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)

Multiple mutations in several ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and KCNJ2) have been shown to cause autosomal dominant long QT syndrome (LQTS), a familial cardiac disorder that causes syncope, seizures, and sudden death. Due to their multiple loci and considerable size, mutation detection in these genes represents a challenge that is only partially met by the conventional screening method of single-stranded conformational polymorphism (SSCP). The recently introduced denaturing high-performance liquid chromatography (dHPLC) offers a promising new method for a fast and sensitive analysis of PCR-amplified DNA fragments. To test the applicability of dHPLC in the molecular diagnosis of LQTS, we first assessed a cohort of 192 patients from our International LQTS Registry for 14 previously identified mutations (including 10 different missense mutations, 1-bp, 2-bp, 3-bp, and 9-bp deletion mutations), and 2 polymorphisms in the LQTS potassium and sodium channel genes. Applying empirically determined exon-specific melting profiles, all mutations (including four previously undetectable by SSCP) were readily identified by dHPLC. We conclude that the dHPLC technology is a highly sensitive and efficient method for the molecular analysis of LQTS, and the same PCR amplicons developed for SSCP testing can be directly used for dHPLC assay.
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PMID:Denaturing high-performance liquid chromatography quickly and reliably detects cardiac ion channel mutations in long QT syndrome. 1464 2

In 1992, Brugada and Brugada described 8 patients with a history of aborted sudden death and a distinct ECG pattern of right bundle-branch block with ST segment elevation in leads V1-V3 and normal QT interval in the absence of any structural heart disease. It is called Brugada syndrome now and is believed to be responsible for 4-12% of all sudden deaths and around 20% of deaths in patients with structurally normal hearts. Although this syndrome is observed worldwide and the exact prevalence is unknown, it is more common in the Southeast Asian countries. Repeated syncope, ventricular fibrillation, and sudden cardiac death have been reported in patients with Brugada syndrome. The clinical presentation of Brugada syndrome is distinguished by a male predominance and the appearance of arrhythmic events at an average age of 40 years. The Brugada syndrome is inherited in an autosomal dominant manner with incomplete penetrance and an incidence ranging between 5 and 66 per 10,000. The surface ECG manifestations of the syndrome can transiently disappear, but can be unmasked by potent sodium channel blockers in some cases. Mutations of the cardiac sodium channel SCN5A have been detectable in <20% of patients with Brugada syndrome. Recent genetic studies have confirmed the genetic heterogeneity of the disorder. Antiarrhythmic drugs appear to be of little use in prolonging survival and in preventing recurrences of ventricular arrhythmias. To date, implantable cardioverter defibrillator remains the best therapy to prevent sudden death in these patients.
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PMID:Brugada syndrome--an under-recognized electrical disease in patients with sudden cardiac death. 1496 59

Brugada syndrome is believed to be responsible for 4 to 12% of all sudden deaths and for 20% of deaths in patients with structurally normal hearts. As a distinct clinical entity with a high risk of sudden cardiac death it was first described in 1992. The syndrome characterized by ST segment elevation in right precoardial leads V1 to V3 unrelated to ischemia and by electrolyte disturbance without obvious structural heart disease. The clinical findings are based on ECG and syncope or sudden death. The arrhythmia leading to sudden death is a rapid polymorphic ventricular tachycardia. The electrocardiographic signature of the syndrome is dynamic and often concealed, but can be unmasked by potent sodium channel blockers such as flecainde, ajmaline. The Brugada syndrome is a familial disease displaying an autosomal dominant mode of transmission with incomplete penetration and with incidence ranging between 5 and 66 per 10,000. The syndrome has been linked to mutations in SCNA5, the gene encoding for the a subunit of the sodium channel. Implantation of an automatic cardiverter-defibrillator is the only currently proven effective therapy.
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PMID:[Brugada syndrome]. 1594 78

