Fondazione Salvatore Maugeri.Division of Cardiology and Molecular Cardiology. University of Pavia, Pavia Italy AND Cardiovascular Genetics- Langone Medical Center. New York University- New York-USA
Abstract: Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na(+) channel (Na(v)1.5) that produce persistent Na(+) currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Na(v)1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na(+) currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na(+) current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na(+) current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na(+) channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na(+) current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Na(v)1.5 channel.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease occurring in patients with a structurally normal heart: the disease is characterized by life-threatening arrhythmias elicited by stress and emotion. In 2001, the ryanodine receptor was identified as the gene that is linked to CPVT; shortly thereafter, cardiac calsequestrin was implicated in the recessive form of the same disease. It became clear that abnormalities in intracellular Ca(2+) regulation could profoundly disrupt the electrophysiological properties of the heart. In this article, we discuss the molecular basis of the disease and the pathophysiological mechanisms that are impacting clinical diagnosis and management of affected individuals. As of today, the interaction between basic scientists and clinicians to understand CPVT and identify new therapeutic strategies is one of the most compelling examples of the importance of translational research in cardiology.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by life-threatening arrhythmias elicited by adrenergic activation. CPVT is caused by mutations in the cardiac ryanodine receptor gene (RyR2). In vitro studies demonstrated that RyR2 mutations respond to sympathetic activation with an abnormal diastolic Ca(2+) leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2(R4496C+/-) knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) counteracts the effects of adrenergic stimulation resulting in an antiarrhythmic activity. CaMKII inhibition with KN-93 completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2(R4496C+/-) mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2(R4496C+/-) mice, CaMKII inhibition with an autocamtide-2 related inhibitory peptide or with KN-93 blunted triggered activity and transient inward currents induced by isoproterenol. Isoproterenol also enhanced the activity of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), increased spontaneous Ca(2+) release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca(2+) content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2(R4496C+/-) knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca(2+) leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT.
Abstract: Informatics for Integrating Biology and the Bedside (i2b2) is an initiative funded by the NIH that aims at building an informatics infrastructure to support biomedical research. The University of Pavia has recently integrated i2b2 infrastructure with a registry of inherited arrhythmogenic diseases. Within this project, the authors created a novel i2b2 cell, named R Engine Cell, which allows the communication between i2b2 and the R statistical software. As survival analyses are routinely performed by cardiology researchers, the authors have first concentrated on making Kaplan-Meier analyses available within the i2b2 web interface. To this aim, the authors developed a web-client plug-in to select the patient set on which to perform the analysis and to display the results in a graphical, intuitive way. R Engine Cell has been designed to easily support the integration of other R-based statistical analyses into i2b2.
Abstract: This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) intervals.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease causing arrhythmias and sudden death in a structurally normal heart. Ventricular and supraventricular arrhythmias are reproducibly triggered by exercise or acute emotion (i.e. sudden adrenergic activation). Two CPVT variants are known: autosomal dominant caused by mutations in the cardiac ryanodine receptor (RyR2) and autosomal recessive due to calsequestrin mutations (CASQ2). Both RyR2 and CASQ2 have a relevant role in the control of intracellular Ca(2+) fluxes. Thus, CPVT pathogenesis is intrinsically bound to catecholamines and Ca(2+) handling. Cardiac Ca(2+)/calmodulin-dependent protein kinase (CaMKII) is an intracellular mediator of the adrenergic cascade and it specifically modulates Ca(2+) homeostasis. Several lines of evidence suggest that CaMKII not only has a key role in CPVT pathogenesis but is also a promising therapeutic target. Here we will review the available evidence on both these issues and the possible future developments in this area.
Abstract: Inherited arrhythmias can be caused by mutations in the cardiac ryanodine receptor (RyR2). The cellular source of these arrhythmias is unknown. Isolated RyR2(R4496C) mouse ventricular myocytes display arrhythmogenic activity related to spontaneous Ca(2+) release during diastole. On the other hand, recent whole-heart epicardial and endocardial optical mapping data demonstrate that ventricular arrhythmias in the RyR2(R4496C) mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT) originate in the His-Purkinje system, suggesting that Purkinje cells, and not ventricular myocytes, may be the cellular source of arrhythmogenic activity. The relative effect of the RyR2(R4496C) mutation on calcium homeostasis in ventricular myocytes versus Purkinje cells is unknown.
Abstract: Sodium channel blockers are used as gene-specific treatments in long-QT syndrome type 3, which is caused by mutations in the sodium channel gene (SCN5A). Response to treatment is influenced by biophysical properties of mutations.
Abstract: To investigate whether a significantly aberrant expression of circulating placental mRNA genes related with cardiogenesis can be detected at the second trimester of pregnancy.
Abstract: In this article, we will review the appropriate use of genetic testing in those patients suspected to have inherited arrhythmogenic diseases, with specific focus on the indications for testing and the expected probability of positive genotyping.
Abstract: Mutations in the cardiac ryanodine receptor Ca(2+) release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) release in response to SR Ca(2+) overload during beta-adrenergic stimulation. However, whether elevated SR Ca(2+) content--in the absence of protein kinase A activation--affects RyR2 function and arrhythmogenesis in CPVT remains elusive.
Abstract: This article serves as an introductory overview to a thematic review series that will present the latest advancements in the field of inherited arrhythmias. This area of cardiac electrophysiology started approximately 15 years ago thanks to the contribution of Mark Keating and coworkers, who discovered the molecular basis of long QT syndrome. The field rapidly expanded when clinicians, molecular biologists, geneticists, and cellular electrophysiologists, who undertook an impressive collaborative effort to clarify the genetic basis of "cardiac channelopathies." As a result of this hard work, the paradigms for diagnosis and management of patients with inherited arrhythmogenic diseases were substantially modified, demonstrating once more the value of "translational research." As more and more genes have been implicated in the genesis of inherited arrhythmias, we keep broadening our understanding of the complexity of ion channels and their multifaceted regulatory processes. Despite the fact that several discoveries have already been made, the field is facing new challenges that are attracting young investigators who share with the pioneers the ambitious goal of finding new therapies and even a cure for these conditions.
Abstract: The Purkinje fiber network has been proposed as the source of arrhythmogenic Ca(2+) release events in catecholaminergic polymorphic ventricular tachycardia (CPVT), yet evidence supporting this mechanism at the cellular level is lacking.
