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

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

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

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

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

Seven forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes have been identified. Genotype-phenotype correlation in clinical and experimental studies involving arterially-perfused canine left ventricular wedges suggest that beta-blockers are protective in LQT1, less so in LQT2, but not protective in LQT3. A class IB sodium channel blocker, mexiletine, is most effective in abbreviating QT interval in LQT3, but effectively reduces transmural dispersion of repolarization (TDR) and prevents the development of Torsade de Pointes (TdP) in all 3 models, suggesting its potential as an adjunctive therapy in LQT1 and LQT2. High concentrations of intravenous nicorandil, a potassium channel opener, have been shown to be capable of decreasing QT and TDR, and preventing TdP in LQT1 and LQT2 but not in LQT3. The calcium channel blocker, verapamil, has also been suggested as adjunctive therapy for LQT1, LQT2 and possibly LQT3. Experimental data using right ventricular wedge preparations suggest that a prominent transient outward current (I(to))-mediated action potential (AP) notch and a loss of AP dome in epicardium, but not in endocardium, give rise to a transmural voltage gradient, resulting in ST segment elevation and the induction of ventricular fibrillation (VF), characteristics of the Brugada syndrome. Since the maintenance of the AP dome is determined by the balance of currents active at the end of phase 1 of the AP, any intervention that reduces the outward current or boosts inward current at the end of phase 1 may normalize the ST segment elevation and suppress VF. Such interventions are candidates for pharmacological therapy of the Brugada syndrome. The infusion of isoproterenol, a beta-adrenergic stimulant, strongly augments L-type calcium current (I(Ca-L)), and is the first choice for suppressing electrical storms associated with Brugada syndrome. Quinidine, by virtue of its actions to block I(to), has been proposed as adjunctive therapy, with an implantable cardioverter defibrillator as backup. Oral denopamine, atropine or cilostazol all increase ICa-L, and for this reason may be effective in reducing episodes of VF.
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PMID:Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome. 1589 62

Enhanced dispersion of repolarization has been proposed as an important mechanism in long QT related arrhythmias. Dispersion can be dynamic and can be augmented with the occurrence of spatially out-of-phase action potential duration (APD) alternans (discordant alternans; DA). We investigated the role of tissue heterogeneity in generating DA using a novel transgenic rabbit model of type 2 long QT syndrome (LQT2). Littermate control (LMC) and LQT2 rabbit hearts (n = 5 for each) were retrogradely perfused and action potentials were mapped from the epicardial surface using di-4-ANEPPS and a high speed CMOS camera. Spatial dispersion (Delta APD and Delta slope of APD restitution) were both increased in LQT2 compared to LMC (Delta APD: 34 +/- 7 ms vs. 23 +/- 6 ms; Delta slope: 1.14 +/- 0.23 vs. 0.59 +/- 0.19). Onset of DA under a ramp stimulation protocol was seen at longer pacing cycle length (CL) in LQT2 compared to LMC hearts (206 +/- 24 ms vs. 156 +/- 5 ms). Nodal lines between regions with APD alternans out of phase from each other were correlated with conduction velocity (CV) alternation in LMC but not in LQT2 hearts. In LQT2 hearts, larger APD dispersion was associated with onset of DA at longer pacing CL. At shorter CLs, closer to ventricular fibrillation induction (VF), nodal lines in LQT2 (n = 2 out of 5) showed persistent complex beat-to-beat changes in nodal line formation of DA associated with competing contribution from CV restitution and tissue spatial heterogeneity, increasing vulnerability to conduction block. In conclusion, tissue heterogeneity plays a significant role in providing substrate for ventricular arrhythmia in LQT2 rabbits by facilitating DA onset and contributing to unstable nodal lines prone to reentry formation.
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PMID:Origin of complex behaviour of spatially discordant alternans in a transgenic rabbit model of type 2 long QT syndrome. 1967 70


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