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Some antidepressant agents can cause electrophysiological changes of cardiac function leading to ventricular arrhythmias and sudden death. However, antidepressants have also protective effects on the heart through their capacity to modulate cardiac autonomic-mediated physiological responses. Heart rate variability and QTc length are two strictly linked parameters that allow us to appreciate the effects of different drugs on cardiac physiology. Heart rate variability reflects functioning of the autonomic nervous system and possibly also regulation by the limbic system. Autonomic regulation of cardiac activity influences also cardiac repolarization and QT length, both directly and via its effects on heart rate. In this review we present the methodologies adopted to study the effect of antidepressant drugs on QT length and heart rate variability and we summarize data on electrophysiological changes related to antidepressant treatment. Clinical implications for the choice of different antidepressants in different clinical populations are discussed. [ABSTRACT FROM PUBLISHER]

Introduction: One form of the hereditary long-QT syndrome, LQT3-ΔKPQ, is associated with sustained inward sodium current during membrane depolarization. Ranolazine reduces late sodium channel current, and we hypothesized that ranolazine would have beneficial effects on electrical and mechanical cardiac function in LQT3 patients with the SCN5A-ΔKPQ mutation. Methods: We assessed the effects of 8-hour intravenous ranolazine infusions (45 mg/h for 3 hours followed by 90 mg/h for 5 hours) on ventricular repolarization and myocardial relaxation in 5 LQT3 patients with the SCN5A-ΔKPQ mutation. Changes in electrocardiographic repolarization parameters from before to during ranolazine infusion were evaluated by time-matched, paired t-test analyses. Cardiac ultrasound recordings were obtained before ranolazine infusion and just before completion of the 8-hour ranolazine infusion. Results: Ranolazine shortened QTc by 26 ± 3 ms (P < 0.0001) in a concentration-dependent manner. At peak ranolazine infusion, there was a significant 13% shortening in left ventricular isovolumic relaxation time, a significant 25% increase in mitral E-wave velocity, and a meaningful 22% decrease in mitral E-wave deceleration time compared with the baseline. No adverse effects of ranolazine were observed in the study patients. Conclusion: Ranolazine at therapeutic concentrations shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3-ΔKPQ mutation, a genetic disorder that is known to cause an increase in late sodium current. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms (SNPs) play a major role in the understanding of the genetic basis of many complex human diseases. It is still a major challenge to identify the functional SNPs in disease-related genes. In this review, the genetic variation that can alter the expression and the function of the genes, namely KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2, with the potential role for the development of congenital long QT syndrome (LQTS) was analyzed. Of the total of 3,309 SNPs in all five genes, 27 non-synonymous SNPs (nsSNPs) in the coding region and 44 SNPs in the 5′ and 3′ un-translated regions (UTR) were identified as functionally significant. SIFT and PolyPhen programs were used to analyze the nsSNPs and FastSNP; UTR scan programs were used to compute SNPs in the 5′ and 3′ untranslated regions. Of the five selected genes, KCNQ1 has the highest number of 26 haplotype blocks and 6 tag SNPs with a complete linkage disequilibrium value. The gene SCN5A has ten haplotype blocks and four tag SNPs. Both KCNE1 and KCNE2 genes have only one haplotype block and four tag SNPs. Four haplotype blocks and two tag SNPs were obtained for KCNH2 gene. Also, this review reports the copy number variations (CNVs), expressed sequence tags (ESTs) and genome survey sequences (GSS) of the selected genes. These computational methods are in good agreement with experimental works reported earlier concerning LQTS. [ABSTRACT FROM AUTHOR]

Background: Type 3 long-QT syndrome (LQT-3) is caused by gain-of-function mutations in the SCN5A encoding the cardiac sodium channel. Familial atrial fibrillation (AF), previously considered a potassium channelopathy, has recently been related to sodium genetic variants, both in isolated forms and in patients with underlying heart disease. Objective: The purpose of this study was to describe the first family associating LQT-3 and AF due to a gain-of-function mutation in SCN5A and assess the usefulness of the sodium blocker flecainide in individuals with both phenotypes. Methods: Complete family screening was performed after identifying a proband showing paroxysmal AF and a long QT interval suggestive of LQT-3. Secondary causes of AF were ruled out in all individuals. Flecainide was used in two patients for LQT-3 diagnosis and therapeutic treatment of AF. Genetic screening was performed by direct sequencing of the exons and exon-intron boundaries of SCN5A. Results: We identified a three-generation family (eight members), all of them showing long QT intervals. Paroxysmal AF initiated between 20 and 35 years of age in all three adults. The flecainide test led to shortening of the QTc interval. Flecainide was also effective in acutely restoring sinus rhythm. A Y1795C mutation was identified in all members. Conclusion: This is the first report showing an association of familial AF and LQT-3 due to a mutation in SCN5A. This finding provides further evidence of the role of SCN5A in AF. We also confirm the usefulness of flecainide in this particular complex phenotype, both as a diagnostic tool for LQT-3 and as an acute treatment for AF. [Copyright &y& Elsevier]

