Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042510 (ventricular fibrillation)
 10,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sudden cardiac death accounts for 19% of sudden deaths in children between 1 and 13 years of age and 30% of sudden deaths that occur between 14 and 21 years of age. The incidence of sudden cardiac death displays 2 peaks: one between 45 and 75 years of age, as a result of coronary artery disease, and the other between birth and 6 months of age, caused by sudden infant death syndrome. The role of cardiac arrhythmias in sudden infant death syndrome has long been a matter of debate and the role of cardiac arrhythmias in children in general is not well defined. Recent findings point to a contribution of primary electrical diseases of the heart including the Brugada and long QT syndromes to sudden death in infants and children. Mutations in SCN5A and HERG and KvLQT1 have been shown to be associated with life-threatening arrhythmias and long QT intervals in young infants. These mutations cause changes in sodium and potassium currents that amplify intrinsic electrical heterogeneities within the heart, thus providing a substrate as well as a trigger for the development of reentrant arrhythmias, including Torsade de Pointes (TdP), commonly associated with the long QT syndrome (LQTS). Mutations in SCN5A have also been shown to cause the sodium channel to turn off prematurely and thus to set the stage for the development of a rapid polymorphic ventricular tachycardia/ventricular fibrillation in patients with the Brugada Syndrome. In LQTS, ion channel mutations cause a preferential prolongation of the M cell action potential that contributes to the development of long QT intervals, wide-based or notched T waves, and a large transmural dispersion of repolarization, which provides the substrate for the development of TdP. An early afterdepolarization-induced triggered beat is thought to provide the extrasystole that precipitates TdP. In the Brugada syndrome, mutations in SCN5A reduce sodium current density, causing premature repolarization of the epicardial action potential due to an all or none repolarization at the end of phase 1. The loss of the action potential dome in epicardium, but not endocardium, creates a dispersion of repolarization across the ventricular wall, resulting in a transmural voltage gradient that manifests in the electrocardiogram (ECG) as an ST-segment elevation and in the development of a vulnerable window during which reentry can be induced. Under these conditions, loss of the action potential dome at some epicardial sites but not others gives rise to phase 2 reentry, which provides an extrasystole capable of precipitating ventricular tachycardia/ventricular fibrillation (or rapid TdP). The practical importance of identifying infants and children with Brugada and LQTS syndromes lies in the fact that most deaths due to these congenital defects can be prevented. A simple ECG is often sufficient to permit diagnosis and thus to prevent the development of life-threatening arrhythmic events. Mass ECG screening of neonates and children however has been the subject of debate focused on issues ranging from the emotional impact of dealing with false positives to those concerning socio-economic and medico-legal factors. These issues are discussed in other articles. These concerns notwithstanding, it is important that we continue to question whether the economic inefficiencies of current screening methodologies supersede the value of a young life.
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PMID:Molecular biology and cellular mechanisms of Brugada and long QT syndromes in infants and young children. 1178 53

The clinical and genetic characteristics of inherited arrhythmic disorders in Japan are briefly summarized. The incidence of hereditary long QT syndrome (LQTS) in Japan seems comparable to that in western countries. The genotypes are mainly LQT1 and LQT2; LQT3 and other types are rare. Mutations found in Japanese LQTS families are mostly novel compared to mutations reported in other countries and in different ethnic populations. Functional assays of the mutants in heterologous expression systems have disclosed novel mechanisms of current suppression in LQT1 and LQT2, and of gain of function in LQT3. Mutations in KCNJ2 may provide a new genotype (LQT7) of LQTS. In addition, mutations or single nucleotide polymorphisms in the channel genes responsible for LQTS (KvLQT1, HERG, and SCN5A) may predispose to drug-induced LQTS. A relatively high prevalence of Brugada syndrome is suspected in the Japanese population, and 1 of approximately 2,000 asymptomatic individuals present Brugada-type ECG changes upon annual examination. Genetic screening of the symptomatic Brugada syndrome and suspected cases has revealed SCN5A mutations in only approximately 12%. Therefore, the genetic basis of the majority of cases is not known. The expressed Na+ current of SCN5A mutant channels showed the phenotype of decreased channel function commonly seen in Brugada mutations. A case of idiopathic ventricular fibrillation was found to have a novel mutation in SCN5A, in which the expressed current showed marked suppression of channel function.
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PMID:Inherited arrhythmic disorders in Japan. 1274 19

