Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sudden cardiac death occurs in the United States with an incidence greater than 300,000 persons per year. The underlying cause of death is commonly considered to be due to primary or secondary arrhythmias. In cases in which no structural heart disease can be identified, the long QT syndromes (LQTS) are now commonly considered as likely causes. Multiple genes causing LQTS have been identified thus far, all encoding cardiac ion channels. These include two potassium channel alpha-subunits (KVLQT1, HERG), two potassium channel beta-subunits (minK, MiRP1), and one sodium channel gene (SCN5A). The purpose of this review is to describe the current understanding of the molecular genetics of LQTS and the resultant phenotypes.
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PMID:Genotype and severity of long QT syndrome. 1125 55

The Brugada syndrome is an arrhythmic syndrome characterized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these patients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator.
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PMID:The Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities. 1134 71

Brugada syndrome is an inherited cardiac disorder caused by mutations in the cardiac sodium channel gene, SCN5A, that leads to ventricular fibrillation and sudden death. This study reports the changes in functional expression and cellular localization of an SCN5A double mutant (R1232W/T1620M) recently discovered in patients with Brugada syndrome. Mutant and wild-type (WT) human heart sodium channels (hNa(v)1.5) were expressed in tsA201 cells in the presence of the beta(1)-auxiliary subunit. Patch-clamp experiments in whole-cell configuration were conducted to assess functional expression. Immunohistochemistry and confocal microscopy were used to determine the spatial distribution of either WT or mutant cardiac sodium channels. The results show an abolition of functional sodium channel expression of the hNa(v)1.5/R1232W/T1620M mutant in the tsA201 cells. A conservative positively charged mutant, hNa(v)1.5/R1232K/T1620M, produced functional channels. Immunofluorescent staining showed that the FLAG-tagged hNa(v)1.5/WT transfected into tsA201 cells was localized on the cell surface, whereas the FLAG-tagged hNa(v)1.5/R1232W/T1620M mutant was colocalized with calnexin within the endoplasmic reticulum (ER). These results indicate that a positively charged arginine or lysine residue at position 1232 in the double mutant is required for the proper transport and functional expression of the hNa(v)1.5 protein. These results support the concept that loss of function of the cardiac Na(+) channel is responsible for the Brugada syndrome. The full text of this article is available at http://www.circresaha.org.
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PMID:Expression and intracellular localization of an SCN5A double mutant R1232W/T1620M implicated in Brugada syndrome. 1178 29

The Brugada syndrome describes a subgroup of patients at risk for the occurrence of ventricular fibrillation who have no definable structural heart disease associated with a right bundle branch block conduction pattern and ST-segment elevation in the right precordial leads. This syndrome is caused by genetic defects in the alpha subunit of the sodium channel. This defect causes a reduction in the sodium channel current, which accentuates the epicardial action potential notch leading to ST-segment elevation. Sodium channel blockers can potentiate these findings and screen for patients with intermittent baseline electrocardiographic findings. Because of the poor prognosis of such patients, symptomatic patients should be treated with an implantable cardioverter-defibrillator.
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PMID:The Brugada syndrome. 1179 Sep 29

The Brugada syndrome (BRS) is a hereditary cardiac condition (characteristically with a gene mutation affecting sodium channel function) identified by an elevated terminal portion of the QRS complex (prominent J wave) followed by a descending ST-segment elevation ending in a negative T wave in the right precordial leads, and malignant tachyarrhythmias in patients without demonstrable structural heart disease. We report a patient with a previous history of epilepsy treated with psychotropic drugs (with a sodium channel blocking effect) and chronic renal failure on haemodialysis who developed hyperkalaemia (6.6 mmol/l) and ECG findings resembling BRS. This condition was manifested by the prominent J wave, the coved-type ST-segment elevation and the negative T wave in the right precordial leads. These ECG changes disappeared after haemodialysis when the potassium became normal. Subsequently, a flecainide test did not reproduce ST-segment elevation. We conclude that hyperkalaemia associated with cardiac membrane active drugs may cause ECG changes mimicking the Brugada syndrome.
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PMID:Transient Brugada-type electrocardiographic abnormalities in renal failure reversed by dialysis. 1241 61