Protein–protein interactions are critical for protein trafficking, localization and the regulation of ion channels. The human ether-a-go-go-related gene ( herg) encodes the α-subunit of the potassium channel underlying the rapid component of the cardiac delayed rectifier current. To identify the cellular proteins involved in the regulation of the HERG channel, a human heart cDNA library was screened using a yeast two-hybrid system, with the N-terminus of HERG as bait. The four and a half LIM domain protein 2 (FHL2) was identified as a potential HERG partner. The interaction between these two proteins was confirmed by co-immunoprecipitation and glutathione transferase pull-down assays and immunocytochemical analysis. The physiological implication of HERG–FHL2 interaction, assessed by whole-cell, patch-clamp electrophysiology experiments, showed a significant increase in the HERG current amplitude and a faster deactivation of the tail current in human embryonic kidney 293 cells co-expressing HERG and FHL2. These data indicate that FHL2 interacts with and regulates the HERG channel. Our findings may aid in the further understanding of the molecular basis of HERG channel diversity and arrhythmogenesis in the long-QT syndrome. [ABSTRACT FROM AUTHOR]

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 only a small proportion are reported to pharmacovigilance agencies. • The extent to which genetic determinants of susceptibility to LQTS are specific to particular drugs, or common to several classes of drug, remains to be determined. WHAT THIS STUDY ADDS • We estimated population prevalence of drug-induced LQTS in the Midi-Pyrenees region, southwest France, using five different institutions and assessed feasibility of tracing potential cases (in addition to pharmacovigilance data), using hospital data and rigorous case definition. • These methods can be adapted to a wider region, used to augment pharmacovigilance reporting, and offer researchers the opportunity to study genetic susceptibility to drug-induced LQTS. 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. [ABSTRACT FROM AUTHOR]

The article focuses on the importance of Long-QT syndrome (LQTS) knowledge on genotype and specific mutations in dealing risk-stratifying individual patients. LQTS is considered as an inherited disorder with long duration ventricular repolarization which can lead patients to sudden cardiac death. Having a knowledge about LTQS will help in selecting appropriate treatment for patient-specific risk-reduction.

Background: The arrhythmogenic effects of hyperthermia have been highlighted in the Brugada syndrome but remain largely unexplored in other arrhythmic syndromes. The present study examines the effect of hyperthermia on transmural dispersion of action potential duration (TD-APD), early afterdepolarization (EAD) activity, and torsade de pointes (TdP) under long-QT conditions.Methods and Results: Standard and floating glass microelectrodes were used to record action potentials from epicardial, M cell, and endocardial regions of the arterially perfused left ventricle wedge, from tissue slices isolated from these regions, and from isolated Purkinje fibers. A transmural ECG was simultaneously recorded across the wedge. Under baseline conditions and in the presence of I(Ks) block (chromanol 293B), hyperthermia (39 degrees C to 40 degrees C) abbreviated APD in tissue slices from all 3 regions. In the presence of I(Kr) block (E-4031), hyperthermia prolonged APD and induced or augmented EADs in M cell and Purkinje preparations at pacing cycle lengths > or = 800 ms but abbreviated APD in epicardium and endocardium, resulting in a marked accentuation of TD-APD. Ryanodine prevented the hyperthermia- induced EAD. In perfused wedge preparations, hyperthermia abbreviated APD throughout both in the absence or presence of I(Kr) or I(Ks) block and did not induce EADs or TdP. Combined I(Kr) and I(Ks) block increased TD-APD and induced EADs (4/12) and spontaneous TdP (3/12) at 36 degrees C to 37 degrees C; hyperthermia (39 degrees C to 40 degrees C) further accentuated TD-APD and facilitated the development of EAD activity (9/12) and TdP (6/12).Conclusions: Our findings suggest that hyperthermia can be associated with an increased arrhythmic risk when the repolarization reserve of the myocardium is compromised. [ABSTRACT FROM AUTHOR]

Background: Ethnic differences may affect the phenotypic expression of genetic disorders. However, data regarding the effect of ethnicity on outcome in patients with genetic cardiac disorders are limited. We compared the clinical course of Caucasian and Japanese long QT type-1 (LQT1) patients who were matched for mutations in the KCNQ1 gene. Methods: The study population comprised 62 Caucasian and 38 Japanese LQT1 patients from the International LQTS Registry who were identified as having six identical KCNQ1 mutations. The biophysical function of the mutations was categorized into dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. The primary end point of the study was the occurrence of a first cardiac event from birth through age 40 years. Results: Japanese patients had a significantly higher cumulative rate of cardiac events (67%) than Caucasian patients (39%; P = 0.01). The respective frequencies of dominant negative mutations in the two ethnic groups were 63% and 28% (P < 0.001). In multivariate analysis, Japanese patients had an 81% increase in the risk of cardiac events (P = 0.06) as compared with Caucasians. However, when the biophysical function of the mutations was included in the multivariate model, the risk associated with Japanese ethnicity was no longer evident (HR = 1.05; P = 0.89). Harboring a dominant negative mutation was shown to be the most powerful and significant predictor of outcome (HR = 3.78; P < 0.001). Conclusions: Our data indicate that ethnic differences in the clinical expression of LQTS can be attributed to the differences in frequencies of the specific mutations within the two populations. [ABSTRACT FROM AUTHOR]

