The genetic and clinical features of cardiac channelopathies.

Sudden cardiac death, secondary to malignant ventricular arrhythmias, has traditionally been associated with structural heart disease. An important exception includes a group of clinical entities referred to as 'channelopathies' that develop secondary to genetic mutations, which alter cardiac ion channel activity. Otherwise healthy individuals affected by these forms of primary electrical disease are vulnerable to fatal arrhythmic events from a very young age. At present, there are four distinct conditions that are classified as cardiac channelopathies, namely congenital long-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia and short-QT syndrome. Our growing insight into the genetics of these conditions has led to an improved understanding of the molecular pathophysiology responsible for the malignant arrhythmias characterizing these disorders. However, despite our knowledge of these conditions, the success of medical therapy remains modest and the prevention of sudden cardiac death may necessitate insertion of an implantable cardioverter-defibrillator. The young age of affected patients makes this a particularly undesirable treatment strategy and emphasizes the importance of translating our insight into the molecular pathophysiology defining these conditions into more effective forms of therapy.

Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti-arrhythmic principle?

The cardiac action potential can be divided into five distinct phases designated phases 0-4. The exact shape of the action potential comes about primarily as an orchestrated function of ion channels. The present review will give an overview of ion channels involved in generating the cardiac action potential with special emphasis on potassium channels involved in phase 3 repolarization. In humans, these channels are primarily K(v)11.1 (hERG1), K(v)7.1 (KCNQ1) and K(ir)2.1 (KCNJ2) being the responsible alpha-subunits for conducting I(Kr), I(Ks) and I(K1). An account will be given about molecular components, biophysical properties, regulation, interaction with other proteins and involvement in diseases. Both loss and gain of function of these currents are associated with different arrhythmogenic diseases. The second part of this review will therefore elucidate arrhythmias and subsequently focus on newly developed chemical entities having the ability to increase the activity of I(Kr), I(Ks) and I(K1). An evaluation will be given addressing the possibility that this novel class of compounds have the ability to constitute a new anti-arrhythmic principle. Experimental evidence from in vitro, ex vivo and in vivo settings will be included. Furthermore, conceptual differences between the short QT syndrome and I(Kr) activation will be accounted for.

Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias.

PURPOSE OF REVIEW: To summarize advances in our understanding of the clinical phenotypes, genetics, and molecular pathophysiology of the periodic paralyses, the nondystrophic myotonias, and other muscle channelopathies. RECENT FINDINGS: The number of pathogenic mutations causing periodic paralysis, nondystrophic myotonias, and ryanodinopathies continues to grow with the advent of exon hierarchy analysis strategies for genetic screening and better understanding and recognition of disease phenotypes. Recent studies have expanded and clarified the role of gating pore current in channelopathy pathogenesis. It has been shown that the gating pore current can account for the molecular and phenotypic diseases observed in the muscle sodium channelopathies, and, given that homologous residues are affected in mutations of calcium channels, it is possible that pore leak represents a pathomechanism applicable to many channel diseases. Improvements in treatment of the muscle channelopathies are on the horizon. A randomized controlled trial has been initiated for the study of mexiletine in nondystrophic myotonias. The class IC antiarrhythmia drug flecainide has been shown to depress ventricular ectopy and improve exercise capacity in patients with Andersen-Tawil syndrome. SUMMARY: Recent studies have expanded our understanding of gating pore current as a disease-causing mechanism in the muscle channelopathies and have allowed new correlations to be drawn between disease genotype and phenotype.

Putative druggable targets for selective enhancement of cardiac conduction.

Putative druggable targets to selectively enhance cardiac conduction can be considered from the level of the ion channels determining the initiation and duration of the cardiac action potential to the gap junction proteins responsible for optimal cellular electrical coupling. Nature has provided a number of inherited disorders of conduction, the pathophysiology of which offer novel insights into future therapeutic targets. This review will focus upon the potential cellular and molecular targets for drug development based upon our knowledge of their pathophysiological impact.

Long QT Syndrome.