Abstract: When an ECG shows (or is suspicious for) a Brugada pattern, i.e., the association of a positive terminal deflection and ST segment elevation in the right precordial leads, the cardiologist often faces several problems. Three important questions are raised by this ECG pattern: (1) is this really a Brugada ECG pattern? (2) How can be determined whether this patient is at risk for sudden death? and (3) Should this patient receive an implantable cardioverter-defibrillator (ICD)? The term "Brugada syndrome" should be restricted to patients who have diagnostic ECG changes, as well as a history of symptoms. Asymptomatic subjects, in contrast, should be categorized as having a "Brugada ECG pattern" rather than the syndrome. Diagnostic ECG (type 1) is characterized by a J wave (a terminal positive wave) whose amplitude is > or =2 mm, and a "coved" type ST segment elevation located in the right precordial leads. These signs are usually present in leads V1 and/or V2 (lead V3 is more rarely involved, and is never the only affected one), but occasionally also can be observed in some of the limb leads. Types 2 and 3 ECGs, which are not truly diagnostic of Brugada pattern, are characterized by a "saddle back" ST segment elevation, that is > or =1 mm in type 2 and <1 mm in type 3. In Brugada ECG pattern, the QRS complex characteristically shows a positive terminal deflection that mimics an r' prime wave (the wave occurring in right bundle branch block), in the right precordial leads. Actually, it is a J wave that is very similar to the "Osborn" one observed during hypothermia. The J wave of Brugada ECG pattern is generated by a voltage gradient across the myocardial wall of the right ventricular outflow tract. This abnormal potential can be recorded only by electrodes located very close to the site where that phenomenon is originating. Displacement of the right precordial leads electrodes one or two intercostal spaces above their normal positions may, at times, disclose the diagnostic pattern when conventional leads, recorded at the fourth intercostal space, are non-diagnostic or even normal. High right precordial leads should be recorded whenever standard V1-V3 leads raise the suspicion of Brugada pattern. For example, when a relatively large positive terminal wave, even of low amplitude, is recorded, placing high right precordial leads is an option that should be considered. The ECG may show a marked variation over time, ranging from the typical pattern to a completely normal ECG and back again. In subjects with a non-diagnostic ECG, a pharmacological test with sodium channel blockers may disclose the typical Brugada pattern. In order to establish the diagnosis, several conditions that can mimic Brugada pattern must be excluded. These include right bundle branch block, early repolarization, acute myocardial ischemia, pericarditis, hypercalcemia, hyperkalemia, hypothermia and primary right ventricular diseases, particularly arrhythmogenic right ventricular dysplasia. Some drugs (e.g., some antiarrhythmic drugs, psychotropic agents or antihistamines), hyperthermia and enhanced vagal tone, as it occurs after a full meal, may render Brugada pattern more evident on the ECG. Typical ventricular arrhythmia in Brugada syndrome is a polymorphic ventricular tachycardia, that can evolve into ventricular fibrillation; its mechanism is assumed to be phase 2 reentry. Monomorphic ventricular tachycardia is rarely seen. Atrial fibrillation occurs more frequently in patients with the Brugada ECG pattern than in the general population. A mutation in the SCN5A gene, which encodes the alpha subunit of the cardiac sodium channel, is found in about 20% of the subjects with Brugada pattern; mutations in other genes have less frequently been described. Genetic testing is not very helpful in formulating the diagnosis, but when a mutation is found it could be useful to extend testing to first degree relatives, enabling early detection of abnormal gene carriers. Patients who have experienced an aborted sudden death have a high risk of recurrence and should receive an ICD. A history of syncope, spontaneous type 1 ECG and male sex, not family history of sudden death, are independent risk factors. The role of programmed ventricular stimulation in risk stratification remains the subject of debate. Asymptomatic patients with a Brugada ECG pattern should: (1) receive adequate information on current knowledge concerning this topic, (2) be given the list of forbidden drugs, (3) be informed to promptly treat hyperthermia, (4) be informed that clinical evaluation should be extended to their first degree relatives, 5) undergo regular cardiology follow-up. Also in this group the role of programmed ventricular stimulation in risk stratification is debated. Subjects showing a Brugada pattern after a pharmacological challenge should be followed-up with ECG and 12-lead Holter monitoring, if available, to identify the appearance of spontaneous type 1 ECG. Symptoms should be promptly reported.
Abstract: mutations of the ryanodine receptor (RyR) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These mutations predispose to the generation of Ca waves and delayed afterdepolarizations during adrenergic stimulation. Ca waves occur when either sarcoplasmic reticulum (SR) Ca content is elevated above a threshold or the threshold is decreased. Which of these occurs in cardiac myocytes expressing CPVT mutations is unknown.
Abstract: A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath.
Abstract: The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study--SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35-0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self-harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups.
Abstract: Beta-blocker efficacy in long-QT syndrome type 1 is good but variably reported, and the causes of cardiac events despite beta-blocker therapy have not been ascertained.
Abstract: Since the identification of the first SCN5A mutation associated with long QT syndrome in 1995, several mutations in this gene for the alpha subunit of the cardiac sodium channel have been identified in a heterogeneous subset of cardiac rhythm syndromes, including Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation and dilated cardiomyopathy. Robust clinical evidence has been accompanied by bench studies performed in different models spanning from in vitro expression systems to transgenic mice. Together, these studies have helped establish genotype-phenotype correlations and have shaped our understanding of the role of the cardiac sodium channel in health and in disease. Remarkably, these advances in understanding have impacted on clinical management by allowing us to start developing gene-specific risk stratification schemes and mutation-specific management strategies. In this Review, we summarize the current understanding of the molecular mechanism of SCN5A-associated inherited arrhythmias, focusing on the most recent development of mutation-specific management in SCN5A-associated long QT syndrome type 3. We also briefly discuss arrhythmia-causing mutations in the genes encoding the beta subunit of the cardiac sodium channel and in those encoding proteins in the associated macromolecular complex.
Abstract: The Brugada syndrome continues to spark intensive investigation since its earliest description. New insight has been gained regarding the genetic, histopathologic, and metabolic mechanisms of this heritable channelopathy - a heterogeneity that is reflected in the diverse clinical presentation. In this review, we will focus on clinical spectrum of patients with a Brugada ECG pattern with a special focus on diagnosis and risk stratification.
Abstract: Charcot-Marie-Tooth disease (CMTD) is a hereditary demyelinating peripheral neuropathy clinically presenting with sensory and motor defects, but rarely affecting cardiac function. Long QT syndrome (LQTS) is a congenital or acquired cardiovascular disorder characterized by ventricular depolarization defect. No studies reported CMTD in association with LQTS. We describe a child and his family who had both CMT1A and LQTS.
Abstract: Thanks to the contribution of molecular genetics, the genetic bases, the pathogenesis and genotype-phenotype correlation of diseases such as the long QT syndrome and catecholaminergic polymorphic ventricular tachycardia have been progressively unveiled and show an extremely high degree of genetic heterogeneity. Data from clinical registries are summarized together with the recommendations provided in clinical practice guidelines for management of patients with these diseases. Furthermore the evidence supporting the importance of genetic analysis for risk stratification and therapy selections is reviewed.
Abstract: The decision of whether and when to replace a device in response to an "advisory" letter requires careful consideration, because device replacement carries related risks and is influenced by the clinical characteristics of the patient.
Abstract: The year 2001 has been pivotal for the identification of the molecular bases of catecholaminergic polymorphic ventricular tachycardia (CPVT): a life-threatening genetic disease that predisposes young individuals with normal cardiac structure to cardiac arrest. Interestingly CPVT has been linked to mutations in genes encoding the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2): two fundamental proteins involved in regulation of intracellular Ca(2+) in cardiac myocytes. The critical role of the two proteins in the heart has attracted interests of the scientific community so that networks of investigators have embarked in translational studies to characterize in vitro and in vivo the mutant proteins. Overall in the last seven years the field has substantially advanced but considerable controversies still exist on the consequences of RyR2 and CASQ2 mutations and on the modalities by which they precipitate cardiac arrhythmias. With so many questions that need to be elucidated it is expected that in the near future the field will remain innovative and stimulating. In this review we will outline how research has advanced in the understanding of CPVT and we will present how the observations made have disclosed novel arrhythmogenic cascades that are likely to impact acquired heart diseases.