The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Congenital loss of function and drug-induced inhibition of the slowly-activating delayed-rectifier K+ current (I Ks) cause impaired cardiac repolarization. β-Adrenergic-receptor stimulation contributes to sympathetically-induced torsades de pointes (TdP). An in vivo model of long-QT1 (LQT1) syndrome and TdP in a species with I Ks characteristics relevant to man is lacking. We investigated the in vivo mechanisms of TdP in a novel canine model of drug-induced LQT1 syndrome. Methods: Adult beagle dogs (n =30; F/M) were anesthetized with lofentanil (0.075 mg/kg i.v.) and etomidate (1.5 mg/kg/hour). ECGs, left- (LV) and right-ventricular (RV) monophasic action potentials (MAPs), and intracavitary pressures were recorded simultaneously. Infusion of the I Ks blocker HMR1556 (0.025–0.050 mg/kg/min) mimicked LQT1, and bolus injections of isoproterenol (1.25–5 μg/kg) reproducibly triggered TdP in 94% of dogs (defibrillated if necessary). Results: Isoproterenol evoked paradoxical repolarization prolongation during heart rate accelerations. Beat-to-beat variability [QT, LV MAP duration (MAPD90)] and spatial dispersion of repolarization (Tpeak–Tend interval, endo-minus epicardial MAPD90, LV-RVMAPD90) were significantly increased. Early afterdepolarizations occurred predominantly in the endocardium and not the epicardium. During isoproterenol, secondary systolic contractions (aftercontractions; peak 25±6 mm Hg) arose in the LV (not RV) when TdP ensued. Prevention of TdP by esmolol (1.25 mg/kg), verapamil (0.4 mg/kg) or mexiletine (5 mg/kg) was only successful when repolarization prolongation was contained and aftercontractions remained absent. Conclusions: β-Adrenergic challenges trigger TdP in a reproducible manner in this model of drug-induced LQT1. Paradoxical prolongation and increased temporal and spatial dispersion of repolarization precipitate TdP. Incremental LV systolic aftercontractions precede TdP, suggesting abnormal cellular Ca2+ handling contributes to the arrhythmogenic mechanism. [Copyright &y& Elsevier]

Intracellular Ca2+ and Ca2+-dependent signaling molecule play an essential role in the genesis of long-QT (LQT) syndrome-related ventricular arrhythmias. The effect of calcium-channel antagonist verapamil on repolarization heterogeneity of ventricular myocardium was assessed in an in vitro rabbit model of LQT syndrome. By using the monophasic action potential (MAP) recording technique, MAPs of epicardium, mid-myocardium and endocardium were simultaneously recorded by specially designed plunge-needle electrodes across the left ventricular free wall in rabbit hearts purfused by Langendorff method with standard Tyrode’s solution. Bradycardia was induced by complete ablation of atrioventricular node. A catheter was introduced into the right ventricle to pace at the cycle lengths (CLs) of 1500, 1000, and 500 ms, successively. Quinidine (2 μmol/L) prolonged QT interval and ventricular MAP duration (MAPD), and increased transmural dispersion of repolarization (TDR) in a reverse rate-dependent fashion in isolated rabbit heart. No polymorphic ventricular tachycardias were induced under this condition. The effective free therapeutic plasma concentrations of verapamil (0.01–0.05 μmol/L) used in this experiment had no effect on quinidine-induced changes of QT interval, MAPD and TDR. This study demonstrated that, in this model of LQT syndrome, blockade of calcium-channel with verapmil had no effect on quinidine-induced changes of repolatiation heterogeneity of ventricular myocardium. [ABSTRACT FROM AUTHOR]

Long QT syndrome (LQTS) is characterized by abnormalities in cardiac repolarization that lead to prolongation of the electrocardiographic (ECG) QT interval. Mutations in the human ether-a-go-go-related gene ( HERG, KCNH2) cause the chromosome 7-linked LQT2 form of congenital LQTS, which is characterized by a prolonged QT interval and a bifid T-wave with an increased susceptibility to life-threatening cardiac arrhythmias, especially in children. We describe the genotypic and phenotypic pedigree of a large Chinese family ( n = 36) in which 11 members were diagnosed with LQTS on the basis of typical ECG patterns for LQT2. Symptomatic syncopal episodes appeared in seven members of this family at a young age; an additional four members had died suddenly at ages of 18, 19, 24 and 70 years, respectively. Screening for SCN5A and HERG candidate genes identified a heterozygous missense mutation 1810G→A in exon 7 of HERG that leads to the substitution of the amino acid glycine by serine (G604S); this mutation was located in the S5/pore region of the HERG protein and was associated with a malignant phenotype. Ten of the family members carrying the mutation showed a prolongation of the corrected QT interval (QTc), and seven of these had experienced multiple syncopal episodes. The retrospective examination of documented ECG records revealed that one family member who had died suddenly also had a prolonged QT interval. This study is the first to demonstrate a close correlation between clinical phenotype and genotype with a 100% penetrance based on the pedigree of a Chinese family with LQT2. [ABSTRACT FROM AUTHOR]