The hereditary Long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity for polymorphic ventricular tachyarrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. The diagnosis of this genetic disorder relies on a constellation of electrocardiographic, clinical, and genetic factors. Accumulating data from recent studies indicate that the clinical course of affected LQTS patients is time-dependent and age-specific, demonstrating important gender differences among age groups. Risk assessment should consider age-gender interactions, prior syncopal history, QT-interval duration, and genetic factors. Beta-blockers constitute the mainstay therapy for LQTS, while left cardiac sympathetic denervation and implantation of a cardioverter defibrillator should be considered in patients who remain symptomatic despite beta-blocker therapy. Current and ongoing studies are also evaluating genotype-specific therapies that may reduce the risk for life-threatening cardiac events in high-risk LQTS patients.

Electrical and structural remodeling in left ventricular hypertrophy-a substrate for a decrease in QRS voltage?

Electrical remodeling in advanced stages of cardiovascular diseases creates a substrate for triggering and maintenance of arrhythmias. The electrical remodeling is a continuous process initiated already in the early stages of cardiological pathology. The aim of this opinion article was to discuss the changes in electrical properties of myocardium in left ventricular hypertrophy (LVH), with special focus on its early stage, as well as their possible reflection in the QRS amplitude of the electrocardiogram. It critically appraises the classical hypothesis related to the QRS voltage changes in LVH. The hypothesis of the relative voltage deficit is discussed in the context of supporting evidence from clinical studies, animal experiments, and simulation studies. The underlying determinants of electrical impulse propagation which may explain discrepancies between "normal" ECG findings and increased left ventricular size/mass in LVH are reviewed.

Toward a unifying model of malaria-induced channel activity.

Infection of RBC by the malaria parasite Plasmodium falciparum activates, at the trophozoite stage, a membrane current 100- to 150-fold larger than in uninfected RBC. This current is carried by small anion channels initially described in supraphysiological ion concentrations (1.115 M Cl(-)) and named plasmodial surface anion channels (PSAC), suggesting their plasmodial origin. Our results obtained with physiological ion concentrations (0.145 M Cl(-)) support the notion that the parasite-induced channels represent enhanced activity versions of anion channels already present in uninfected RBCs. Among them, an 18-pS inwardly rectifying anion channel (IRC) and a 4- to 5-pS small conductance anion channel (SCC) were present in most single-channel recordings of infected membranes. The aim of this study was to clarify disparities in the reported electrophysiological data and to investigate possible technical reasons why these discrepancies have arisen. We demonstrate that PSAC is the supraphysiological correlate of the SCC and is inhibited by Zn(2+), suggesting that it is a ClC-2 channel. We show that in physiological solutions 80% of the membrane conductance in infected cells can be accounted for by IRC and 20% can be accounted for by SCC whereas in supraphysiological conditions the membrane conductance is almost exclusively carried by SCC (PSAC) because the IRC is functionally turned off.

Pathophysiology of HCN channels.

Hyperpolarization-activated cation currents termed I (f/h) are observed in many neurons and cardiac cells. Four genes (HCN1-4) encode the channels underlying these currents. New insights into the pathophysiological significance of HCN channels have been gained recently from analyses of mice engineered to be deficient in HCN genes. Lack of individual subunits results in markedly different phenotypes. Disruption of HCN1 impairs motor learning but enhances spatial learning and memory. Deletion of HCN2 results in absence epilepsy, ataxia, and sinus node dysfunction. Mice lacking HCN4 die during embryonic development and develop no sinoatrial node-like action potentials. In the present review, we summarize the physiology and pathophysiology of HCN channel family members based primarily on information from the transgenic mouse models and on data from human patients carrying defects in HCN4 channels.

Bloqueo de los canales de potasio en el shock séptico, ¿otra esperanza perdida? / Blockage of potassium channels in septic shock, another lost hope?

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The pacemaker current: from basics to the clinics.

Activation of the pacemaker ("funny," I(f)) current during diastole is the main process underlying generation of the diastolic depolarization and spontaneous activity of cardiac pacemaker cells. I(f) modulation by autonomic transmitters is responsible for the chronotropic regulation of heart rate. Given its role in pacemaking, I(f) has been a major target of investigation aimed to exploit its rate-controlling function in a clinical perspective. In this short review, we describe some of the most recent clinically relevant applications of the concept of I(f)-based pacemaking.