The congenital long QT syndrome (LQTS) is a variable clinical and genetic entity characterised by prolongation of the QT interval on the ECG associated with the risk of serious ventricular arrhythmias (torsades de pointe, ventricular fibrillation) which may cause syncope and sudden death in patients with otherwise normal hearts. To date, 6 loci have been identified with the genes responsible for the forms LQT1, LQT2, LQT5 and LQT6, coding for the potassium channels (KCNQ1, HERG, KCNE1 and KCNE2, respectively) which, in the heterozygote state, are responsible for the main forms of LQTS without deafness and, in the homozygote state (KCNQ1 and KCNE1) for the recessive forms of LQTS with or without deafness. The gene for the LQT3 form codes for the cardiac sodium channel (SCN5A). The genetic variability observed in the LQTS corresponds to the diversity of cardiac ionic channels implicated in the genesis of the action potential, so making the LQTS a disease of the ionic channels or a "channelopathy". The potential severity of the prognosis justifies testing of subjects with long QT intervals on the ECG and Holter recording. In order to identify subjects with the genetic abnormality who are asymptomatic, these investigations associated with genetic testing should be made in all close members of the family of an affected person. The major problem remains the evaluation of the risk of sudden death in asymptomatic subjects with a genetic abnormality. At present, in the absence of clearly proven prognostic factors and in the knowledge that effective treatment without major secondary effects is available, all patients should be given prophylactic betablocker therapy.
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PMID:[Value of genetic testing in the management of the congenital long QT syndrome]. 1283 49

Macrolides, ketolides and fluoroquinolones as well as other classes of antimicrobial agents have been associated with prolongation of cardiac repolarisation. This effect is most notable with erythromycin, clarithromycin, gatifloxacin, moxifloxacin, levofloxacin and telithromycin. All of these agents produce a blockage of the HERG channel dependent potassium current in myocyte membranes resulting in a prolonged QTc interval which may give rise to polymorphic ventricular tachycardia, Torsades de Pointes or ventricular fibrillation. The risk of malignant arrhythmias is increased by concomitant usage with Type Ia or III anti-arrhythmic agents or with other drugs that prolong the QTc interval or have competitive metabolic routes. Electrolyte disturbances or underlying cardiac disease also increase the risk of ventricular arrhythmias. The best clinical outcome indicator is the incidence of the associated arrhythmias. The rough rank order of risk with these agents, albeit with limited and incomplete data, is in decreasing order; erythromycin, clarithromycin, gatifloxacin, levofloxacin and moxifloxacin. Telithromycin outcomes for associated arrhythmia are yet to be determined. The essential point is that the overall risk of ventricular arrhythmias is very small with these agents but can be reduced further by avoiding their usage for patients with other multiple risk factors for Torsades de Pointes.
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PMID:Cardiotoxicity of macrolides, ketolides and fluoroquinolones that prolong the QTc interval. 1290 46

An 18-year old female taking anti-epileptic medication was found unconscious in her bed early in the morning. After documented ventricular fibrillation and successful resuscitation, the patient was admitted to our emergency care unit. According to ECG criteria a long-QT syndrome of the subtype 2 was suspected. A few days later, however, the patient died because of hypoxic brain death. From previous hospital reports it turned out that the patient had repeatedly experienced syncopes in the past, which were interpreted as epileptic seizures. Her 17-year old sister and the female twin of her mother had both recently died from sudden cardiac death of unknown cause. An ECG screening in the family revealed six members with LQTS. A genetic analysis revealed in all of them a previously not described rearrangement mutation (888 delG insAA) in the LQT2 gene ( HERG) that was predicted to cause a protein truncation (360X) in the amino acid chain of the I(Kr)-channel subunit. This casuistic contribution exemplifies some classical aspects of LQTS (typical adrenergic trigger mechanism, classical false diagnosis "epilepsy") and demonstrates the possibility of a genotypic classification guided by phenotypic ECG characteristics. It represents an unusual case of a LQTS with a high degree of malignancy, which requires aggressive therapeutic interventions for the family survivors.
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PMID:[18-year old patient with anti-epileptic therapy and sudden cardiac death]. 1508 78