People with epilepsy may die suddenly and unexpectedly without a structural pathological cause. Most SUDEP cases are likely to be related to seizures. SUDEP incidence varies and is <1:1,000 person-years among prevalent cases in the community and ∼1:250 person years in specialist centres. Case–control studies identified certain risk factors, some potentially amenable to manipulation, including uncontrolled convulsive seizures and factors relating to treatment and supervision. Both respiratory and cardiac mechanisms are important. The apparent protective effect of lay supervision supports an important role for respiratory factors, in part amenable to intervention by simple measures. Whereas malignant tachyarrhythmias are rare during seizures, sinus bradycardia/arrest, although infrequent, is well documented. Both types of arrhythmias can have a genetic basis. This article reviews SUDEP and explores the potential of coexisting liability to cardiac arrhythmias as a contributory factor, while acknowledging that at present, bridging evidence between cardiac inherited gene determinants and SUDEP is lacking. [ABSTRACT FROM AUTHOR]

Population profiles of industrialized countries show dramatic increases in cardiovascular disease with age, but the molecular and genetic basis of disease progression has been difficult to study because of the lack of suitable model systems. Our studies of Drosophila show a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in the expression of the Drosophila homolog of human KCNQ1-encoded K+ channel α subunits. In humans, this channel is involved in myocardial repolarization, and alterations in the function of this channel are associated with an increased risk for Torsades des Pointes arrhythmias and sudden death. Hearts from young KCNQ1 mutant fruit flies exhibit prolonged contractions and fibrillations reminiscent of Torsades des Pointes arrhythmias, and they exhibit severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in WT flies. The fibrillations observed in mutant flies correlate with delayed relaxation of the myocardium, as revealed by increases in the duration of phasic contractions, extracellular field potentials, and in the baseline diastolic tension. These results suggest that K+ currents, mediated by a KCNQ channel, contribute to the repolarization reserve of fly hearts, ensuring normal excitation-contraction coupling and rhythmical contraction. That arrhythmias in both WT and KCNQ1 mutants become worse as flies age suggests that additional factors are also involved. [ABSTRACT FROM AUTHOR]

Pharmacological management of cardiac arrhythmias has been a long and widely sought goal. One of the difficulties in treating arrhythmia stems, in part, from incomplete understanding of the mechanisms of drug block and how intrinsic properties of channel gating affect drug access, binding affinity, and unblock. In the last decade, a plethora of genetic information has revealed that genetics may play a critical role in determining arrhythmia susceptibility and in efficacy of pharmacological therapy. In this context, we present a theoretical approach for investigating effects of drug-channel interaction. We use as an example open-channel or inactivated-channel block by the local anesthetics mexiletine and lidocaine, respectively, of normal and ΔKPQ mutant Na+ channels associated with the long-QT syndrome type 3. Results show how kinetic properties of channel gating, which are affected by mutations, are important determinants of drug efficacy. Investigations of NaΔ channel blockade are conducted at multiple scales (single channel and macroscopic current) and, importantly, during the cardiac action potential (AP). Our findings suggest that channel mean open time is a primary determinant of open state blocker efficacy. Channels that remain in the open state longer, such as the ΔKPQ mutant channels in the abnormal burst mode, are blocked preferentially by low mexiletine concentrations. AP simulations confirm that a low dose of mexiletine can remove early afterdepolarizations and restore normal repolarization without affecting the AP upstroke. The simulations also suggest that inactivation state block by lidocaine is less effective in restoring normal repolarization and adversely suppresses peak Na+ current. [ABSTRACT FROM AUTHOR]

The aim of this review is to present the properties of the slow component of the delayed rectifier potassium current (IKs) in the human ventricle. The review gives a detailed description of the physiology, molecular biology and pharmacology of the IKs current, including kinetic properties, genetic structures, agonists and antagonists. The authors also present the role of the IKs current in the human cardiac repolarization focusing on several pathophysiological situations, such as the LQT syndrome and the Torsade de Pointes arrhythmia. [ABSTRACT FROM AUTHOR]

Introduction: Data regarding risk factors and clinical course of patients affected with Jervell and Lange-Nielsen syndrome (JLNS), an autosomal recesssive form of the congenital long-QT syndrome (LQTS), are limited to several reported cases and a retrospective analysis. Methods and Results: We prospectively followed-up 44 JLNS patients from the U.S. portion of the International LQTS Registry and compared their clinical course with 2,174 patients with the phenotypically determined dominant form of LQTS (Romano-Ward syndrome [RWS]) and a subgroup of 285 patients with type 1 LQTS (LQT1). Mean (±SD) corrected QT interval (QTc) in the JLNS, RWS, and LQT1 groups were 548 ± 73, 500 ± 48, and 502 ± 46 msec, respectively (P < 0.001). The cumulative rates of cardiac events from birth through age 40 among JLNS and RWS patients were 93% (mean [±SD] age: 5.0 ± 7.0 years) and 54% (mean [±SD] age: 14.2 ± 9.3 years), respectively (P < 0.001). The JLNS:RWS and JLNS:LQT1 adjusted hazard ratios (HR) for cardiac events were highest among patients with a baseline QTc ≥550 msec (HR = 15.83 [P < 0.001] and 13.80 [P < 0.001], respectively). Among JLNS patients treated with beta-blockers, the cumulative probability of LQTS-related death was 35%; defibrillator therapy was associated with a 0% mortality rate during a mean (±SD) follow-up period of 4.9 ± 3.4 years. Conclusions: Patients with JLNS experience a high rate of cardiac and fatal events from early childhood despite medical therapy. Defibrillator therapy appears to improve outcome in this high-risk population, although longer follow-up is needed to establish its long-term efficacy. [ABSTRACT FROM AUTHOR]

