, also called Duane retraction syndrome (DRS), is a congenital and non-progressive ... Is Duane syndrome congenital (present from birth)? Duane retraction syndrome is present from birth, even if it ...

Utility of the exercise electrocardiogram testing in sudden cardiac death risk stratification.

PubMed

Refaat, Marwan M; Hotait, Mostafa; Tseng, Zian H

2014-07-01

Sudden cardiac death (SCD) remains a major public health problem. Current established criteria identifying those at risk of sudden arrhythmic death, and likely to benefit from implantable cardioverter defibrillators (ICDs), are neither sensitive nor specific. Exercise electrocardiogram (ECG) testing was traditionally used for information concerning patients' symptoms, exercise capacity, cardiovascular function, myocardial ischemia detection, and hemodynamic responses during activity in patients with hypertrophic cardiomyopathy. We conducted a systematic review of MEDLINE on the utility of exercise ECG testing in SCD risk stratification. Exercise testing can unmask suspected primary electrical diseases in certain patients (catecholaminergic polymorphic ventricular tachycardia or concealed long QT syndrome) and can be effectively utilized to risk stratify patients at an increased (such as early repolarization syndrome and Brugada syndrome) or decreased risk of SCD, such as the loss of preexcitation on exercise testing in asymptomatic Wolff-Parkinson-White syndrome. Exercise ECG testing helps in SCD risk stratification in patients with and without arrhythmogenic hereditary syndromes. © 2014 Wiley Periodicals, Inc.

Seckel syndrome: an overdiagnosed syndrome.

PubMed Central

Thompson, E; Pembrey, M

1985-01-01

Five children in whom a diagnosis of Seckel syndrome had previously been made were re-examined in the genetic unit. One child had classical Seckel syndrome, a sib pair had the features of the syndrome with less severe short stature, and in two children the diagnosis was not confirmed. Seckel syndrome is only one of a group of low birth weight microcephalic dwarfism and careful attention should be paid to fulfillment of the major criteria defined by Seckel before the diagnosis is made. There remains a heterogeneous group of low birth weight microcephalic dwarfism yet to be defined. Images PMID:4040172

Can sudden cardiac death in the young be predicted and prevented? Lessons from autopsy for the emergency physician.

PubMed

White, Jennifer L; Chang, Anna Marie; Cesar, Sergi; Sarquella-Brugada, Georgia

2018-06-01

Sudden unexpected death in the young, though rare, is devastating for both the family and the community. Although only 1.3 to 8.5 cases of sudden cardiac death (SCD) occur per 100 000 young people, autopsy is often inconclusive. Many causes of SCD are related to autosomal dominant inherited risk, however; therefore, answers are important for survivors. Causes of autopsy-positive SCD in young patients include hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia. Autopsy-negative SCD has been related to inherited arrhythmogenic causes such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, Wolff- Parkinson-White syndrome, and idiopathic ventricular fibrillation. The important question for the emergency physician is how SCD can be predicted and prevented in the young so that there is no need for an autopsy.

Effect of nicorandil on QT dispersion in patients with stable angina pectoris undergoing elective angioplasty: A triple-blind, randomized, placebo-controlled study

PubMed Central

Suleimani, Homa Fal; Eshraghi, Ali; Daloee, Mehdi Hasanzadeh; Hoseini, Sara; Nakhaee, Nima

2017-01-01

Background Nicorandil leads to the relaxation of fine vascular smooth muscle, and thus causes vasodilatation of major epicardial. Also, it has anti-arrhythmic and cardio-protective effects by improving reperfusion, and ultimately leads to a reduction in microvascular damage caused by percutaneous coronary intervention (PCI). Objective The aim of this study was to determine the effect of nicorandil on QT interval dispersion (QTd) in patients with stable angina pectoris during elective angioplasty. Methods This triple-blind and randomized clinical trial was performed on patients with stable angina pectoris, candidates for elective angiography referred to Imam Reza and Ghaem hospitals in Mashhad, Iran, between January and October 2016. The patients were randomly assigned to one of two groups receiving nicorandil (60 mg as 20 mg before and 40 mg after PCI) and placebo. All the patients underwent electrocardiography 12 hours before and 12 hours after PCI. The values of maximal corrected QT interval (QTc max) and QTd in these intervals, and the levels of changes in the QTd (QTd difference before angiography and after PCI) were compared between the two groups. Data were analyzed statistically using SPSS version 18 software via Chi-square and Independent-samples t-test. Results This study was performed on 90 patients (55 males and 35 females) with a mean age of 58.6±10.8 years, on two groups of 45 people. The two groups were matched for age, body mass index, cardiovascular risk factors and baseline testing. The QTd before angiography had no statistically significant difference between the patients of both groups (control: 77.7±17.1 vs. nicorandil: 80.7±14.2 ms; p=0.371). The QTd after PCI in the nicorandil group was lower than the control group (48.1±14.2 vs. 59.2±15.6 ms; p=0.000). The decrease rate in QTd had a statistically significant difference between the two groups (control: 18.9±11.0 vs. nicorandil: 33.5±9.5 ms; p=0.000). Conclusions The results of this