Abstract: Cardiac ryanodine receptor (RyR2) mutations are associated with autosomal dominant catecholaminergic polymorphic ventricular tachycardia, suggesting that alterations in Ca(2+) handling underlie this disease. Here we analyze the underlying Ca(2+) release defect that leads to arrhythmia in cardiomyocytes isolated from heterozygous knock-in mice carrying the RyR2(R4496C) mutation. RyR2(R4496C-/-) littermates (wild type) were used as controls. [Ca(2+)](i) transients were obtained by field stimulation in fluo-3-loaded cardiomyocytes and viewed using confocal microscopy. In our basal recording conditions (2-Hz stimulation rate), [Ca(2+)](i) transients and sarcoplasmic reticulum Ca(2+) load were similar in wild-type and RyR2(R4496C) cells. However, paced RyR2(R4496C) ventricular myocytes presented abnormal Ca(2+) release during the diastolic period, viewed as Ca(2+) waves, consistent with the occurrence of delayed afterdepolarizations. The occurrence of this abnormal Ca(2+) release was enhanced at faster stimulation rates and by beta-adrenergic stimulation, which also induced triggered activity. Spontaneous Ca(2+) sparks were more frequent in RyR2(R4496C) myocytes, indicating increased RyR2(R4496C) activity. When permeabilized cells were exposed to different cytosolic [Ca(2+)](i), RyR2(R4496C) showed a dramatic increase in Ca(2+) sensitivity. Isoproterenol increased [Ca(2+)](i) transient amplitude and Ca(2+) spark frequency to the same extent in wild-type and RyR2(R4496C) cells, indicating that the beta-adrenergic sensitivity of RyR2(R4496C) cells remained unaltered. This effect was independent of protein expression variations because no difference was found in the total or phosphorylated RyR2 expression levels. In conclusion, the arrhythmogenic potential of the RyR2(R4496C) mutation is attributable to the increased Ca(2+) sensitivity of RyR2(R4496C), which induces diastolic Ca(2+) release and lowers the threshold for triggered activity.
Abstract: Recent data suggest that sub-clinical structural abnormalities may be part of the Brugada syndrome (BrS) phenotype, a disease traditionally thought to occur in the structurally normal heart. In this study, we carried out detailed assessment of cardiac morphology and function using cardiac magnetic resonance imaging (CMRI).
Abstract: Identification of mutations in cardiac ion channel genes concurs to the diagnosis of long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. However, because availability of genetic screening is still limited and reimbursement policies are lacking, there is a need of evidence-based criteria to prioritize access to genetic testing for these diseases.
Abstract: Three decades of ongoing research into the identification of genes responsible for both cardiomyopathies and ion channel diseases has facilitated a progressive understanding of the pathophysiology of inherited arrhythmogenic diseases. Recent discoveries in the area of genetics promise to significantly change the current clinical practice of cardiology, as rapid advances in technology and a coincident reduction of costs associated with sequencing have pushed the "translation" of genomic information from bench to bedside. In turn, clinicians have at their disposal new tools for more accurate diagnosis of diseases, as well as for better calculation of health risks for affected families. It is clear, however, that the integration of genetic analysis into frontline clinical cardiology has not yet occurred, especially for heritable cardiomyopathic processes; no one simplified method exists for diagnosing these complex cardiac disease states. It therefore is important to assess the present and future roles of genetic analysis and counseling in clinical practice and how to assist the transition of genetic screening into current care to ensure the appropriate practical use of genetic tests in the routine clinical setting. The purpose of this discussion is to provide a concise review of recent developments in the field of heritable cardiomyopathies, with specific regard to genetic testing and genetic counseling.
Abstract: Heart failure (HF) patients increasingly receive device therapy, either an implantable cardioverter defibrillator (ICD) or a biventricular pacemaker, also called cardiac resynchronization therapy (CRT), or a CRT device with an ICD (CRT-D). However, epidemiological data on the use of device therapy in Europe are limited.
Abstract: The European cardiac resynchronization therapy (CRT) survey is a joint initiative taken by the Heart Failure Association and the European Heart Rhythm Association of the European Society of Cardiology. The primary aim of this survey is to describe current European practice associated with CRT implantations.
Abstract: This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy).
Abstract: Worldwide, the Brugada syndrome has been recognized as an important cause of sudden cardiac death in individuals at a relatively young age. Importantly, many drugs have been reported to induce the characteristic Brugada syndrome-linked ECG abnormalities and/or (fatal) ventricular tachyarrhythmias.
Abstract: In the 8 years since the discovery of the genetic bases of catecholaminergic polymorphic ventricular tachycardia (CPVT), we have witnessed a remarkable improvement of knowledge on arrhythmogenic mechanisms involving disruption of cardiac Ca(2+) homeostasis. Studies on the consequences of RyR2 and CASQ2 mutations in cellular systems and mouse models have shed new light on pathways that are also implicated in arrhythmias occurring in highly prevalent diseases, such as heart failure. This research track has also led to the identification of therapeutic targets of potential clinical impact to abate the burden of sudden death in CPVT. Here, we review the current knowledge on the pathophysiology of CPVT also highlighting the existing controversies and possible future development.
Abstract: Previous studies that assessed the risk of life-threatening cardiac events in patients with congenital long-QT syndrome (LQTS) have focused mainly on the first 4 decades of life, whereas the clinical course of this inherited cardiac disorder in the older population has not been studied.
Abstract: Two missense mutations, R33Q and L167H, of hCASQ2 (human cardiac calsequestrin), a protein segregated to the lumen of the sarcoplasmic reticulum, are linked to the autosomal recessive form of CPVT (catecholaminergic polymorphic ventricular tachycardia). The effects of these mutations on the conformational, stability and Ca(2+) sensitivity properties of hCASQ2, were investigated. Recombinant WT (wild-type) and mutant CASQ2s were purified to homogeneity and characterized by spectroscopic (CD and fluorescence) and biochemical (size-exclusion chromatography and limited proteolysis) methods at 500 and 100 mM KCl, with or without Ca(2+) at a physiological intraluminal concentration of 1 mM; Ca(2+)-induced polymerization properties were studied by turbidimetry. In the absence of Ca(2+), mutations did not alter the conformation of monomeric CASQ2. For L167H only, at 100 mM KCl, emission fluorescence changes suggested tertiary structure alterations. Limited proteolysis showed that amino acid substitutions enhanced the conformational flexibility of CASQ2 mutants, which became more susceptible to tryptic cleavage, in the order L167H>R33Q>WT. Ca(2+) at a concentration of 1 mM amplified such differences: Ca(2+) stabilized WT CASQ2 against urea denaturation and tryptic cleavage, whereas this effect was reduced in R33Q and absent in L167H. Increasing [Ca(2+)] induced polymerization and precipitation of R33Q, but not that of L167H, which was insensitive to Ca(2+). Based on CASQ2 models, we propose that the Arg(33)-->Gln exchange made the Ca(2+)-dependent formation of front-to-front dimers more difficult, whereas the Leu(167)-->His replacement almost completely inhibited back-to-back dimer interactions. Initial molecular events of CPVT pathogenesis begin to unveil and appear to be different depending upon the specific CASQ2 mutation.
Abstract: Magnetic resonance (MR) imaging has unparalleled soft-tissue imaging capabilities. The presence of devices such as pacemakers and implantable cardioverter-defibrillators (ICDs), however, was historically considered a contraindication to MR imaging. We summarize the potential hazards of the device-MR environment interaction, and present updated information regarding in vitro and in vivo experiments suggesting that certain pacemaker and ICD systems may indeed be MR-safe. Recent reports on several hundred patients with implantable pacemakers and ICDs who underwent MR scan safely indicate that, under certain conditions, individuals with these implanted systems may benefit from MR imaging. We believe that, on a case-by-case basis, the diagnostic benefit from MR imaging outweighs the presumed risks for some pacemaker and ICD patients. Thus for some patients, the risks presented by MR imaging under specific, characterized scanning and monitoring conditions may be acceptable given the diagnostic benefit of this powerful imaging modality. This may have major clinical implications on current imaging practice. A strategy for the performance of MR imaging in these individuals is proposed.
Abstract: Development of cardiac arrhythmias in several degenerative cardiac disorders such as heart failure is precipitated by abnormalities in intracellular calcium regulation. Recently, the identification of mutations in proteins responsible for the control of intracellular calcium has been associated with an inherited arrhythmogenic syndrome called catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we review the current knowledge about the molecular pathophysiology of CPVT and we discuss some potentially innovative strategies for controlling calcium-handling abnormalities in CPVT that may provide novel therapeutic options for affected patients.