Background and Purpose: Fluoxetine (Prozac) is a widely prescribed drug in adults and children, and it has an active metabolite, norfluoxetine, with a prolonged elimination time. Although uncommon, Prozac causes QT interval prolongation and arrhythmias; a patient who took an overdose of Prozac exhibited a prolonged QT interval (QTc 625 msec). We looked for possible mechanisms underlying this clinical finding by analysing the effects of fluoxetine and norfluoxetine on ion channels in vitro.Experimental Approach: We studied the effects of fluoxetine and norfluoxetine on the electrophysiology and cellular trafficking of hERG K+ and SCN5A Na+ channels heterologously expressed in HEK293 cells.Key Results: Voltage clamp analyses employing square pulse or ventricular action potential waveform protocols showed that fluoxetine and norfluoxetine caused direct, concentration-dependent, block of hERG current (IhERG). Biochemical studies showed that both compounds also caused concentration-dependent reductions in the trafficking of hERG channel protein into the cell surface membrane. Fluoxetine had no effect on SCN5A channel or HEK293 cell endogenous current. Mutations in the hERG channel drug binding domain reduced fluoxetine block of IhERG but did not alter fluoxetine's effect on hERG channel protein trafficking.Conclusions and Implications: Our findings show that both fluoxetine and norfluoxetine at similar concentrations selectively reduce IhERG by two mechanisms, (1) direct channel block, and (2) indirectly by disrupting channel protein trafficking. These two effects are not mediated by a single drug binding site. Our findings add complexity to understanding the mechanisms that cause drug-induced long QT syndrome. [ABSTRACT FROM AUTHOR]

This article presents a list of abstracts of pediatric research, including "Patient Visits to a National Practice-Based Research Network: Comparing Pediatric Research in Office Settings With the National Ambulatory Medical Care Survey," by E. J. Slora et al, "Childhood Bullying Involvement and Exposure to Intimate Partner Violence," by N. S. Bauer, "Barriers to Following the Supine Sleep Recommendation Among Mothers at Four Centers for the Women, Infants and Children Program," by E. R. Colson et al and "Use of a New Combined Vaccine in Pediatric Practices," by G. L. Freed et al.

Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT-3 patients with the ΔKPQ deletion to evaluate the safety and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the ΔKPQ deletion. Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted with flecainide and placebo in six male LQT-3 subjects with the ΔKPQ deletion. Results: The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open-label, dose-ranging investigation using one-fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6-month alternating periods of flecainide and placebo therapy based on the open-label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of −27.1 ms (95% confidence interval: −36.8 ms to −17.4 ms; P < 0.001) at a mean flecainide blood level of 0.11 ±0.05 μg/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects. Conclusions: Chronic low-dose flecainide significantly shortens the QTc interval in LQT-3 subjects with the ΔKPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainide therapy in patients with this mutation. [ABSTRACT FROM AUTHOR]

The goals of electrocardiographic (ECG) monitoring in hospital settings have expanded from simple heart rate and basic rhythm determination to the diagnosis of complex arrhythmias, myocardial ischemia, and prolonged QT interval. Whereas Computerized arrhythmia analysis is automatic in cardiac monitoring systems, computerized ST-segment ischemia analysis is available only in newer-generation monitors, and computerized QT-interval monitoring is currently unavailable. Even in hospitals with ST-monitoring capability, ischemia monitoring is vastly underutilized by healthcare professionals. Moreover, because no computerized analysis is available for QT monitoring, healthcare professionals must determine when it is appropriate to manually measure QT intervals (eg, when a patient is started on a potentially proarrhythmic drug). The purpose of the present review is to provide "best practices" for hospital ECG monitoring. Randomized clinical trials in this area are almost nonexistent; therefore, expert opinions are based upon clinical experience and related research in the field of electrocardiography. This consensus document encompasses all areas of hospital cardiac monitoring in both children and adults. The emphasis is on Information clinicians need to know to monitor patients safely and effectively Recommendations are made with regard to indications, time frames, and strategies to improve the diagnostic accuracy of cardiac arrhythmia, ischemia, and QT-interval monitoring. Currently available ECG lead systems are described, and recommendations related to staffing, training, and methods to improve quality are provided. [ABSTRACT FROM AUTHOR]

Repolarization of cardiomyocytes is mainly performed by the rapid component of the delayed rectifier potassium current, lKr which is encoded by the human ether-a-go-go- related gene (HERG). Inhibition of HERG potassium currents by class Ill antiarrhythmic drugs causes lengthening of the cardiac action potential, which produces a beneficial antiarrhythmic effect. Conversely, excessive prolongation of the action potential by a wide variety of antiarrhythmic and non-antiarrhythmic drugs may lead to acquired long- QT syndrome, which is associated with a risk for 'torsade de pointes'-arrhythmias and sudden cardiac death. As a result, this undesirable side effect has prompted the withdrawal of several drugs from the market. Recent studies on HERG channel inhibition provide significant insights into the molecular factors that determine state-, voltage-, and use- dependency of HERG current block. In addition, crucial properties of the putative drug binding site in HERG have been identified. The broad diversity in response to pharmacologic treatment among individuals is likely to depend on a combination of multiple factors from the fields of arrhythmia genetics, physiology and pharmacology. In conclusion, the increasing understanding of the molecular mechanisms that underlie HERG channel block by antiarrhythmic and non-antiarrhythmic drugs may improve prevention and treatment of drug-induced long-QT syndrome. [ABSTRACT FROM AUTHOR]