Brugada syndrome is a clinical entity characterized by ST-segment elevation in the right precordial leads (V1-V3) and an episode of ventricular fibrillation in the absence of structural heart disease. Data regarding genotype-phenotype relationships are limited, since SCN5A, the gene encoding the a subunit of the sodium channel, is as yet the only gene linked to Brugada syndrome. Studies of SCN5A mutations responsible for the Brugada phenotype have shown the presence of functional defects in the sodium-channel current. Experimental studies employing arterially perfused right-ventricular wedge preparations have elucidated cellular mechanisms for this phenotype. Data indicate that an accentuated action-potential notch, mediated by a prominent transient outward current and loss of the action-potential dome in the epicardium (but not in the endocardium) of the right ventricle give rise to a transmural voltage gradient, resulting in ST-segment elevation and the induction of ventricular fibrillation. On the basis of cellular mechanisms, it might be possible to normalize the Brugada phenotype by use of therapeutic agents or interventions that decrease net outward currents by decreasing the transient outward current or outward potassium currents, or increasing the L-type inward calcium current or fast sodium current. Interventions that increase net outward currents through raising the transient outward current or outward potassium currents or decreasing the L-type inward calcium current or fast sodium current might aggravate or unmask the Brugada phenotype, resulting in an acquired form of this syndrome. In this review, we discuss future challenges relating to risk stratification, genetic heterogeneity, sex and ethnic differences in Brugada syndrome.
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PMID:Mechanisms of disease: current understanding and future challenges in Brugada syndrome. 1611 3

The Brugada syndrome is characterized by ST-segment elevation in the right precordial leads (V1 through V3) and an episode of ventricular fibrillation in the absence of structural heart disease. SCN5A, the gene encoding the alpha subunit of the sodium channel, is the only gene thus far linked to the Brugada syndrome but is identified in only 18% to 30% of patients with clinically diagnosed Brugada syndrome. On the other hand, experimental studies have suggested that an intrinsically prominent transient outward current-mediated action potential (AP) notch and a subsequent loss of the AP dome in the epicardium but not in the endocardium of the right ventricular outflow tract give rise to a transmural voltage gradient, resulting in ST-segment elevation and phase 2 reentry-induced ventricular fibrillation. Therefore, any intervention that increases outward currents (eg, transient outward current, adenosine triphosphate-sensitive potassium current, delayed modifier potassium current) or decreases inward currents (eg, L-type calcium current, fast sodium current) at the end of phase 1 of the AP can accentuate or unmask ST-segment elevation, similar to that found in the Brugada syndrome, thus producing acquired forms of the Brugada syndrome. In this review, several drugs in addition to sodium-channel blockers and conditions that induce transient ST-segment elevation such as that in the Brugada syndrome, developing acquired forms of the Brugada syndrome, are discussed.
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PMID:Acquired forms of the Brugada syndrome. 1622 70

Brugada syndrome is characterized by ST-segment elevation in the right precordial leads (V1-V3) and an episode of ventricular fibrillation (VF) in the absence of structural heart disease. A number of reports from the world have unveiled the clinical, electrocardiographic, electrophysiologic and prognostic features of Brugada syndrome, and two recent consensus reports have suggested the diagnostic criteria of Brugada syndrome and the risk stratification for the identification of high risk Brugada patients for sudden cardiac death. SCN5A, the gene encoding the alpha subunit of the sodium channel, is the only gene thus far linked to Brugada syndrome; its prognostic value remains unclear. On the other hand, advances in the understanding of the cellular mechanism for Brugada phenotype derived from experimental studies have suggested possibilities for the development of strategies for managing and treating patients with Brugada syndrome. In this review, the recent understanding and knowledge of Brugada syndrome will be updated.
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PMID:The Brugada syndrome--an update. 1641 41

Brugada syndrome (BS) is an inherited cardiac disorder characterized by typical electrocardiographic patterns of ST segment elevation in the precordial leads, right bundle branch block, fast polymorphic ventricular tachycardia in patients without any structural heart disease, and a high risk of sudden cardiac death. The incidence of BS is high in male vs. female (i.e., 8-10/1: male/female). The disorder is caused by mutations in the SCN5A gene encoding Nav1.5, the cardiac sodium channel, which is the only gene in which mutations were found to cause the disease. Mutations in SCN5A associated with the BS phenotype usually result in a loss of channel function by a reduction in Na+ currents. We review the clinical aspects, risk stratification, and therapeutic management of this important syndrome.
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PMID:Clinical aspects and physiopathology of Brugada syndrome: review of current concepts. 1711 Oct 25