Abstract: The luminal Ca2+ regulation of cardiac ryanodine receptor (RyR2) was explored at the single channel level. The luminal Ca2+ and Mg2+ sensitivity of single CSQ2-stripped and CSQ2-associated RyR2 channels was defined. Action of wild-type CSQ2 and of two mutant CSQ2s (R33Q and L167H) was also compared. Two luminal Ca2+ regulatory mechanism(s) were identified. One is a RyR2-resident mechanism that is CSQ2 independent and does not distinguish between luminal Ca2+ and Mg2+. This mechanism modulates the maximal efficacy of cytosolic Ca2+ activation. The second luminal Ca2+ regulatory mechanism is CSQ2 dependent and distinguishes between luminal Ca2+ and Mg2+. It does not depend on CSQ2 oligomerization or CSQ2 monomer Ca2+ binding affinity. The key Ca2+-sensitive step in this mechanism may be the Ca2+-dependent CSQ2 interaction with triadin. The CSQ2-dependent mechanism alters the cytosolic Ca2+ sensitivity of the channel. The R33Q CSQ2 mutant can participate in luminal RyR2 Ca2+ regulation but less effectively than wild-type (WT) CSQ2. CSQ2-L167H does not participate in luminal RyR2 Ca2+ regulation. The disparate actions of these two catecholaminergic polymorphic ventricular tachycardia (CPVT)-linked mutants implies that either alteration or elimination of CSQ2-dependent luminal RyR2 regulation can generate the CPVT phenotype. We propose that the RyR2-resident, CSQ2-independent luminal Ca2+ mechanism may assure that all channels respond robustly to large (>5 muM) local cytosolic Ca2+ stimuli, whereas the CSQ2-dependent mechanism may help close RyR2 channels after luminal Ca2+ falls below approximately 0.5 mM.
Abstract: The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified.
Abstract: Implanted biventricular pacemakers (cardiac resynchronisation therapy, CRT) with or without implantable cardioverter defibrillators (ICD) improve survival and morbidity in some patients with chronic heart failure (CHF) who are optimally treated with pharmacologic agents according to current guidelines. Correspondingly, ICDs improve survival. However, there is only limited evidence for device treatment in certain patient subgroups, such as the impact of ICD on outcomes in patients with reduced ejection fraction in New York Heart Association (NYHA) Class I or IV heart failure. Similarly, limited evidence exists for CRT in patients with only modest QRS prolongation or only modestly reduced ejection fraction. Despite evidence for a beneficial effect of device therapy in CHF, only a minority of eligible patients are currently offered these options. Multiple reasons contribute to the underuse of these potentially life-saving therapies. A lack of adherence to guidelines by health care professionals is an important barrier. Clearly, efforts should be made to improve the standard of care and to familiarise all physicians involved in managing CHF patients with the indications and potential efficacy of these devices. Increased collaboration between structured heart failure care and pacemaker clinics as well as between electrophysiologists, heart failure clinicians, and primary care physicians is required. Such team collaborations should lead to improved care with reduced mortality and morbidity and increased cost effectiveness. Treatment strategy should be based on a structured approach tailored to local practice and national priorities.
Abstract: Sudden death of a sibling is thought to be associated with greater risk of death in long QT syndrome (LQTS). However, there is no evidence of such an association.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by life threatening arrhythmias elicited by physical and emotional stress in young individuals. The recessive form of CPVT is associated with mutation in the cardiac calsequestrin gene (CASQ2). We engineered and characterized a homozygous CASQ2(R33Q/R33Q) mouse model that closely mimics the clinical phenotype of CPVT patients. CASQ2(R33Q/R33Q) mice develop bidirectional VT on exposure to environmental stress whereas CASQ2(R33Q/R33Q) myocytes show reduction of the sarcoplasmic reticulum (SR) calcium content, adrenergically mediated delayed (DADs) and early (EADs) afterdepolarizations leading to triggered activity. Furthermore triadin, junctin, and CASQ2-R33Q proteins are significantly decreased in knock-in mice despite normal levels of mRNA, whereas the ryanodine receptor (RyR2), calreticulin, phospholamban, and SERCA2a-ATPase are not changed. Trypsin digestion studies show increased susceptibility to proteolysis of mutant CASQ2. Despite normal histology, CASQ2(R33Q/R33Q) hearts display ultrastructural changes such as disarray of junctional electron-dense material, referable to CASQ2 polymers, dilatation of junctional SR, yet normal total SR volume. Based on the foregoings, we propose that the phenotype of the CASQ2(R33Q/R33Q) CPVT mouse model is portrayed by an unexpected set of abnormalities including (1) reduced CASQ2 content, possibly attributable to increased degradation of CASQ2-R33Q, (2) reduction of SR calcium content, (3) dilatation of junctional SR, and (4) impaired clustering of mutant CASQ2.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant form of arrhythmogenic disorder characterized by exercise- or emotional-induced polymorphic ventricular tachycardia in the absence of detectable structural heart disease. Because of the typical pattern of arrhythmias (bidirectional ventricular tachycardia and the occurrence and severity of arrhythmia correlated well with exercise workload) during exercise stress test, CPVT can be identified promptly. Molecular genetic screening of the genes encoding the cardiac ryanodine receptor and calsequestrin is critical to confirm uncertain diagnosis of CPVT. With the exception of beta-blockers, no pharmacologic therapy of proven effectiveness is available: although beta-blockers reduce the occurrence of ventricular tachycardia, 30% of patients treated with beta-blockers still experience cardiac arrhythmias and eventually require implantable cardioverter defibrillator implantation to prevent cardiac arrest.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly lethal form of inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic ventricular tachycardia. The mutations in cardiac ryanodine receptor and calsequestrin genes are responsible for the autosomal dominant and recessive variants of CPVT, respectively. The clinical presentation encompasses exercise- or emotion-induced syncopal events and a distinctive pattern of reproducible, stress-related, bidirectional ventricular tachycardia in the absence of both structural heart disease and a prolonged QT interval. The mortality rate in untreated individuals is 30-50% by age 40. Clinical evaluation by exercise stress testing and holter monitoring and genetic screening can facilitate early diagnosis. beta-adrenergic blockers are the most effective pharmacological treatment in controlling arrhythmias in CPVT patients, yet about 30% of patients still experience cardiac arrhythmias and eventually require an implantable cardioverter defibrillator.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by adrenergically mediated polymorphic ventricular tachyarrhythmias. Genetic investigations have identified two variants of the disease: an autosomal dominant form associated with mutations in the gene encoding the cardiac ryanodine receptor (RyR2) and a recessive form associated with homozygous mutations in the gene encoding the cardiac isoform of calsequestrin (CASQ2). Functional characterization of mutations identified in the RyR2 and CASQ2 genes has demonstrated that CPVT are caused by derangements of the control of intracellular calcium. Investigations in a knock-in mouse model have shown that CPVT arrhythmias are initiated by delayed afterdepolarizations and triggered activity. In the present article, we review clinical and molecular understanding of CPVT and discuss the most recent approaches to develop novel therapeutic strategies for the disease.
Abstract: The Brugada syndrome has been an area of intensive investigation since its earliest description in 1992, both on a clinical and on a basic research level. In this review, we will focus on recent achievements in the molecular dissection of the disease pathophysiology and on large multicenter studies dealing with prognostic markers and the natural history of the Brugada syndrome.
Abstract: Atypical antipsychotics are the treatment of choice for patients with schizophrenia. They are generally better tolerated than conventional antipsychotics since most do not cause debilitating extrapyramidal symptoms. They are associated though with an array of cardiovascular adverse events that may affect morbid-mortality of schizophrenic patients. Orthostatic hypotension, electrocardiographic changes and metabolic syndrome (MS) are the main cardiovascular effects of atypical antipsychotics. They contribute to the overall disease burden associated with schizophrenia even though the benefit risk of such treatments still is highly favourable. We aim to review the main cardiovascular side effects of new atypical oral antipsychotics, the pharmacological mechanisms involved, and to which drugs they are particularly attributed.