Regional differences in repolarization characteristics of distinct cell types are responsible for the inscription of the J wave and T wave of the electrocardiogram (ECG). Amplification of these electrical heterogeneities contributes to the development of a variety of cardiac arrhythmias. This brief review examines the ionic and cellular basis for these heterogeneities and their role in the Brugada and long-QT syndromes. Both cases involve an accentuation of transmural dispersion of repolarization (TDR). In the case of the Brugada syndrome, TDR is accentuated as a result of a preferential abbreviation of the right ventricular epicardial action potential, whereas in the long-QT syndrome, accentuation of TDR is secondary to a preferential prolongation of the action potential of the M cell. [ABSTRACT FROM AUTHOR]

BACKGROUND. Mutations in five cardiac voltage-gated ion channel genes, including KCNQ1, HERG, SCN5A. KCNE1 and KCNE2, constitute the principal cause of inherited long-QT syndrome (LQTS). Typically, each family carries its own private mutation, and the disease manifests with varying phenotype and incomplete penetrance, even within particular families. We had previously identified 14 different LQTS-causing mutations in 92 Finnish families. AIM. In order to complete the characterization of Finnish spectrum of LQTS genes, we conducted a systematic search for mutations in the five LQTS genes among 188 additional unrelated probands. METHODS. The screening was performed by denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing. RESULTS. Nineteen novel and 12 previously described mutations were identified. Collectively, these data extend the number of molecularly defined affected Finnish LQTS families and patients at present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1 G589D and IVS7-2A >G, HERG R176W and L552S) together account for as much as 73% of all established Finnish LQTS cases. CONCLUSIONS. The extent of genetic homogeneity under- lying LQTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LQTS, and constituting an excellent basis to study the role of genetic and non-genetic factors influencing phenotypic variability in this disease. [ABSTRACT FROM AUTHOR]

Prolongation of the QT interval is a known risk factor for syncope, seizures and sudden cardiac death. Most patients with QT prolongation have an acquired cause, but congenital forms of QT prolongation are being increasingly recognized. However, existing advanced cardiac life support (ACLS) treatment algorithms for prolonged QT mediated ventricular fibrillation pertains to acquired long-QT syndrome (LQTS). Here, a young patient with out-of-hospital cardiac arrest secondary to congenital LQTS illustrates critical exceptions to the current ACLS treatment algorithms for ventricular fibrillation and unstable ventricular tachycardia when QT prolongation is congenital in origin. A clarified ACLS algorithm is proposed. [Copyright &y& Elsevier]

Aims Women have a longer QT interval and a greater incidence of torsades de pointes than men. It has been suggested that oestrogens may influence the duration of cardiac repolarization. We thus investigated the influence of oestradiol (E2) on ventricular repolarization within the physiological concentration range of this hormone.Methods and results We studied QT interval duration in 21 healthy women aged 18 to 35 years with regular menstrual cycle (mean duration: 29±1 days) during two periods associated with a wide range of oestradiol plasma levels: low level during menses (105±34pmol/l) and high level during the pre-ovulatory phase (750±277pmol/l). We used heart rate-independent assessment of QT. QT–RR pairs were measured over a wide range of RR intervals obtained at rest and during a sub-maximal exercise test. Using a monoexponential nonlinear curve fitting for the QT–RR relation, the QT1000msduring nadir and peak oestradiol periods was then determined for each subject. QT1000msinterval was not different between both study periods: 382.1±18.4ms at peak versus 382.2±19.4ms at nadir oestradiol level (P=0.98).Conclusion No significant change in QT interval duration was observed within the large range of physiological E2 variations found during the menstrual cycle. [ABSTRACT FROM PUBLISHER]

Aims The aim of this pilot study was to evaluate provocative sotalol testing to unmask abnormal repolarization due to altered myocardial electrical properties as the key feature in acquired Long-QT-Syndrome. Reliable diagnosis and risk stratification for the individual patient are complicated by the multitude of mechanisms involved in acquired QT-prolongation. The combined influence of all components determines susceptibility to arrhythmias related to QT-prolongation.Methods Twenty consecutive patients who had experienced torsades de pointes in association with QT-prolonging drugs were tested with i.v. d,l-sotalol (2mg/kg) with 24-h intensive care monitoring to evaluate the repolarization process by determining QT- and QTc-prolongations. Results were compared to age and sex matched controls.Results At baseline, no differences between control and study population with regard to QT and QTc were detected. After sotalol infusion, QTc increased from 422±17 to 450±22ms in controls and from 434±20 to 541±37ms in the study population. Torsades de pointes occurred in three out of 20 patients (15%) in the study population but in none of the control patients following i.v. sotalol testing.Conclusions Controlled exposure to sotalol successfully identifies patients with normal QTc intervals but altered myocardial repolarization. This may be useful for clarifying diagnosis and pathogenesis of acquired Long-QT-Syndrome. [ABSTRACT FROM PUBLISHER]