Brief Report: Repetitive Behaviour Profiles in Williams syndrome: Cross Syndrome Comparisons with Prader-Willi and Down syndromes.

PubMed

Royston, R; Oliver, C; Moss, J; Adams, D; Berg, K; Burbidge, C; Howlin, P; Nelson, L; Stinton, C; Waite, J

2018-01-01

This study describes the profile of repetitive behaviour in individuals with Williams syndrome, utilising cross-syndrome comparisons with people with Prader-Willi and Down syndromes. The Repetitive Behaviour Questionnaire was administered to caregivers of adults with Williams (n = 96), Prader-Willi (n = 103) and Down (n = 78) syndromes. There were few group differences, although participants with Williams syndrome were more likely to show body stereotypies. Individuals with Williams syndrome also showed more hoarding and less tidying behaviours than those with Down syndrome. IQ and adaptive ability were negatively associated with repetitive questioning in people with Williams syndrome. The profile of repetitive behaviour amongst individuals with Williams syndrome was similar to the comparison syndromes. The cognitive mechanisms underlying these behaviours in genetic syndromes warrant further investigation.

Development of quercetin-phospholipid complex to improve the bioavailability and protection effects against carbon tetrachloride-induced hepatotoxicity in SD rats.

PubMed

Zhang, Kexia; Zhang, Meiyu; Liu, Ziying; Zhang, Yuanyuan; Gu, Liqiang; Hu, Gaosheng; Chen, Xiaohui; Jia, Jingming

2016-09-01

Quercetin (QT) is a natural flavonoid with various biological activities and pharmacological actions. However, the bioavailability of QT is relatively low due to its low solubility which severely limits its use. In this study, we intended to improve the bioavailability of QT by preparing quercetin-phospholipid complex (QT-PC) and investigate the protective effect of QT-PC against carbon tetrachloride (CCl4) induced acute liver damage in Sprague-Dawley (SD) rats. The physicochemical properties of QT-PC were characterized in terms of infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and water/n-octanol solubility. FTIR, DSC and XRPD data confirmed the formation of QT-PC. The water solubility of QT was improved significantly in the prepared complex, indicating its increased hydrophilicity. Oral bioavailability of QT and QT-PC was evaluated in SD rats, and the plasma QT was estimated by HPLC-MS. QT-PC exhibited higher Cmax (1.58±0.11 vs. 0.67±0.08μg/mL), increased AUC0-∞ (8.60±1.25 vs. 2.41±0.51mg/Lh) and t1/2z (7.76±1.09 vs. 4.81±0.87h) when compared to free QT. The greater absorption of QT-PC group suggested the improved bioavailability. Moreover, biochemical changes and histopathological observations revealed that QT-PC provided better protection to rat liver than free QT at the same dose. Thus, phospholipid complexation might be one of the suitable approaches to improve the oral bioavailability of QT and obtain better protective effects against CCl4 induced acute liver damage in SD rats than free QT at the same dose level. Copyright © 2016 Elsevier B.V. All rights reserved.

[Association Budd Chiari syndrome, antiphospholipid syndrome and Grave's disease].