Delayed rectifier K+ current (IK) is the major outward current responsible for ventricular repolarization. Two components of IK (IKr and IKs) have been identified in many mammalian species including humans. IKr plays a pivotal role in normal ventricular repolarization. A prolongation of action potential duration (APD) under a variety of conditions would favor the activation of IKs so that to prevent excessive repolarization delay causing early afterdepolarization. The pore-forming a subunits of IKr and IKs are composed of HERG (KCNH2) and KvLQT1 (KCNQ1), respectively. KvLQT1 is associated with a function-altering beta subunit, minK to form IKs. HERG may be associated with mink (KCNE1) and/or minK-related protein (MiRP1) to form IKr, but the issue remains to be established. IKs is enhanced, whereas IKr is usually attenuated by beta-adrenergic stimulation via cyclic adenosine 3',5'-monophosphate (cAMP)/protein kinase A-dependent pathways. There exist regional differences in the density of IKr and IKs transmurally (endo-epicardial) and along the apico-basal axis, contributing to the spatial heterogeneity of ventricular repolarization. A decrease of IKr or IKs by mutations in either HERG, KvLQT1, or KCNE family results in inherited long QT syndrome (LQTS) with high risk for Torsades de pointes (TdP)-type polymorphic ventricular tachycardia and ventricular fibrillation. As to the pharmacological treatment and prevention of ventricular tachyarrhythmias, selectively block of IKs is expected to be more beneficial than selectively block of IKr in terms of homogeneous prolongation of refractoriness at high heart rates especially in diseased hearts including myocardial ischemia.
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PMID:Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization. 1476 99

Many non-cardiovascular drugs can prolong the QT interval of the electrocardiogram (ECG); this is an accessory property not necessary for their pharmacological action and generally linked to the block of the potassium HERG channels and delayed cardiac repolarization. The QT prolongation can lead to a dangerous tachyarrhythmia, called torsade de pointes, and potentially to fatal ventricular fibrillation. The experimental approaches, aimed at an early identification of this undesidered property, often require sophisticated and expensive equipment or the use of superior animal species (dog, primates) that cannot be employed easily for ethical and/or economic reasons. This work aimed to study drug-induced QT prolongation in anaesthetized guinea-pigs and to evaluate the reliability of such an experimental approach to obtain a satisfying predictive parameter of the torsadogenicity of drugs in humans. Seven drugs that were torsadogenic in humans (astemizole, cisapride, haloperidol, quinidine, sotalol, terfenadine and thioridazine) and two that were non-torsadogenic (chlorprotixene and diazepam) were administered i.v. to guinea-pigs under pentobarbital anaesthesia. The ECGs were recorded by four electrodes inserted in the subcutaneous layer of the limbs. Both RR and QT intervals were measured in Leads II and III and then the correct QT values were calculated by Bazett and Fridericia algorithms (QTcB and QTcF, respectively). All the drugs, with the exception of chlorprotixene and diazepam, produced a dose-dependent prolongation of the QT and RR intervals and a significant increase of QTcB and QTcF values. It can be concluded that this method represents a rapid and low-cost procedure to evaluate the cardiac safety pro fi le in the preliminary screening of a high number of drugs or drug candidates.
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PMID:QT prolongation in anaesthetized guinea-pigs: an experimental approach for preliminary screening of torsadogenicity of drugs and drug candidates. 1521 16