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An abundance of literature describes physiological and pathological determinants of cardiac performance, building on the principles of excitation-contraction coupling. However, the mutual influencing of excitation-contraction and mechano-electrical feedback in the beating heart, here designated 'electromechanical reciprocity', remains poorly recognized clinically, despite the awareness that external and cardiac-internal mechanical stimuli can trigger electrical responses and arrhythmia. This review focuses on electromechanical reciprocity in the long-QT syndrome (LQTS), historically considered a purely electrical disease, but now appreciated as paradigmatic for the understanding of mechano-electrical contributions to arrhythmogenesis in this and other cardiac conditions. Electromechanical dispersion in LQTS is characterized by heterogeneously prolonged ventricular repolarization, besides altered contraction duration and relaxation. Mechanical alterations may deviate from what would be expected from global and regional repolarization abnormalities. Pathological repolarization prolongation outlasts mechanical systole in patients with LQTS, yielding a negative electromechanical window (EMW), which is most pronounced in symptomatic patients. The electromechanical window is a superior and independent arrhythmia-risk predictor compared with the heart rate-corrected QT. A negative EMW implies that the ventricle is deformed-by volume loading during the rapid filling phase-when repolarization is still ongoing. This creates a 'sensitized' electromechanical substrate, in which inadvertent electrical or mechanical stimuli such as local after-depolarizations, after-contractions, or dyssynchrony can trigger abnormal impulses. Increased sympathetic-nerve activity and pause-dependent potentiation further exaggerate electromechanical heterogeneities, promoting arrhythmogenesis. Unraveling electromechanical reciprocity advances the understanding of arrhythmia formation in various conditions. Real-time image integration of cardiac electrophysiology and mechanics offers new opportunities to address challenges in arrhythmia management., Competing Interests: Conflicts of interest: K.E.O, H.J.v.d.L, P.G.A.V., and R.M.A.t.B declare no conflict of interest. M.J.A. declares royalties from AliveCor, Anumana, Pfizer; consulting fees from Abbott, ARMGO Pharma, Boston Scientific, Bristol Myers Squipp, Daiichi Sankyo, Invitae, Medtronic, UpToDate; and a leadership role (President of Board) at the Sudden Arrhythmia Death Syndromes (SADS) Foundation., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: Congenital long-QT syndrome (LQTS) is a major cause of sudden cardiac death (SCD) in young individuals, calling for sophisticated risk assessment. Risk stratification, however, is challenging as the individual arrhythmic risk varies pronouncedly, even in individuals carrying the same variant., Materials and Methods: In this study, we aimed to assess the association of different electrical parameters with the genotype and the symptoms in patients with LQTS. In addition to the heart-rate corrected QT interval (QTc), markers for regional electrical heterogeneity, such as QT dispersion (QT max -QT min in all ECG leads) and delta T peak/end (T peak/end V5 - T peak/end V2), were assessed in the 12-lead ECG at rest and during exercise testing., Results: QTc at rest was significantly longer in symptomatic than asymptomatic patients with LQT2 (493.4 ms ± 46.5 ms vs. 419.5 ms ± 28.6 ms, p = 0.004), but surprisingly not associated with symptoms in LQT1. In contrast, post-exercise QTc (minute 4 of recovery) was significantly longer in symptomatic than asymptomatic patients with LQT1 (486.5 ms ± 7.0 ms vs. 463.3 ms ± 16.3 ms, p = 0.04), while no such difference was observed in patients with LQT2. Enhanced delta T peak/end and QT dispersion were only associated with symptoms in LQT1 (delta T peak/end 19.0 ms ± 18.1 ms vs. -4.0 ms ± 4.4 ms, p = 0.02; QT-dispersion: 54.3 ms ± 10.2 ms vs. 31.4 ms ± 10.4 ms, p = 0.01), but not in LQT2. Delta T peak/end was particularly discriminative after exercise, where all symptomatic patients with LQT1 had positive and all asymptomatic LQT1 patients had negative values (11.8 ± 7.9 ms vs. -7.5 ± 1.7 ms, p = 0.003)., Conclusion: Different electrical parameters can distinguish between symptomatic and asymptomatic patients in different genetic forms of LQTS. While the classical "QTc at rest" was only associated with symptoms in LQT2, post-exercise QTc helped distinguish between symptomatic and asymptomatic patients with LQT1. Enhanced regional electrical heterogeneity was only associated with symptoms in LQT1, but not in LQT2. Our findings indicate that genotype-specific risk stratification approaches based on electrical parameters could help to optimize risk assessment in LQTS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rieder, Kreifels, Stuplich, Ziupa, Servatius, Nicolai, Castiglione, Zweier, Asatryan and Odening.)