PubMed

Mouelhi, Leila; Chaieb, Mouna; Debbeche, Radhouane; Salem, Mohamed; Sfar, Imene; Trabelsi, Sinda; Gorgi, Yosr; Najjar, Taoufik

2009-02-01

Antiphospholipid syndrome is revealed by Budd Chiari syndrome in 5% of the cases. Antiphospholipid syndrome is characterized by venous or arterial thrombosis, foetal loss and positivity of antiphospholipid antibodies, namely lupus anticoagulant, anticardiolipin antibodies and anti-beta2-glycoprotein I. Anticardiolipin antibodies was reported in auto-immune thyroid disorders, particularly in Grave's disease. Antiphospholipid syndrome associated to Grave's disease was reported in only three cases. To describe a case report of association of Grave's disease and antiphospholipid syndrome. We report the first case of Grave's disease associated with antiphospholipid syndrome, revealed by Budd Chiari syndrome. Our observation is particular by the fact that it is about a patient presenting a Grave's disease associated with antiphospholipid syndrome revealed by Budd Chiari syndrome. This triple association has never been reported in literature. Although association between antiphospholipid syndrome and Grave's disease was previously described, further studies evaluating the coexistence of these two affections in the same patient would be useful.

Wells syndrome and its relationship to Churg-Strauss syndrome.

PubMed

Ratzinger, Gudrun; Zankl, Julia; Zelger, Bernhard

2013-08-01

  Wells syndrome has been described as an inflammatory disorder based on typical clinical appearance combined with the histopathological presence of eosinophilic infiltrates and flame figures in the absence of vasculitis. Churg-Strauss syndrome, on the other hand, is primarily a diffuse, necrotizing vasculitis but is also typically displaying eosinophils and flame figures. Despite several parallels, the present understanding of these two diseases excludes any pathogenetic relationship.   We describe the clinical course and histopathological appearance of three patients who had initially been diagnosed with Wells syndrome that developed into Churg-Strauss syndrome during the course of their disease.   The clinical presentation of all three patients led to the diagnosis of Wells syndrome by independent specialists. Histopathology showed an eosinophilic infiltrate and flame figures next to features of leukocytoclastic vasculitis. Detailed examination revealed asthma bronchiale and additional symptoms indicating Churg-Strauss syndrome. The initial diagnosis of Wells syndrome had to be revised to Churg-Strauss syndrome.   We conclude that Wells syndrome could be the starting point of a pathogenetic process that might reach its maximum in Churg-Strauss syndrome. As a clinical consequence, patients with Wells syndrome should be evaluated and followed for Churg-Strauss syndrome. © 2013 The International Society of Dermatology.

Kindler syndrome.

PubMed

Kaviarasan, P K; Prasad, P V S; Shradda; Viswanathan, P

2005-01-01

Kindler syndrome is a rare autosomal recessive disorder associated with skin fragility. It is characterized by blistering in infancy, photosensitivity and progressive poikiloderma. The syndrome involves the skin and mucous membrane with radiological changes. The genetic defect has been identified on the short arm of chromosome 20. This report describes an 18-year-old patient with classical features like blistering and photosensitivity in childhood and the subsequent development of poikiloderma. The differential diagnosis of Kindler syndrome includes diseases like Bloom syndrome, Cockayne syndrome, dyskeratosis congenita, epidermolysis bullosa, Rothmund-Thomson syndrome and xeroderma pigmentosum. Our patient had classical cutaneous features of Kindler syndrome with phimosis as a complication.

"Syndrome in syndrome": Wernicke syndrome due to afferent loop syndrome. Case report and review of the literature.

PubMed

D'Abbicco, D; Praino, S; Amoruso, M; Notarnicola, A; Margari, A

2011-01-01

Wernicke syndrome is a rare neurological pathology due to a deficit in vitamin B1. The syndrome is common among alcohol abusers, patients with malignant tumor or gastrointestinal diseases, those who undergo hemodialysis or long-term peritoneal dialysis, pregnant women with hyperemesis, women who breast-feed, patients with hyperthyroidism or anorexia nervosa or gastric or jejunal-ileal bypass surgery for obesity, patients submitted to gastric surgery or prolonged total parenteral nutrition or prolonged intravenous therapy. We report a case of Wernicke syndrome due to afferent loop syndrome characterized by incoercible vomiting.

A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients.

PubMed

Florian, J; Garnett, C E; Nallani, S C; Rappaport, B A; Throckmorton, D C

2012-04-01

Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.