Brugada syndrome (BS) is an inherited cardiac disorder associated with a high risk of sudden cardiac death and is caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit (Na(v)1.5). The aim of this study was to identify the genetic cause of familial BS and characterize the electrophysiological properties of a novel SCN5A mutation (W1191X). Four families and one patient with BS were screened for SCN5A mutations by PCR and direct sequencing. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in tsA201 cells, and the sodium currents (I(Na)) were analyzed using the whole-cell patch-clamp technique. A novel mutation, W1191X, was identified in a family with BS. Expression of the WT or the mutant channel (Na(v)1.5/W1191X) co-transfected with the beta(1)-subunit in tsA201 cells resulted in a loss of function of Na(v)1.5 channels. While voltage-clamp recordings of the WT channel showed a distinct acceleration of Na(v)1.5 activation and fast inactivation kinetics, the Na(v)1.5/W1191X mutant failed to generate any currents. Co-expression of the WT channel and the mutant channel resulted in a 50% reduction in I(Na). No effect on activation and inactivation were observed with this heterozygous expression. The W1191X mutation is associated with BS and resulted in the loss of function of the cardiac sodium channel.
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PMID:A novel mutation in the SCN5A gene is associated with Brugada syndrome. 1714 Dec 78

Amiloride was originally described in 1967 as a potassium-sparing diuretic, the mechanism of action of which is to block the epithelial sodium channel (ENaC) within the distal tubule of the kidney. In addition, higher doses of amiloride were found to be capable of inhibiting the Na(+)/H(+) exchangers (NHE) and the Na(+)/Ca(2+) exchangers. In time, several amiloride analogs have been synthesized to have a marked increase in their specificity to inhibit the ENaC, the NHE or the Na(+)/Ca(2+) exchangers. Although the NHE inhibitors have received the most recent attention, large-scale clinical trials using NHE inhibitors in ischemic cardiac states have shown them to be either ineffective or associated with an unacceptable risk profile. Aldosterone excess in animal models is known to cause cardiovascular injury, and blockade of mineralocorticoid receptors in human beings with heart disease improves outcomes. However, the exact mechanisms of aldosterone injury in animal models of hypertensive disease and protection with mineralocorticoid receptor antagonists in human trials of heart failure remain unknown. These effects are unexplained by changes in BP, potassium, or sodium balance. An additional possibility is that aldosterone action and mineralocorticoid receptor blockade is conferred by alterations in ENaC activity. Emerging experimental evidence suggests the possibility that systemic or central ENaC inhibition or both may be an alternative to the treatment of hypertension and cardiovascular disease states. Clinical trials to evaluate further the potential beneficial cardiovascular effects of ENaC blockade are needed. This article reviews the case for ENaC inhibition as a potential target for cardiovascular and renal protection in human beings.
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PMID:Epithelial sodium channel inhibition in cardiovascular disease. A potential role for amiloride. 1719 22

The long QT syndrome type-3 (LQT3) is an inherited cardiac disorder caused by mutations in the sodium channel gene SCN5A. LQT3 has been associated with ventricular arrhythmias and sudden cardiac death, specially at low heart rates. Based on computer simulations and experimental investigations, analysis of the morphology of the Action Potential (AP) has shown that it undergoes early afterdepolarizations (EADs) and spontaneous discharges, which are thought to be the trigger for reentry like-activity. However, dynamic characteristics of cardiac tissue are also important factors of arrhythmia mechanisms. In this work, we propose a dynamical analysis of the LQT3 at cellular level. We use a detailed Markovian model of the DeltaKPQ mutation, which is associated with LQT3, and we study beat-to-beat AP Duration (APD) variations by using a long-term stimulation protocol. Compared to wild-type (WT) cells, DeltaKPQ mutant cells are found to develop APD alternans over a narrow range of stimulation frequencies. Moreover, the interval of frequency dependence of APD alternans is related to the degree of severity of the EADs present in the AP. In conclusion, dynamical analysis of paced cells is a useful approach to understand the mechanisms of rate dependent arrhythmias.
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PMID:Action potential alternans in LQT3 syndrome: a simulation study. 1800 37


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