The long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of the QT interval on electrocardiograms (ECGs), syncope and sudden death caused by a specific ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in ion channel genes including the cardiac sodium channel gene SCN5A, and potassium channel subunit genes KCNQ1, KCNH2, KCNE1, and KCNE2. Little information is available about LQTS mutations in the Chinese population. In this study, we characterized 42 Chinese LQTS families for mutations in the two most common LQTS genes, KCNQ1 and KCNH2. We report here the identification of four novel KCNQ1 mutations and three novel KCNH2 mutations. The KCNQ1 mutations include L191P in the S2-S3 cytoplasmic loop, F275S and S277L in the S5 transmembrane domain, and G306V in the channel pore. The KCNH2 mutations include L413P in transmembrane domain S1, E444D in the extracellular loop between S1 and S2, and L559H in domain S5. The location and character of these mutations expand the spectrum of KCNQ1 and KCNH2 mutations causing LQTS. Excitement, exercises, and stress appear to be the triggers for developing cardiac events (syncope, sudden death) for LQTS patients with KCNQ1 mutations F275S, S277L, and G306V, and all three KCNH2 mutations L413P, E444D and L559H. In contrast, cardiac events for an LQTS patient with KCNQ1 mutation L191P occurred during sleep or awakening from sleep. KCNH2 mutations L413P and L559H are associated with the bifid T waves on ECGs. Inderal or propanolol (a beta blocker) appears to be effective in preventing arrhythmias and syncope for an LQTS patient with the KCNQ1 L191P mutation.
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PMID:KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. 1244 76

Atrial fibrilliation (AF) is often combined with advanced age and structural heart disease, conditions known to invite serious proarrhythmic complications of antiarrhythmic drug therapy. Recent controlled trials comparing two AF treatment strategies-rhythm control requiring atrial defibrilliation and antiarrhythmic drugs to prevent AF and ventiricular rate control obviating sinus rhythm maintenance with such drugs-showed equal or superior results with rate control. AF is associated with derepressions of "fetospecific" expression patterns that may profoundly alter the responsiveness of atrial muscle to antiarrhythmic drugs. Therefore, effects of drugs predicted according to pharmacological classifications evaluating drug actions in intact myocardium only should be interpreted cautiously. The classification proposed by Vaughan Williams fails to distinguish between acute and chronic drug efficacy and toxicity as recommended in classical pharmacology. There is, however, overwhelming evidence that acute and chronic drug effects often differ fundamentally. For instance, amiodarone acts acutely as a sodium channel blocker, whereas chronic effects may be mediated by a downregulation of thyroid hormone receptors. Meaningful direct effects of amiodarone on atrial potassium channels is questionable, since the main candidate target-current (IKr) may not be expressed in human atrial muscle. Multiple biophysical factors contribute to the lack of ion channel-selective actions of antiarrhythmic agents. Nonselectivity becomes particularly important in the context of mechanisms of action of Vaughan Williams Class I and III agents on human atrial muscle. Preclinical studies indicate that Class I agents such as flecainide and propafenone may act in AF predominantly as Class III agents. Meta-analyses of antiarrhythmic agents for the prevention of AF have failed to reveal superior drugs or drug classes. Superiority of amiodarone over other agents may depend on arbitrary amiodarone-favoring loading protocols producing significant differential effects exclusively during the acute phase of treatment. In conclusion, the classification of current antiarrhythmic agents into Class I and III may not be a useful simplification when applied to the pharmacotherapy of AF.
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PMID:Class I or class III agents for atrial fibrillation: are asking the right question? 1291 11

A 69-year-old woman had acute cholecystitis that mimicked right bundle branch block with coved-type ST-segment elevation in the precordial electrocardiogram leads (Brugada-type ST shift). The patient did not have obvious heart disease, syncope, or a family history of sudden death. The coved-type ST-segment elevation disappeared as the acute inflammation subsided. Intravenous administration of pilsicainide, a pure sodium channel blocker, could reproduce the Brugada-type ST shift. This is the first report of the Brugada-type ST shift occurring in association with acute cholecystitis.
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PMID:Right bundle branch block and coved-type ST-segment elevation mimicked by acute cholecystitis. 1293 60

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the alpha subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.
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PMID:Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). 1452 39

A 42 year old male patient presented with atypical ECG pattern at rest and reported that his brother died suddenly of unknown reasons at the age of 40. A performed pharmacological testing with ajmalin discovered strong ST-segment elevations in lead V(1) and V(2) in combination with an incomplete right bundle branch block. As a result, the diagnosis Brugada syndrome was established. The Brugada syndrome is a primary cardiac conduction disturbance without structural heart disease and is associated with an increased risk of sudden cardiac death caused by life threatening ventricular tachyarrhythmia. It is an inherited disease displaying an autosomal dominant mode of transmission with an incomplete penetrance, especially prevalent in females. In some regions like the southeast of Asia and Japan it is endemic. The mutation is linked to the sodium channel gene SCN5A. The annual mortality rate is estimated 30 per 100.000 persons. Today, exact diagnostic criteria do not exist. The diagnosis is based on the typical ECG pattern, combined with clinical symptoms, and a family history of sudden cardiac death. The currently suggested therapy consists of the implantation of an internal defibrillator.
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PMID:[Atypical resting ecg pattern in a patient with a positive family history of sudden cardiac death]]. 1456 68


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