Fanconi syndrome

MedlinePlus

De Toni-Fanconi syndrome ... Fanconi syndrome can be caused by faulty genes, or it may result later in life due to kidney damage. Sometimes the cause of Fanconi syndrome is unknown. Common causes of Fanconi syndrome in ...

Cardiovascular safety of prokinetic agents: A focus on drug-induced arrhythmias.

PubMed

Giudicessi, J R; Ackerman, M J; Camilleri, M

2018-02-14

Gastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use. The purpose of this review is to detail the cellular and molecular mechanisms that lead commonly to drug-induced cardiac arrhythmias, specifically drug-induced long QT syndrome, torsades de pointes, and ventricular fibrillation, to examine the cardiovascular safety profiles of several classes of prokinetic agents currently in clinical use, and to explore potential strategies by which the risk of drug-induced cardiac arrhythmia associated with prokinetic agents and other QT interval prolonging medications can be mitigated successfully. © 2018 John Wiley & Sons Ltd.

Comparison of antioxidant activity of compounds isolated from guava leaves and a stability study of the most active compound.

PubMed

Nantitanon, W; Okonogi, S

2012-02-01

In the present study, quercetin (QT), morin (MR), and quercetin-3-O-glucopyranoside (QG) isolated from guava leaves were comparatively tested for antioxidant activity using DPPH, ABTS, and FRAP methods. QT was the most active among them. The free radical scavenging activity of QT was approximately four times higher than MR and two times higher than QG. The reducing power of QT was eight times higher than MR and two times higher than QG. A mixture of QT with MR or QG showed interesting combination effect. The synergistic antioxidant activity was obtained when QT was mixed with MR whereas the antagonistic effect was found when mixed with QG. The stability study of QT in liquid preparations indicated that the decomposition reaction rate of QT could be explained by a kinetic model assuming a first-order chemical reaction. The aqueous solution of QT was rapidly decomposed with t1/2 of approximately five days whereas QT entrapped in chitosan nanoparticles was five times longer. It was concluded that QT was the most active antioxidant from guava leaves. Entrapment of QT in chitosan nanoparticles could significantly enhance its stability.

Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers

PubMed Central

Loghin, Corina; Haber, Harry; Beasley, Charles M; Kothare, Prajakti A; Kauffman, Lynnette; April, John; Jin, Ling; Allen, Albert J; Mitchell, Malcolm I

2013-01-01

Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QTcM) on day 7 was the primary endpoint. Results QTcM differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration−QTc change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations. PMID:22803597

[Kenny-Caffey syndrome and its related syndromes].

PubMed

Isojima, Tsuyoshi; Kitanaka, Sachiko

2015-11-01

Kenny-Caffey syndrome (KCS) is a very rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. Two types of KCS were known: the autosomal recessive form (KCS type 1), which is caused by mutations of the TBCE gene, and the autosomal dominant form (KCS type 2), which is caused by mutations of the FAM111A gene. TBCE mutation also causes hypoparathyroidism-retardation-dysmorphism syndrome, and FAM111A mutation also causes gracile bone dysplasia. These two diseases can be called as KCS-related syndromes. In this article, we review the clinical manifestations of KCS and discuss its related syndromes.

Metabolic syndrome and polycystic ovary syndrome: an intriguing overlapping.

PubMed

Caserta, Donatella; Adducchio, Gloria; Picchia, Simona; Ralli, Eleonora; Matteucci, Eleonora; Moscarini, Massimo

2014-06-01

Metabolic syndrome is an increasing pathology in adults and in children, due to a parallel rise of obesity. Sedentary lifestyle, food habits, cultural influences and also a genetic predisposition can cause dyslipidemia, hypertension, abdominal obesity and insulin resistance which are the two main features of metabolic syndrome. Polycystic ovary syndrome (PCOS) is a condition directly associated with obesity, insulin resistance (HOMA index) and metabolic syndrome, and it is very interesting for its relationship and overlap with the metabolic syndrome. The relationship between the two syndromes is mutual: PCOS women have a higher prevalence of metabolic syndrome and also women with metabolic syndrome commonly present the reproductive/endocrine trait of PCOS. Prevention and treatment of metabolic syndrome and PCOS are similar for various aspects. It is necessary to treat excess adiposity and insulin resistance, with the overall goals of preventing cardiovascular disease and type 2 diabetes and improving reproductive failure in young women with PCOS. First of all, lifestyle changes, then pharmacological therapy, bariatric surgery and laparoscopic ovarian surgery represent the pillars for PCOS treatment.

