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)

In the long QT syndrome (LQT), individuals suffer from syncope, seizures and sudden death due to cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. Many of these individuals also have prolongation of the QT interval on electrocardiograms, suggesting abnormal cardiac repolarization. To improve our understanding of the mechanisms underlying LQT and to facilitate presymptomatic diagnosis, we have begun to study families with autosomal dominant LQT. In 1991, we reported tight linkage between the LQT phenotype and the Harvey ras-1 gene (HRAS) in several families of Northern European descent. This discovery localized an LQT gene to chromosome 11p15.5 and made presymptomatic diagnosis in some families possible. In initial experiments, no recombination between HRAS and LQT was observed, making this protoncogene a candidate for LQT. This hypothesis was supported by physiologic data; other investigators had shown that ras proteins modulate cardiac potassium channels and an abnormality of potassium homeostasis could explain LQT. We eliminated HRAS as a candidate, however, by sequencing the coding region in 10 unrelated patients and finding no mutations. This indicated that the LQT locus was nearby, but not HRAS. Autosomal dominant LQT was previously thought to be genetically homogeneous and the first seven LQT families we studied were linked to 11p15.5. In 1992, however, several groups, including my laboratory, identified locus heterogeneity for LQT. Recently we identified a second LQT locus, LQT2, on chromosome 7q35-36. Because several families were unlinked, at least one more LQT locus exists. This degree of heterogeneity presents opportunities. It seems likely, for example, that proteins encoded by distinct LQT genes interact to modulate cardiac repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular genetics of long QT syndrome. 767 24

Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.
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PMID:SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. 788 74

Romano-Ward syndrome, one of familial long QT syndromes, is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. By linkage analyses, three LQT loci were previously mapped: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, LQT3 on 3p21-24. It was recently brought to light that LQT2 and LQT3 were caused by mutations of the gene encoding cardiac ion channels. Mutations in HERG on chromosome 7q35-36, encoding potassium channels (Ikr), cause LQT2, and block of Ikr is a known mechanism for drug-induced prolongation of cardiac action potentials, which provides a mechanistic link between LQT2 and certain forms of acquired LQT. Mutations in SCN5A on chromosome 3p21, encoding the human heart voltage-gated sodium-channel alpha-subunit, cause LQT3. Mutant channels show a sustained inward sodium current during membrane depolarization, which explains prolongation of cardiac action potentials.
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PMID:[Long QT syndrome]. 890 36

A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors.
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PMID:MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. 1021 39

Mutations of eag, first identified in Drosophila on the basis of their leg-shaking phenotype, cause repetitive firing and enhanced transmitter release in motor neurons. The encoded EAG polypeptide is related both to voltage-gated K+ channels and to cyclic nucleotide-gated cation channels. Homology screens identified a family of eag-related channel polypeptides, highly conserved from nematodes to humans, comprising three subfamilies: EAG, ELK, and ERG. When expressed in frog oocytes, EAG channels behave as voltage-dependent, outwardly rectifying K(+)-selective channels. Mutations of the human eag-related gene (HERG) result in a form of cardiac arrhythmia that can lead to ventricular fibrillation and sudden death. Electrophysiological and pharmacological studies have provided evidence that HERG channels specify one component of the delayed rectifier, IKr, that contributes to the repolarization phase of cardiac action potentials. An important role for HERG channels in neuronal excitability is also suggested by the expression of these channels in brain tissue. Moreover, mutations of ERG-type channels in the Drosophila sei mutant cause temperature-induced convulsive seizures associated with aberrant bursting activity in the flight motor pathway. The in vivo function of ELK channels has not yet been established, but when these channels are expressed in frog oocytes, they display properties intermediate between those of EAG- and ERG-type channels. Coexpression of the K(+)-channel beta subunit encoded by Hk with EAG in oocytes dramatically increases current amplitude and also affects the gating and modulation of these currents. Biochemical evidence indicates a direct physical interaction between EAG and HK proteins. Overall, these studies highlight the diverse properties of the eag family of K+ channels, which are likely to subserve diverse functions in vivo.
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PMID:The eag family of K+ channels in Drosophila and mammals. 1041 5

1. RP58866 possesses a unique electrophysiological property: highly effective against various types of arrhythmias including ventricular fibrillation in animal models, noticeably those occurring during ischaemia with depolarized membrane due to elevated extracellular K+ concentrations. To understand the potential ionic mechanisms, we performed detailed studies on the effects of RP58866 on the HERG channels expressed in Xenopus oocytes, which are believed to be important compositions of the rapid component of delayed rectifier K+ current in the hearts. 2. RP58866 significantly inhibited the HERG channels in a concentration-dependent manner, with approximately 50% decrease in the current amplitude at a concentration of 1 microM. RP58866 produced more pronounced inhibition with voltage protocols which favoured inactivation of the HERG channels. It caused substantial negative shift of the inactivation curves but did not alter the activation properties. The inhibition was considerably relieved by elevating [K+]o from 5 - 20 mM, which weakened the channel inactivation. More importantly, the potency was reduced by approximately 100 fold on the mutated HERG channels (S631A) in which the C-type inactivation was substantially weakened. 4. We conclude that blockade of the HERG channels by RP58866 is mainly associated with the binding of the drugs to the inactivated channels. This unique property of HERG blockade might explain some previously reported but unexplained observations: RP58866 maintains its efficacy in APD prolongation with depolarized membrane potential and in arrhythmias during ischaemia with manifested membrane depolarization.
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PMID:Inactivation block of the HERG human cardiac K+ channels by RP58866. 1048 22