Abstract: The effects of two SCN5A mutations (Y1795C, Y1795H), previously identified in one Long QT syndrome type 3 (LQT3) and one Brugada syndrome (BrS) families, were investigated by means of numerical modeling of ventricular action potential (AP). A Markov model capable of reproducing a wild-type as well as a mutant sodium current (I(Na)) was identified and was included into the Luo-Rudy ventricular cell model for action potential (AP) simulation. The characteristics of endocardial, midmyocardial, and epicardial cells were reproduced by differentiating the transient outward current (I(TO)) and the ratio of slow delayed rectifier potassium (I(Ks)) to rapid delayed rectifier current (I(Kr)). Administration of flecainide and mexiletine was simulated by appropriately modifying I(Na), calcium current (I(Ca)), I(TO), and I(Kr). Y1795C prolonged AP in a rate-dependent manner, and early afterdepolarizations (EADs) appeared during bradycardia in epicardial and midmyocardial cells; flecainide and mexiletine shortened AP and abolished EADs. Y1795H resulted in minimal changes in the APs; flecainide but not mexiletine induced APs heterogeneity across the ventricular wall that accounts for the ST segment elevation induced by flecainide in Y1795H carriers. The AP abnormalities induced by Y1795H and Y1795C can explain the clinically observed surface ECG phenotype. For the first time by modeling the effects of flecainide and mexiletine, we are able to gather mechanistic insights on the response to drugs administration observed in affected patients.
Abstract: The aims of this study were: 1) to evaluate risk factors influencing the clinical course of mutation-confirmed adult patients with long QT syndrome (LQTS), 2) to study life-threatening cardiac events as a specific end point in adults, and 3) to examine the protective effect of beta-blocker therapy on cardiac events in adult LQTS patients with known cardiac channel mutations.
Abstract: This study was designed to investigate the clinical course of women with long QT syndrome (LQTS) throughout their potential childbearing years.
Abstract: Atrial fibrillation (AF), the most common atrial arrhythmia, has a complex aetiology and causes relevant morbidity and mortality due to different mechanisms, including but not limited to stroke, heart failure, and tachy- or bradyarrhythmia. Current therapeutic options (rate control, rhythm control, antithrombotic therapy, 'upstream therapy') only prevent a part of this burden of disease. New treatment modalities are therefore currently under evaluation in clinical trials. Given the multifold clinical consequences of AF, controlled trials in AF patients should assess the effect of therapy in each of the main outcome domains. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains, namely death, stroke, symptoms and quality of life, rhythm, left ventricular function, cost, and emerging outcome parameters. In addition to these 'requirements' for outcome assessment in AF trials, further outcome parameters are described in each outcome domain. In addition to a careful selection of a relevant primary outcome parameter, coverage of outcomes in all major domains of AF-related morbidity and mortality is desirable for any clinical trial in AF.
Abstract: Atrial fibrillation (AF), the most common atrial arrhythmia, has a complex aetiology and causes relevant morbidity and mortality due to different mechanisms, including but not limited to stroke, heart failure, and tachy- or bradyarrhythmia. Current therapeutic options (rate control, rhythm control, antithrombotic therapy, 'upstream therapy') only prevent a part of this burden of disease. Several new treatment modalities are therefore under evaluation in controlled trials. Given the multifold clinical consequences of AF, trials in AF patients should assess the effect of therapy in each of the main outcome domains. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains, namely death, stroke, symptoms and quality of life, rhythm, left ventricular function, cost, and emerging outcome parameters. In addition to these 'requirements' for outcome assessment in AF trials, further, more detailed outcome parameters are described. In addition to a careful selection of a relevant primary outcome parameter, coverage of outcomes in all major domains of AF-related morbidity and mortality is desirable for any clinical trial in AF.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca2+ release through defective ryanodine receptor (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol's solution, and patch clamping in a knockin (RyR2/RyR2(R4496C)) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2(R4496C) and in 9% of 11 wild-type (P=0.03) littermates perfused with Ca2+and isoproterenol; 66% of 12 RyR2/RyR2(R4496C) and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias (P=0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His-Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol's solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2(R4496C) mice. Under current clamp, single Purkinje cells from RyR2/RyR2(R4496C) mouse hearts generated delayed afterdepolarization-induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His-Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT.
Abstract: Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations.
Abstract: Cardiologists are involved in evaluating the eligibility of athletes to practise competitive sport and they should therefore be able to identify the electrocardiographic markers of long QT syndrome (LQTS) and short QT syndrome (SQTS). An overview of the clinical criteria to perform measurement of QT interval on 12-lead electrocardiogram is provided herein and several instances in which the diagnosis of either LQTS or SQTS may leave the clinician uncertain are discussed. A critical appraisal of current recommendations for eligibility to competitive sport is also provided as well as some of the authors' personal opinions on the practice of recreational activities in patients with abnormal repolarization.
Abstract: A significant number of preventable cardiac deaths in infancy and childhood are due to long QT syndrome (LQTS) and to unrecognized neonatal congenital heart diseases (CHDs). Both carry a serious risk for avoidable mortality and morbidity but effective treatments exist to prevent lethal arrhythmias or to allow early surgical correction before death or irreversible cardiac damage. As an electrocardiogram (ECG) allows recognition of LQTS and of some of the CHDs that have escaped medical diagnosis, and as LQTS also contributes to sudden infant death syndrome, we have analysed the cost-effectiveness of a nationwide programme of neonatal ECG screening. Our primary analysis focused on LQTS alone; a secondary analysis focused on the possibility of identifying some CHDs also.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2(R4496C+/-)). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (n=20) in WT but induced DADs in 21 of 33 (63%) RyR2(R4496C+/-) myocytes (P=0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2(R4496C+/-) myocytes (P=0.001). DADs and triggered activity were abolished by ryanodine (10 micromol/L) but not by K201 (1 micromol/L or 10 micromol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2(R4496C+/-) mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2-FKBP12.6 interaction both in WT and RyR2(R4496C+/-) either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2(R4496C+/-) myocytes and ventricular arrhythmias in RyR2(R4496C+/-) mice; and (3) RyR2-FKBP12.6 interaction in RyR2(R4496C+/-) is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex.
Abstract: Genetic analysis can be performed to identify the molecular substrate of inherited arrhythmogenic diseases; however, the role of this information in helping the management of patients is still debated. Here, we support the view that the practical value of genetic analysis is different in the various inherited conditions and that it is strongly influenced by the amount of information available in each disease about genotype-phenotype correlations. In some diseases, clinical management of patients is profoundly affected by the type of the underlying genetic defect; therefore, in these conditions, there is a high priority to introduce genetic analysis into clinical practice. In the absence of genotype-phenotype correlations, genetic testing still can be very useful when there is a clinical advantage in establishing presymptomatic diagnosis or when screening of family members may point to reproductive counseling. Finally, there is a high priority for introducing genetic testing for those genetic diseases in which a limited number of genes allow a high yield of successfully genotyped patients. We have developed a "score" to compare the value of genetic testing in arrhythmogenic diseases and to convey our view that the clinical role of genetic analysis is different in the various inherited cardiomyopathies and channelopathies. Healthcare authorities should become responsive to the advancement of knowledge in this field and should help facilitate access to genotyping for families affected by those conditions in which genetic analysis provides useful information for clinical management.