Electrophysiological studies of malaria parasite-infected erythrocytes: current status.

The altered permeability characteristics of erythrocytes infected with malaria parasites have been a source of interest for over 30 years. Recent electrophysiological studies have provided strong evidence that these changes reflect transmembrane transport through ion channels in the host erythrocyte plasma membrane. However, conflicting results and differing interpretations of the data have led to confusion in this field. In an effort to unravel these issues, the groups involved recently came together for a week of discussion and experimentation. In this article, the various models for altered transport are reviewed, together with the areas of consensus in the field and those that require a better understanding.

Short QT syndrome: clinical findings and diagnostic-therapeutic implications.

AIMS: Clinical presentation, occurrence of sudden infant death, and results of the available therapies in the largest group of patients with short QT syndrome (SQTS), studied so far, are reported. METHODS AND RESULTS: Clinical history, physical examination, electrocardiogram (ECG), exercise stress testing, electrophysiological study, morphological evaluation, genetic analysis and therapy results in 29 patients with SQTS and personal and/or familial history of cardiac arrest are reported. The median age at diagnosis was 30 years (range 4-80). In all subjects, structural heart disease was excluded. Eighteen patients were symptomatic (62%): 10 had cardiac arrest (34%) and in 8 (28%) this was the first clinical presentation. Cardiac arrest had occurred in the first months of life in two patients. Seven patients had syncope (24%); 9 (31%) had palpitations with atrial fibrillation documented even in young subjects. At ECG, patients exhibited a QT interval < or = 320 ms and QTc < or = 340 ms. Fourteen patients received an implantable cardioverter-defibrillator (ICD) and 10 hydroquinidine prophylaxis. At a median follow-up of 23 months (range 9-49), one patient received an appropriate shock from the ICD; no patient on hydroquinidine had sudden death or syncope. CONCLUSION: SQTS carries a high risk of sudden death and may be a cause of death in early infancy. ICD is the first choice therapy; hydroquinidine may be proposed in children and in the patients who refuse the implant.

The long QT syndrome family of cardiac ion channelopathies: a HuGE review.

Long QT syndrome (LQTS) refers to a group of "channelopathies"-disorders that affect cardiac ion channels. The "family" concept of syndromes has been applied to the multiple LQTS genotypes, LQT1-8, which exhibit converging mechanisms leading to QT prolongation and slowed ventricular repolarization. The 470+ allelic mutations induce loss-of-function in the passage of mainly K+ ions, and gain-of-function in the passage of Na+ ions through their respective ion channels. Resultant early after depolarizations can lead to a polymorphic form of ventricular tachycardia known as torsade de pointes, resulting in syncope, sudden cardiac death, or near-death (i.e., cardiac arrest aborted either spontaneously or with external defibrillation). LQTS may be either congenital or acquired. The genetic epidemiology of both forms can vary with subpopulation depending on the allele, but as a whole, LQTS appears in every corner of the globe. Many polymorphisms, such as HERG P448R and A915V in Asians, and SCN5A S1102Y in African Americans, show racial-ethnic specificity. At least nine genetic polymorphisms may enhance susceptibility to drug-induced arrhythmia (an "acquired" form of LQTS). Studies have generally demonstrated greater QT prolongation and more severe outcomes among adult females. Gene-gene interactions, e.g., between SCN5A Q1077del mutations and the SCN5A H558B polymorphism, have been shown to seriously reduce ion channel current. While phenotypic ascertainment remains a mainstay in the clinical setting, SSCP and DHPLC-aided DNA sequencing are a standard part of mutational investigation, and direct sequencing on a limited basis is now commercially available for patient diagnosis.

The congenital long QT syndromes from genotype to phenotype: clinical implications.

The long QT syndrome (LQTS) is a genetic disorder responsible for many sudden deaths before age 20. The identification of several LQTS genes, all encoding cardiac ion channels, has had a major impact on the management strategy for both patients and family members. Genotype-guided therapy allows more effective individually tailored therapy. Therapeutic options, including beta-blockers, left cardiac sympathetic denervation, and implantable defibrillators are discussed for patients of known and of unknown genotype. The recent identification of modifier genes which amplify the effect of an LQTS mutation may change the approach to risk stratification.