West syndrome in a patient with Schinzel-Giedion syndrome.

PubMed

Miyake, Fuyu; Kuroda, Yukiko; Naruto, Takuya; Ohashi, Ikuko; Takano, Kyoko; Kurosawa, Kenji

2015-06-01

Schinzel-Giedion syndrome is a rare recognizable malformation syndrome defined by characteristic facial features, profound developmental delay, severe growth failure, and multiple congenital anomalies. The causative gene of Schinzel-Giedion syndrome, SETBP1, has been identified, but limited cases have been confirmed by molecular analysis. We present a 9-month-old girl affected by West syndrome with Schinzel-Giedion syndrome. Congenital severe hydronephrosis, typical facial features, and multiple anomalies suggested a clinical diagnosis of Schinzel-Giedion syndrome. Hypsarrhythmia occurred at 7 months of age and was temporarily controlled by adrenocorticotropic hormone (ACTH) therapy during 5 weeks. SETBP1 mutational analysis showed the presence of a recurrent mutation, p.Ile871Thr. The implications in management of Schinzel-Giedion syndrome are discussed. © The Author(s) 2014.

Involvement of Caveolin in Low K+-induced Endocytic Degradation of Cell-surface Human Ether-a-go-go-related Gene (hERG) Channels*

PubMed Central

Massaeli, Hamid; Sun, Tao; Li, Xian; Shallow, Heidi; Wu, Jimmy; Xu, Jianmin; Li, Wentao; Hanson, Christian; Guo, Jun; Zhang, Shetuan

2010-01-01

Reduction in the rapidly activating delayed rectifier K+ channel current (IKr) due to either mutations in the human ether-a-go-go-related gene (hERG) or drug block causes inherited or drug-induced long QT syndrome. A reduction in extracellular K+ concentration ([K+]o) exacerbates long QT syndrome. Recently, we demonstrated that lowering [K+]o promotes degradation of IKr in rabbit ventricular myocytes and of the hERG channel stably expressed in HEK 293 cells. In this study, we investigated the degradation pathways of hERG channels under low K+ conditions. We demonstrate that under low K+ conditions, mature hERG channels and caveolin-1 (Cav1) displayed a parallel time-dependent reduction. Mature hERG channels coprecipitated with Cav1 in co-immunoprecipitation analysis, and internalized hERG channels colocalized with Cav1 in immunocytochemistry analysis. Overexpression of Cav1 accelerated internalization of mature hERG channels in 0 mm K+o, whereas knockdown of Cav1 impeded this process. In addition, knockdown of dynamin 2 using siRNA transfection significantly impeded hERG internalization and degradation under low K+o conditions. In cultured neonatal rat ventricular myocytes, knockdown of caveolin-3 significantly impeded low K+o-induced reduction of IKr. Our data indicate that a caveolin-dependent endocytic route is involved in low K+o-induced degradation of mature hERG channels. PMID:20605793

Role of the activation gate in determining the extracellular potassium dependency of block of HERG by trapped drugs.

PubMed

Pareja, Kristeen; Chu, Elaine; Dodyk, Katrina; Richter, Kristofer; Miller, Alan

2013-01-01

Drug induced long QT syndrome (diLQTS) results primarily from block of the cardiac potassium channel HERG (human-ether-a-go-go related gene). In some cases long QT syndrome can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with serum potassium abnormalities due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, and aging. Extracellular potassium influences HERG channel inactivation and can alter block of HERG by some drugs. However, block of HERG by a number of drugs is not sensitive to extracellular potassium. In this study, we show that block of WT HERG by bepridil and terfenadine, two drugs previously shown to be trapped inside the HERG channel after the channel closes, is insensitive to extracellular potassium over the range of 0 mM to 20 mM. We also show that bepridil block of the HERG mutant D540K, a mutant channel that is unable to trap drugs, is dependent on extracellular potassium, correlates with the permeant ion, and is independent of HERG inactivation. These results suggest that the lack of extracellular potassium dependency of block of HERG by some drugs may in part be related to the ability of these drugs to be trapped inside the channel after the channel closes.