Abstract: The European Society of Cardiology (ESC) organized a one-day workshop with clinicians, health economic experts, and health technology appraisal experts to discuss the equity of patient access to novel medical technologies in Europe. Two index technologies were considered: implantable cardioverter defibrillators (ICDs) and drug-eluting stents (DES). The use of ICDs range from 35 implants/million population in Portugal to 166 implants/million population in Germany, whereas for implants of DES (as percentage of total stents) it is lowest in Germany at 14% and high in Portugal at 65%. These differences can in part be explained by a lack of structured implementation of guidelines, the direct cost in relation to the overall healthcare budget, and to differences in procedures and models applied by Health Technology Assessment (HTA) agencies in Europe. The workshop participants concluded that physicians need to be involved in a more structured way in HTA and need to become better acquainted with its methods and terminology. Clinical guidelines should be systematically translated, explained, disseminated, updated, and adopted by cardiologists in Europe. Clinically appropriate, consistent and transparent health economic models need to be developed and high-quality international outcome and cost data should be used. A process for funding of a technology should be developed after a positive recommendation from HTA agencies. Both the ESC and the national cardiac societies should build-up health economic expertise and engage more actively in discussions with stakeholders involved in the provision of healthcare.
Abstract: In the last few years, major advancement has been made in the understanding of the genetic basis of inherited arrhythmogenic diseases. Interestingly, the information obtained with the application of molecular genetics to these diseases is now influencing their clinical management, allowing gene-specific risk stratification and gene-specific management. The first attempt for a gene-specific therapy was made in 1995 with the use of mexiletine in long-QT syndrome (LQTS) patients with mutations in the SCN5A gene. Since then, several investigators have proposed novel therapeutic approaches based on the identification of the functional consequences of genetic mutations. In some instances, these novel therapies have already been introduced in clinical practice, and data are being collected to establish their long-term efficacy. In this review, we will summarize the current understanding of the molecular bases of inherited arrhythmias, with a specific focus toward discussing the most recent advancements toward the development of gene-specific therapies.
Abstract: Four distinct mutations in the human cardiac calsequestrin gene (CASQ2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). The mechanisms leading to the clinical phenotype are still poorly understood because only 1 CASQ2 mutation has been characterized in vitro.
Abstract: Cardiovascular diseases (CVD) are the leading cause of mortality both in men and women. In Europe, about 55% of all females' deaths are caused by CVD, especially coronary heart disease and stroke. Unfortunately, however, the risk of heart disease in women is underestimated because of the perception that women are 'protected' against ischaemic heart disease. What is not fully understood is that women during the fertile age have a lower risk of cardiac events, but this protection fades after menopause thus leaving women with untreated risk factors vulnerable to develop myocardial infarction, heart failure, and sudden cardiac death. Furthermore, clinical manifestations of ischaemic heart disease in women may be different from those commonly observed in males and this factor may account for under-recognition of the disease. The European Society of Cardiology has recently initiated an extensive 'Women at heart' program to coordinate research and educational initiatives on CVD in women. A Policy Conference on CVD in Women was one of the first steps in the development of this program. The objective of the conference was to collect the opinion of experts in the field coming from the European Society of Cardiology member countries to: (1) summarize the state-of-the-art from an European perspective; (2) to identify the scientific gaps on CVD in women; and (3) to delineate the strategies for changing the misperception of CVD in women, improving risk stratification, diagnosis, and therapy from a gender perspective and increasing women representation in clinical trials. The Policy Conference has provided the opportunity to review and comment on the current status of knowledge on CVD in women and to prioritize the actions needed to advance this area of knowledge in cardiology. In the preparation of this document we intend to provide the medical community and the stakeholders of this field with an overview of the more critical aspects that have emerged during the discussion. We also propose some immediate actions that should be undertaken with the hope that synergic activities will be implemented at European level with the support of national health care authorities.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2) genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact as parts of a multimolecular Ca(2+)-signaling complex; however, direct evidence for such interactions and their potential significance to myocardial function remain to be determined. We identified a novel CASQ2 mutation in a young female with a structurally normal heart and unexplained syncopal episodes. This mutation results in the nonconservative substitution of glutamine for arginine at amino acid 33 of CASQ2 (R33Q). Adenoviral-mediated expression of CASQ2(R33Q) in adult rat myocytes led to an increase in excitation-contraction coupling gain and to more frequent occurrences of spontaneous propagating (Ca2+ waves) and local Ca2+ signals (sparks) with respect to control cells expressing wild-type CASQ2 (CASQ2WT). As revealed by a Ca2+ indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized myocytes, the increased occurrence of spontaneous Ca2+ sparks and waves was associated with a dramatic decrease in intra-SR [Ca2+]. Recombinant CASQ2WT and CASQ2R33Q exhibited similar Ca(2+)-binding capacities in vitro; however, the mutant protein lacked the ability of its WT counterpart to inhibit RyR2 activity at low luminal [Ca2+] in planar lipid bilayers. We conclude that the R33Q mutation disrupts interactions of CASQ2 with the RyR2 channel complex and impairs regulation of RyR2 by luminal Ca2+. These results show that intracellular Ca2+ cycling in normal heart relies on an intricate interplay of CASQ2 with the proteins of the RyR2 channel complex and that disruption of these interactions can lead to cardiac arrhythmia.
Abstract: A task force has been established by the European Society of Cardiology to investigate the role of progenitor/stem cell therapy in the treatment of cardiovascular disease. This article is the consensus of this group, of what clinical studies are needed in this field, and the challenges to be addressed in the translation of progenitor/stem cell biology to repair of the heart.
Abstract: The integration between molecular biology and clinical practice requires the achievement of fundamental steps to link basic science to diagnosis and management of patients. In the last decade, the study of genetic bases of human diseases has achieved several milestones, and it is now possible to apply the knowledge that stems from the identification of the genetic substrate of diseases to clinical practice. The first step along the process of linking molecular biology to clinical medicine is the identification of the genetic bases of inherited diseases. After this important goal is achieved, it becomes possible to extend research to understand the functional impairments of mutant protein(s) and to link them to clinical manifestations (genotype-phenotype correlation). In genetically heterogeneous diseases, it may be possible to identify locus-specific risk stratification and management algorithms. Finally, the most ambitious step in the study of genetic disease is to discover a novel pharmacological therapy targeted at correcting the inborn defect (locus-specific therapy) or even to "cure" the DNA abnormality by replacing the defective gene with gene therapy. At present, this curative goal has been successful only for very few diseases. In the field of inherited arrhythmogenic diseases, several genes have been discovered, and genetics is now emerging as a source of information contributing not only to a better diagnosis but also to risk stratification and management of patients. The functional characterization of mutant proteins has opened new perspectives about the possibility of performing gene-specific or mutation-specific therapy. In this chapter, we will briefly summarize the genetic bases of inherited arrhythmogenic conditions and we will point out how the information derived from molecular genetics has influenced the "optimal use of traditional therapies" and has paved the way to the development of gene-specific therapy.
Abstract: The European Society of Cardiology (ESC) has recently promoted the "Women at Heart" program in order to organize initiatives targeted at promoting research and education in the field of cardiovascular diseases in women. Comparisons of the gender differences in specific disease and treatment trends across Europe are provided by analyzing data from the Euro Heart Surveys. A Policy Conference has been organized with the objective to summarize the state of the art from an European perspective, to identify the scientific gaps and to delineate the strategies for changing the misperception of cardiovascular diseases in women, improving risk stratification, diagnosis, and therapy from a gender perspective and increasing women representation in clinical trials. A Statement from the Policy Conference has been provided and published in the European Heart Journal. Synergic activities should be undertaken at European level with the support of national scientific societies, European institutions, national health care authorities, patients' associations, and foundations. The commitment of the Board of the ESC is that these initiatives contribute to increase the awareness across Europe that cardiovascular disease is the primary cause of death in women and to improve the knowledge of risk factors, presentation and treatment of cardiovascular diseases in women.
Abstract: Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait.