The congenital long QT syndrome is characterised by the presence of syncopes due to torsades de pointe which may degenerate to ventricular fibrillation and cause sudden death. These syncopes occur in young subjects with electrocardiographic abnormalities and prolongation of the QT interval. Patients with the autosomally dominant transmitted Romano-Ward syndrome with normal audition are classically opposed to those with the Jervell and Lange-Nielsen autosomally recessive syndrome who have bilateral total deafness. Our understanding of the congenital long QT syndrome has improved in recent years with respect to the physiopathology, diagnosis and treatment, due to research in the fields of genetics, electrocardiography and electrophysiology. The diagnosis is based on analysis of the phenotype and genotypes. A family enquiry is always necessary to detect unrecognised forms. Five culprit genes have been identified for the Romano-Ward syndrome. All code for subunits of sodium or potassium channels: two a subunits of the potassium channels (QVLQT1 for LQT1, HERG for LQT2), the a subunit of the sodium channel INa (SCN5A for LQT3), and two regulatory subunits of potassium channels (KCNE1 for LQT5 regulating the KvLQT1 channel and MiRP1 regulating HERG). The concept of genetic heterogeneity of the congenital long QT syndrome may thus be understood: different genes may be responsible for the same phenotype. Except for specific cases, the usual treatment is life-long betablocker therapy and the avoidance of a large number of drugs, the list of which is continually updated. A multicentre trial is underway to validate betablocker therapy for the prevention of cardiac events in a LQT1 genotype population. Prospective studies will be necessary to assess gene-specific treatments.
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PMID:[Present concepts of congenital long QT syndrome]. 1081 97

The hallmark of long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram and a propensity to the occurrence of syncopes resulting from polymorphic ventricular tachycardia, called torsades de pointes. They may degenerate to ventricular fibrillation, possibly causing sudden death. Congenital LQTS, which implicates at least six chromosomal loci, LQT1 to LQT6, three of them corresponding to mutations concerning the coding of K+ channel proteins, give useful information about the mechanism underlying the arrhythmia. One of the potassium channel genes implicated in congenital LQTS is HERG, which encodes the IKr current channel protein. This current has provided a relevant insight into the occurrence of drug-acquired LQTS, since all drugs associated with torsades, such as erythromycin, terfenadine, haloperidol, or cisapride, also block IKr.
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PMID:Cardiac K+ channels and drug-acquired long QT syndrome. 1086 23

A progressively increasing number of cardiac and noncardiac drugs prolong the ventricular action potential duration (QT interval of the electrocardiogram) and cause a distinctive polymorphic ventricular tachycardia termed torsades de pointes (TdP) that can degenerate into ventricular fibrillation and sudden cardiac death. Drugs prolong the QT interval and cause TdP by blocking cardiac K+ channels in general and selectively blocking the rapidly activating delayed rectifier channel IKr. Coassembly of HERG (human-ether-a-go-go-related gene) alpha-subunits and MiRP1 (MinK-related peptide 1) beta-subunits recapitulate the behavior of native human IKr and mutations of HERG and MiRP1 decrease the repolarizing current, delay ventricular repolarization and prolong the QT. Thus, drug-induced QT prolongation and TdP might represent an iatrogenic reproduction of the congenital LQTS. In patients with silent forms of the congenital LQTS associated with mutations in IKr, arrhythmic symptoms developed almost exclusively after exposure to QT-prolonging drugs. This review centers on the possible cellular mechanisms underlying drug-induced QT prolongation and TdP, the description of specific drugs and risk factors facilitating the development of TdP, and the recommendations for preventing and treating this potentially fatal arrhythmia.
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PMID:Drug-induced torsade de pointes: from molecular biology to bedside. 1088 35

Catecholamines have long been used as a provocative test in some forms of tachyarrhythmias including long QT syndrome (LQTS). In contrast, catecholamines are reported to decrease ST-segment elevation in leads V1-V3 in some patients with Brugada syndrome. Differential effects of catecholamines on QT interval, action potential duration, transmural dispersion of repolarization and Torsade de Pointes between LQT1, LQT2, and LQT3 forms of the LQTS were shown in experimental models of the LQTS by using arterially-perfused wedge preparations as well as in patients with congenital LQTS including children. In our preliminary result of patients with Brugada syndrome including a child, isoproterenol infusion was effective to decrease the ST-segment elevation in leads V1-V2 and to suppress the electrical storm of ventricular fibrillation.
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PMID:Catecholamines in children with congenital long QT syndrome and Brugada syndrome. 1178 52


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