Kindler syndrome.

PubMed

Lai-Cheong, Joey E; McGrath, John A

2010-01-01

Kindler syndrome (MIM173650) is an autosomal recessive genodermatosis characterized by poikiloderma, trauma-induced skin blistering, mucosal inflammation, and photosensitivity. Loss-of-function mutations in the FERMT1 gene are the cause of Kindler syndrome. Kindler syndrome is categorized as a subtype of epidermolysis bullosa (EB). During infancy and childhood, there is clinical overlap between Kindler syndrome and dystrophic EB. Unlike other forms of EB, Kindler syndrome is characterized by impaired actin cytoskeleton-extracellular matrix interactions and a variable plane of blister formation at or close to the dermal-epidermal junction. This article reviews clinicopathologic and molecular features of Kindler syndrome and discusses patient management.

Diagnostic Value of Electrocardiogram in Predicting Exaggerated Blood Pressure Response to Exercise Stress Testing.

PubMed

Eshraghi, Ali; Ebdali, Reyhaneh Takalloo; Sajjadi, Seyed Sajed; Golnezhad, Reza

2016-08-01

It is believed that an exaggerated blood pressure response (EBPR) to exercise stress test is associated with a higher risk of cardiovascular events. It is also assumed that QT dispersion (QT-d), which was originally proposed to measure the spatial dispersion of ventricular recovery times, may have a relationship to cardiovascular events. The objective of this study was to examine the difference of changes in QT-d, Maxi-QT, Mini-QT, and QT-c (corrected QT interval) of the electrocardiogram in two groups of patients with exaggerated blood pressure responses (EBPR group) and normal responses (control group) to exercise testing. Also, the diagnostic value of each of these criteria in the prediction of EBPR was studied. This cross-sectional study was conducted from May 2015 to February 2016 on patients suspected of coronary artery disease (CAD) undergoing exercise testing who had been referred to Ghaem and Imam Reza hospitals in Mashhad (Iran). All patients underwent a treadmill exercise test with the 12-lead ECG, which was optically scanned and digitized for analysis of QT-d, QT max, and QT min. Patients were divided into two groups of normal and EBPR to exercise testing. QT changes of ECG were compared between the two groups, and the diagnostic accuracy of QT variables for prediction of EBPR to exercise testing was studied. A multiple linear regression analysis (MLR), Pearson Chi-qquare, independent samples t-test, and receiver operating characteristic (ROC) curve were used as statistical methods in IBM SPSS version 19. Sixty patients (55% male) with a mean age of 50.48 ± 10.89 years were studied in two groups of normal (n=30) and exaggerated blood pressure response (n=30) to exercise testing. Maximum QT and QT dispersion were statistically different in individuals' exaggerated blood pressure response to exercise stress test (p < 0.05). The logistic regression analysis revealed that none of our parameters predicted the EBPR. The ROC curve showed that 50 and 345

Obstructive sleep apnoea/hypopnoea syndrome in adults with Down syndrome

PubMed Central

2016-01-01

Key points Adults with Down syndrome are predisposed to obstructive sleep apnoea/hypopnoea syndrome (OSAHS) due to overlap between the Down syndrome phenotype and OSAHS risk factors. The prevalence of OSAHS in adults with Down syndrome is estimated at 35–42%. This is up to ten-times higher than in the general adult population. Symptoms of OSAHS, including behavioural and emotional disturbances as well as standard symptoms such as sleepiness, should be monitored as part of regular health surveillance in adults with Down syndrome. There is evidence that the use of continuous positive airway pressure (CPAP) therapy in adults with Down syndrome and comorbid OSAHS can lead to significant improvements in subjective sleepiness, behaviour and cognitive function, though further large-scale trials are required. Educational aims To discuss the relationship between the phenotypic features of Down syndrome and the risk factors for obstructive sleep apnoea/hypopnoea syndrome (OSAHS). To examine the prevalence of OSAHS in adults with Down syndrome. To review recent research into the effectiveness of treatment of OSAHS in adults with Down syndrome using continuous positive airway pressure (CPAP) therapy. Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is characterised by repeated cycles of upper airway obstruction during sleep, leading to diurnal symptoms. Individuals with Down syndrome are predisposed to OSAHS due to overlap between the Down syndrome phenotype and OSAHS risk factors. Recent large studies using subjective and objective measures estimate that OSAHS affects around 40% of adults with Down syndrome, in contrast to 2–4% of the general adult population. The “double-hit” of comorbid Down syndrome and OSAHS may accelerate cognitive decline in adults with Down syndrome. However, with the appropriate care and support, OSAHS can be treated effectively in this group using continuous positive airway pressure (CPAP) therapy, improving daytime function and behaviour

Obstructive sleep apnoea/hypopnoea syndrome in adults with Down syndrome.