Abstract: A novel clinical entity characterized by ST segment elevation in right precordial leads (V1 to V3), incomplete or complete right bundle branch block, and susceptibility to ventricular tachyarrhythmia and sudden cardiac death has been described by Brugada et al. in 1992. This disease is now frequently called "Brugada syndrome" (BrS). The prevalence of BrS in the general population is unknown. The suggested prevalence ranges from 5/1,000 (Caucasians) to 14/1,000 (Japanese). Syncope, typically occurring at rest or during sleep (in individuals in their third or fourth decades of life) is a common presentation of BrS. In some cases, tachycardia does not terminate spontaneously and it may degenerate into ventricular fibrillation and lead to sudden death. Both sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance. In approximately 20% of the cases BrS is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the cardiac sodium channel, a protein involved in the control of myocardial excitability. Since the use of the implantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest, the identification of high-risk subjects is one of the major goals in the clinical decision-making process. Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients with multiple recurrences.
Abstract: Several relatively uncommon, but important cardiovascular diseases are associated with increased risk for acute cardiac events during exercise (including sudden death), such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and myo-pericarditis. Practising cardiologists are frequently asked to advise on exercise programmes and sport participation in young individuals with these cardiovascular diseases. Indeed, many asymptomatic (or mildly symptomatic) patients with cardiomyopathies aspire to a physically active lifestyle to take advantage of the many documented benefits of exercise. While recommendations dictating the participation in competitive sport for athletes with cardiomyopathies and myo-pericarditis have recently been published as a consensus document of the European Society of Cardiology, no European guidelines have addressed the possible participation of patients with cardiomyopathies in recreational and amateur sport activities. The present document is intended to offer a comprehensive overview to practising cardiologists and sport physicians of the recommendations governing safe participation in different types of competitive sport, as well as the participation in a variety of recreational physical activities and amateur sports in individuals with cardiomyopathies and myo-pericarditis. These recommendations, based largely on the experience and insights of the expert panel appointed by the European Society of Cardiology, include the most up-to-date information concerning regular exercise and sports activity in patients with cardiomyopathies and myo-pericarditis.
Abstract: Analysis of predictors of cardiac events in hereditary long-QT syndrome (LQTS) has primarily considered syncope as the predominant end point. Risk factors specific for aborted cardiac arrest and sudden cardiac death have not been investigated.
Abstract: Beta-adrenergic receptor-mediated cAMP or protein kinase A (PKA)-dependent modulation of cardiac potassium currents controls ventricular action potential duration (APD) at faster heart rates. HERG (KCNH2) gene mutations are associated with congenital long-QT syndrome (LQT2) and affect IKr activity, a key determinant in ventricular repolarization. Physical activity or emotional stress often triggers lethal arrhythmias in LQT2 patients. Beta-adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by the adaptor protein 14-3-3epsilon. In LQT2 families, we identified three novel heterozygous HERG mutations (G965X, R1014PfsX39, V1038AfsX21) in the C-terminus that led to protein truncation and loss of a PKA phosphorylation site required for binding of 14-3-3epsilon. When expressed in CHO cells, the mutants produced functional HERG channels with normal kinetic properties. We now provide evidence that HERG channel regulation by 14-3-3epsilon is of physiological significance in humans. Upon co-expression with 14-3-3epsilon, mutant channels still bound 14-3-3epsilon but did not respond with a hyperpolarizing shift in voltage dependence as seen in wild-type channels. Co-expression experiments of wild-type and mutant channels revealed dominant-negative behavior of all three HERG mutations. Simulations of the effects of sympathetic stimulation of HERG channel activity on the whole-cell action potential suggested a role in rate-dependent control of APD and an impaired ability of mutant cardiac myocytes to respond to a triggered event or an ectopic beat. In summary, the attenuated functional effects of 14-3-3epsilon on C-terminally truncated HERG channels demonstrate the physiological importance of coupling beta-adrenergic stimulation and HERG channel activity.
Abstract: Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited diseases predisposing to ventricular arrhythmias and sudden death. Genetic studies linked LQTS and BrS to mutations in genes encoding for cardiac ion channels. Recently, two novel missense mutations at the same codon in the gene encoding the cardiac Na+ channel (SCN5A) have been identified: Y1795C (causing the LQTS phenotype) and Y1795H (causing the BrS phenotype). Functional studies in HEK293 cells showed that both mutations alter the inactivation of Na+ current and cause a sustained Na+ current upon depolarisation. In this paper, a nine state Markov model was used to simulate the Na+ current in wild-type Na+ cardiac channel and the current alterations observed in Y1795C and Y1795H mutant channels. The model includes three distinct closed states, a conducting open state and five inactivation states (one fast-, two intermediate- and two closed-inactivation). Transition rates between these states were identified on the basis of previously published voltage-clamp experiments. The model was able to reproduce the experimental Na+ current in mutant channels just by altering the assignment of model parameters with respect to wild-type case. Parameter assignment was validated by performing action potential clamp experiments and comparing experimental and simulated I(Na) current. The Markov model was subsequently introduced in the Luo-Rudy model of ventricular myocyte to investigate "in silico" the consequences on the ventricular cell action potential of the two mutations. Coherently with their phenotypes, the Y1795C mutation prolongs the action potential, while the Y1795H mutation causes only negligible changes in action potential morphology.
Abstract: Implementing clinical practice guidelines improves outcomes. This has been shown by several large scale registries. However, in spite of this, guidelines are poorly implemented in clinical practice for a wide variety of reasons. We examine the reasons behind the low uptake of guidelines into routine medical practice. Many physicians are simply not aware that guidelines exist; or they do not believe in them; or they simply do not care to implement them. Economic and social factors may also influence uptake of guidelines. It is the role of professional societies to disseminate best scientific knowledge, and ensure optimum implementation of guidelines. This can be achieved through educational activities and CME credit. Close collaboration between the profession, health authorities, and maybe even the industry could improve uptake of clinical practice guidelines, and thereby improve patient outcome.
Abstract: The increasing interaction between molecular biology and clinical cardiology has allowed to demonstrate that mutations on the genes encoding cardiac ion channels or regulatory proteins can cause inherited arrhythmogenic disorders predisposing to sudden death in young individuals. These diseases are the long QT syndrome, the Brugada syndrome, the catecholaminergic polymorphic ventricular tachycardia, and the short QT syndrome. Since incomplete penetrance is present, genetic screening is pivotal to perform a correct diagnosis in mutation carriers who do not manifest phenotype, but are still at increased risk of cardiac events if left untreated. All these syndromes show genetic heterogeneity and it is becoming evident that each genetic variant of the disease presents distinguishing clinical characteristics suggesting that genetics may be used for targeting risk stratification and treatment of these diseases. In this chapter, the molecular bases, the clinical features and the current therapeutic approach of these syndromes are presented.