There have been extensive efforts to develop I(Kr) channel blockers as a new antiarrhythmic agent for atrial or ventricular fibrillation, since it was demonstrated that selective blockade of the rapidly activating delayed rectifier K+ channel (I(Kr)) in the heart is not deleterious for the total mortality in fatal ventricular arrhythmia patients. Among them, dofetilide and KCB-328 blocks the I(Kr) specifically. Therefore, it increases the action potential duration (APD) selectively. Ibutilide, trecetilide, nifekalant, dronedarone, BRL-32872, H345/52 and ersentilide block the I(Kr). However, they modify also other cardiac channels or receptors. The frequency dependence of the compounds in prolonging the APD varies from the strong reversed tendency of dofetilide to the relatively neutral profile of KCB-328 and BRL-32872. Every compound reported so far has a proarrhythmic potential of torsade de pointes induction under certain conditions, although depending on the structure, the intensity may be somewhat different. In the coming decade, efforts to improve the reverse frequency dependence profile of the I(Kr) blockers by optimizing the onset and recovery time constant of the HERG block (e.g. KCB-328, vesnarinone) or the balance between the block of I(Kr) and Ca++ channels in the heart (e.g. BRL-32872, H 345/52) to eliminate the proarrhythmic potential of the currently known I(Kr) blockers are warranted. Further trials are also needed to discover more favorable compounds with multiple receptors including I(Kr) (e.g. nifekalant, dronedarone) for treating ventricular arrhythmias.
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PMID:IKr channel blockers: novel antiarrhythmic agents. 1532 13

Many non-cardiovascular drugs of common clinical use cause, as an unwanted accessory property, the prolongation of the cardiac repolarisation process, due to the block of the HERG (Human Ether-a-go-go Related Gene) potassium channel, responsible for the repolarising I(Kr) current. This delayed cardiac repolarisation process can be often unmasked by a prolongation of the QT interval of the ECG. In these conditions, premature action potentials can generate morphologically anomalous after-polarisations, and trigger a dangerous kind of polymorphic ventricular tachyarrhythmia, known as torsade de pointes, which can evolve in ventricular fibrillation and death. The risk associated with the torsadogenic cardiotoxicity of drugs, which prolong the QT interval has been the topic of documents produced by many health authorities, giving important issues about the preclinical and clinical evaluation of cardiac safety. Besides, public and private research laboratories developed several experimental in vitro or in vivo strategies, aimed to an early recognition of the influence of a drug (or of a drug-candidate) on the HERG channel and/or on the cardiac repolarisation process. Also the identification of a possible pharmacophore model, common in all or at least in numerous torsadogenic drugs, could represent a first step for the development of useful in silico approaches, allowing a preliminary indication about the potential torsadogenic property of a given molecule. In this work, we described the electrophysiological basis of torsade de pointes and listed several pharmacological classes of torsadogenic drugs. Among them, we focused our attention on antipsychotics, with an accurate overview on the experimental and clinical reports about their torsadogenic properties. Moreover, a common structural feature exhibited by these drugs, despite of their remarkable chemical differences, is evidenced by a computational approach and is indicated as a possible "facilitating" requirement for their torsadogenic properties. Together with other remarks, coming from different computational studies, the individuation of a satisfactory "toxicophore" model could be greatly useful, for the theoretical prediction of torsadogenic properties of a given chemical moiety and for the design of new drugs devoid of such an undesired and potentially lethal side-effect.
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PMID:Torsadogenic cardiotoxicity of antipsychotic drugs: a structural feature, potentially involved in the interaction with cardiac HERG potassium channels. 1554 70

Torsades de pointes (TdP) is a potentially fatal form of ventricular arrhythmia that occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings). A likely mechanism for QT prolongation and TdP is blockade of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by HERG (human ether-a-go-go-related gene). The gastroprokinetic agent cisapride is a potent blocker of HERG currents and serious cardiac arrhythmias and deaths from TdP and ventricular fibrillation have been reported in patients taking cisapride. The aim of the present study was to compare the effects of the gastroprokinetic agents domperidone and metoclopramide on HERG channels transiently expressed in human embryonic kidney (HEK 293) cells using the whole-cell configuration of the patch-clamp technique. Both domperidone and metoclopramide concentration-dependently blocked HERG currents, and the following values were calculated for IC(50) (the concentrations causing half-maximal inhibition) and n (the Hill coefficient): 57.0 nmol/l and 0.99 for domperidone, 5.4 micromol/l and 0.95 for metoclopramide. The observation that the extent of block of HERG currents by domperidone increased at more positive membrane potentials whereas block of HERG currents by metoclopramide displayed a smaller degree of voltage dependency seems to indicate that domperidone and metoclopramide have distinct binding sites on HERG channels. In conclusion, the potency for block of HERG currents is about 100-fold lower for metoclopramide when compared to domperidone.
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PMID:Comparison of the effects of metoclopramide and domperidone on HERG channels. 1564 Jun 12


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