Introduction: The long-QT syndrome (LQTS) is the most common ion channelopathy, typically presenting with a prolonged QT interval and clinical symptoms such as syncope or sudden cardiac death. Patients may present with a concealed phenotype making the diagnosis challenging. Correctly diagnosing at-risk patients is pivotal to starting early preventive treatment., Objective: Identification of congenital and often concealed LQTS by utilizing novel deep learning network architectures, which are specifically designed for multichannel time series and therefore particularly suitable for ECG data., Design and Results: A retrospective artificial intelligence (AI)-based analysis was performed using a 12-lead ECG of genetically confirmed LQTS ( n = 124), including 41 patients with a concealed LQTS (33%), and validated against a control cohort ( n = 161 of patients) without known LQTS or without QT-prolonging drug treatment but any other cardiovascular disease. The performance of a fully convolutional network (FCN) used in prior studies was compared with a different, novel convolutional neural network model (XceptionTime). We found that the XceptionTime model was able to achieve a higher balanced accuracy score (91.8%) than the associated FCN metric (83.6%), indicating improved prediction possibilities of novel AI architectures. The predictive accuracy prevailed independently of age and QT c parameters., Conclusions: In this study, the XceptionTime model outperformed the FCN model for LQTS patients with even better results than in prior studies. Even when a patient cohort with cardiovascular comorbidities is used. AI-based ECG analysis is a promising step for correct LQTS patient identification, especially if common diagnostic measures might be misleading.

Background: Limited data exist regarding implantable cardioverter defibrillator (ICD) usage in infants and toddlers. This study evaluates ICD placement indications, procedural techniques, programming strategies, and outcomes of ICDs in infants and toddlers.Methods: This is a single-center retrospective review of all patients ≤3 years old who received an ICD from 2009 to 2021.Results: Fifteen patients received an ICD at an age of 1.2 years (interquartile range [IQR], 0.1-2.4; 12 [80%] women; weight, 8.2 kg [IQR, 4.2-12.6]) and were followed for a median of 4.28 years (IQR, 1.40-5.53) or 64.2 patient-years. ICDs were placed for secondary prevention in 12 patients (80%). Diagnoses included 8 long-QT syndromes (53%), 4 idiopathic ventricular tachycardias/ventricular fibrillations (VFs; 27%), 1 recurrent ventricular tachycardia with cardiomyopathy (7%), 1 VF with left ventricular noncompaction (7%), and 1 catecholaminergic polymorphic ventricular tachycardia (7%). All implants were epicardial, with a coil in the pericardial space. Intraoperative defibrillation safety testing was attempted in 11 patients (73%), with VF induced in 8 (53%). Successful restoration of sinus rhythm was achieved in all tested patients with a median of 9 (IQR, 7.3-11.3) J or 0.90 (IQR, 0.68-1.04) J/kg. Complications consisted of 1 postoperative chylothorax and 3 episodes of feeding intolerance. VF detection was programmed to 250 (IQR, 240-250) ms with first shock delivering 10 (IQR, 5-15) J or 1.1 (IQR, 0.8-1.4) J/kg. Three patients (20%) received appropriate shocks for ventricular tachycardia/VF. No patient received an inappropriate shock. There were 2 (13%) ventricular lead fractures (at 2.6 and 4.2 years post-implant), 1 (7%) pocket-site infection, and 2 (13%) generator exchanges. All patients were alive, and 1 patient (7%) received a heart transplant.Conclusions: ICDs can be safely and effectively placed for sudden death prevention in infants and toddlers with good midterm outcomes. [ABSTRACT FROM AUTHOR]

The article focuses on the cardiovascular risks associated with stimulant medications for the treatment of attention deficit hyperactivity disorder (ADHD). It discusses the study conducted by C. Zhang and colleagues to analyse the occurrence of cardiac events in patients receiving stimulant therapy, and presents the mild side effects associated with the stimulant therapy, such as increased heart rate and blood pressure.

The author discusses the research "Identification of low-risk adult congenital LQTS patients" by C. Zhang and colleagues, published within the issue. Topics discussed include increase in chances of sudden cardiac arrest (SCA) in genotype-positive long QT syndrome (LQTS) patients, need of genetic testing for the patients, and improving outcome in LQTS by lifestyle changes and need to check for QT-prolonging properties of potential QT-prolonging drugs.

Intravenous administration of pentamidine is known to cause long-QT syndrome (Torsade de pointes tachycardias and large QT prolongation) in rare cases and to cause small QT prolongation regulary. A similar pattern is seen with other drugs known to cause a long-QT syndrome. Pentamidine aerosol prophylaxis is commonly used to prevent Pneumocystis carinii pneumonia in HIV-infected persons. The goal of this study was to clarify whether pentamidine aerosol prophylaxis induces QT prolongation. We examined 100 patients receiving pentamidine aerosol prophylaxis at a rather high dose (300 mg biweekly) for at least 1 month (range 1-24) by determinating the QT interval corrected for heart rate (QTc), blind for treatment. In a cross-sectional study, QTc was not different in 50 HIV-infected patients with chronic pentamidine aerosol prophylaxis (413 ms), 50 similar HIV-infected patients without pentamidine (407 ms), and 50 similar patients without HIV-infection and without pentamidine (407 ms). In a longitudinal study in another 50 HIV-infected patients, QTc was the same before (414 ms) and on long-term (median 9-month) pentamidine aerosol prophylaxis (414 ms). In contrast to the case with intravenous pentamidine, we found no QT prolongation and thereby no risk of long-QT syndrome with pentamidine aerosol prophylaxis. [ABSTRACT FROM AUTHOR]