PubMed

Hill, Elizabeth A

2016-12-01

Adults with Down syndrome are predisposed to obstructive sleep apnoea/hypopnoea syndrome (OSAHS) due to overlap between the Down syndrome phenotype and OSAHS risk factors.The prevalence of OSAHS in adults with Down syndrome is estimated at 35-42%. This is up to ten-times higher than in the general adult population.Symptoms of OSAHS, including behavioural and emotional disturbances as well as standard symptoms such as sleepiness, should be monitored as part of regular health surveillance in adults with Down syndrome.There is evidence that the use of continuous positive airway pressure (CPAP) therapy in adults with Down syndrome and comorbid OSAHS can lead to significant improvements in subjective sleepiness, behaviour and cognitive function, though further large-scale trials are required. To discuss the relationship between the phenotypic features of Down syndrome and the risk factors for obstructive sleep apnoea/hypopnoea syndrome (OSAHS).To examine the prevalence of OSAHS in adults with Down syndrome.To review recent research into the effectiveness of treatment of OSAHS in adults with Down syndrome using continuous positive airway pressure (CPAP) therapy. Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is characterised by repeated cycles of upper airway obstruction during sleep, leading to diurnal symptoms. Individuals with Down syndrome are predisposed to OSAHS due to overlap between the Down syndrome phenotype and OSAHS risk factors. Recent large studies using subjective and objective measures estimate that OSAHS affects around 40% of adults with Down syndrome, in contrast to 2-4% of the general adult population. The "double-hit" of comorbid Down syndrome and OSAHS may accelerate cognitive decline in adults with Down syndrome. However, with the appropriate care and support, OSAHS can be treated effectively in this group using continuous positive airway pressure (CPAP) therapy, improving daytime function and behaviour. Symptoms of OSAHS should be routinely

Alarming atrioventricular block and mitral valve prolapse in the Kearns-Sayre syndrome.

PubMed

Katsanos, Konstantinos H; Pappas, Christos J; Patsouras, Dimitrios; Michalis, Lambros K; Kitsios, Georgios; Elisaf, Moses; Tsianos, Epameinondas V

2002-05-01

Kearns-Sayre syndrome (KSS) is a multisystem mitochondrial disorder characterized by the invariant triad: onset before 20, progressive external ophthalmoplegia and pigmentary retinal degeneration, plus at least one of the following: complete (or not) heart block, cereberal dysfunction and CSF protein above 100 mg/dl. Autopsies from patients with KSS revealed widespread tissue distribution mtDNA deletions. These deletions result in significantly lower activities of the enzymes of the respiratory chain. The same deletion of mitochondrial DNA present in skeletal muscle is found in myocardial tissue. An 18-year-old girl diagnosed with the KSS was admitted to our hospital because of an upper respiratory tract infection and dysphagia. ECG showed cardiac conduction defects. The patient had no history of syncope. At her surface ECG there was a complete RBBB (QRS duration approximately 130 ms), a clockwise rotation with an axis of approximately 90 degrees and a slight QT prolongation (420 ms). Echocardiography showed prolapse with thickening and degeneration of both mitral valve leaflets but without mitral regurgitation. The patient was started on a diet rich in potassium and pharmaceutical therapy with magnesium oxide (240 mg of elemental Mg p.o. per day), 1 g of calcium carbonate t.i.d., vitamin D (calcitriol 0.25 microg p.o. per day) and coenzyme Q(10) 100 mg daily and discharged 6 days later with slightly improved biochemical profile but apparent clinical improvement. Urgent pacemaker implantation was decided but unfortunately the patient died due to acute cardiac arrest 10 days later.