Abstract: The 1996 American Heart Association consensus panel recommendations stated that pre-participation cardiovascular screening for young competitive athletes is justifiable and compelling on ethical, legal, and medical grounds. The present article represents the consensus statement of the Study Group on Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology and the Working Group on Myocardial and Pericardial diseases of the European Society of Cardiology, which comprises cardiovascular specialists and other physicians from different European countries with extensive clinical experience with young competitive athletes, as well as with pathological substrates of sudden death. The document takes note of the 25-year Italian experience on systematic pre-participation screening of competitive athletes and focuses on relevant issues, mostly regarding the relative risk, causes, and prevalence of sudden death in athletes; the efficacy, feasibility, and cost-effectiveness of population-based pre-participation cardiovascular screening; the key role of 12-lead ECG for identification of cardiovascular diseases such as cardiomyopathies and channelopathies at risk of sudden death during sports; and the potential of preventing fatal events. The main purpose of the consensus document is to reinforce the principle of the need for pre-participation medical clearance of all young athletes involved in organized sports programmes, on the basis of (i) the proven efficacy of systematic screening by 12-lead ECG (in addition to history and physical examination) to identify hypertrophic cardiomyopathy-the leading cause of sports-related sudden death-and to prevent athletic field fatalities; (ii) the potential screening ability in detecting other lethal cardiovascular diseases presenting with ECG abnormalities. The consensus document recommends the implementation of a common European screening protocol essentially based on 12-lead ECG.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. The autosomal dominant form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac isoform of the ryanodine receptor. In vitro functional characterization of mutant RyR2 channels showed altered behavior on adrenergic stimulation and caffeine administration with enhanced calcium release from the sarcoplasmic reticulum. As of today no experimental evidence is available to demonstrate that RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias. Twenty-six mice (12 wild-type (WT) and 14RyR(R4496C)) underwent exercise stress testing followed by epinephrine administration: none of the WT developed ventricular tachycardia (VT) versus 5/14 RyR(R4496C) mice (P=0.02). Twenty-one mice (8 WT, 8 RyR(R4496C), and 5 RyR(R4496C) pretreated with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR(R4496C) mice but none of the WT developed VT (P=0.02); 4/5 RyR(R4496C) mice pretreated with propranolol developed VT (P=0.56 nonsignificant versus RyR(R4496C) mice). These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation. Furthermore, the results show that analogous to what is observed in patients, beta adrenergic stimulation seems ineffective in preventing life-threatening arrhythmias.
Abstract: Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (I(Kr)) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I(Ks)) channel. Here we identify a new variant, "SQT3", which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I(K1) than the wild-type (P<0.05) at potentials between -75 mV and -45 mV, with the peak current being shifted in the former with respect to the latter (WT, -75 mV; D172N, -65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I(K1) greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients' consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (VT) is a rare arrhythmogenic disease characterized by exercise- or stress-induced ventricular tachyarrhythmias, syncope, or sudden death, usually in the pediatric age group. Familial occurrence has been noted in about 30% of cases. Inheritance can be autosomal dominant or recessive, usually with high penetrance. The causative genes have been mapped to chromosome 1. Mutations of the cardiac ryanodine receptor gene (RyR2) have been identified in autosomal dominant pedigrees, while calsequestrin gene (CASQ2) mutations are seen in recessive cases. Ankyrin-B mutations may also be implicated in catecholaminergic polymorphic VT: mutations in this gene were previously linked to the long-QT 4 phenotype. Ventricular ectopy, bidirectional VT, and polymorphic VT occur in a predictable and progressive manner with increasing heart rate during exercise or isoproterenol infusion. Estimated mortality of untreated cases ranges from 30% to 50% before the age of 20-30 years according to family studies. Although beta-blocker therapy was considered to be effective in preventing clinical recurrence in the initial series, recent data show low efficacy. As there is a chance for sudden cardiac death if even a single dose of beta-blocker is missed, there is a trend toward implantation of defibrillators in more and more patients.
Abstract: Experience in endovascular/endocardial techniques for implanting implantable cardioverter defibrillators in early childhood is limited. Potentially, this type of approach could limit the surgical risk, while increasing ICD therapy efficacy. The safety and feasibility of adopting a complete endovascular/endocardial approach for implanting ICDs is assessed by considering the cases of two young children.
Abstract: In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis.
Abstract: Emotional stress is well established as a trigger of sudden death in the context of coronary heart disease (CHD), but its role in patients experiencing cardiac arrest with apparently normal hearts is unknown. This study sought to determine the role of psychosocial stress as a precipitant of cardiac arrest in patients with apparently normal hearts, so-called idiopathic ventricular fibrillation (IVF).
Abstract: The role of structural heart disease and sodium channel dysfunction in the induction of electrical instability in Brugada syndrome is still debated.
Abstract: Here we review the current knowledge about the mutations of the gene encoding the cardiac ryanodine receptor (RyR2) that cause cardiac arrhythmias. Similarities between the mutations identified in the RyR2 gene and those found in the gene RyR1 that cause malignant hyperthermia and central core disease are discussed. In vitro functional characterization of RyR1 and RyR2 mutants is reviewed, with a focus on the contribution that in vitro expression studies have made to our understanding of related human diseases.
Abstract: Ventricular fibrillation is one of the leading causes of death in North America. Brugada syndrome is characterized by ST segment elevation on the right precordial leads V1 through V3 and right bundle branch block, and may cause sudden death. Mutations in the SCN5A gene encoding the cardiac voltage-gated Na+ channel (hNav1.5) are associated with Brugada syndrome.
Abstract: The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite beta-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients.
Abstract: Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits.
Abstract: Catecholaminergic polymorphic ventricular tachycardia (VT) is a rare arrhythmogenic disorder, which may cause sudden death and whose relationships with mutations in cardiac ryanodine receptor gene have been recently established. The present article reports a catecholaminergic polymorphic VT case of a 9-year-old girl, without any previous history of syncope, who has been found unconscious while playing and referred comatose to pediatric intensive care unit. The electrocardiogram pattern showed runs of bidirectional and polymorphic VT degenerating into ventricular fibrillation, without QT interval abnormalities. Various attempts of cardioversion, lidocaine, and magnesium sulfate intravenous infusions were only partially effective. Owing to catecholaminergic polymorphic VT highly suggesting electrocardiogram pattern, intravenous propranolol was administered, achieving immediate VT interruption. Long-term nadolol therapy effectively prevented further arrhythmias, with no relapses up to 10 months later; a good neurologic recovery was also obtained. Genetic evaluation revealed in this patient-but not in relatives-a mutation in ryanodine receptor gene on chromosome 1.
Abstract: Twelve years after the identification of the molecular bases of the long-QT syndrome, it is now possible to express some considerations on the impact that genetic findings have had in the understanding of inherited arrhythmogenic diseases. Along with the excitement for the emerging data on genotype/phenotype correlation and for the development of the first recommendations for gene-specific management of patients, it is also important to acknowledge the unexpected complexity that has emerged. The focus of this article is to analyze the elusive aspects of the relationship between genetic defects and clinical manifestations and to propose some research directions that may provide the needed answers to move forward in the understanding of the genetics of heart rhythm abnormalities.
Abstract: Mutations in human cardiac calsequestrin (CASQ2), a high-capacity calcium-binding protein located in the sarcoplasmic reticulum (SR), have recently been linked to effort-induced ventricular arrhythmia and sudden death (catecholaminergic polymorphic ventricular tachycardia). However, the precise mechanisms through which these mutations affect SR function and lead to arrhythmia are presently unknown. In this study, we explored the effect of adenoviral-directed expression of a canine CASQ2 protein carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation D307H (CASQ2(D307H)) on Ca2+ signaling in adult rat myocytes. Total CASQ2 protein levels were consistently elevated approximately 4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2(WT)) or CASQ2(D307H). Expression of CASQ2(D307H) reduced the Ca2+ storing capacity of the SR. In addition, the amplitude, duration, and rise time of macroscopic I(Ca)-induced Ca2+ transients and of spontaneous Ca2+ sparks were reduced significantly in myocytes expressing CASQ2(D307H). Myocytes expressing CASQ2(D307H) also displayed drastic disturbances of rhythmic oscillations in [Ca2+]i and membrane potential, with signs of delayed afterdepolarizations when undergoing periodic pacing and exposed to isoproterenol. Importantly, normal rhythmic activity was restored by loading the SR with the low-affinity Ca2+ buffer, citrate. Our data suggest that the arrhythmogenic CASQ2(D307H) mutation impairs SR Ca2+ storing and release functions and destabilizes the Ca2+-induced Ca2+ release mechanism by reducing the effective Ca2+ buffering inside the SR and/or by altering the responsiveness of the Ca2+ release channel complex to luminal Ca2+. These results establish at the cellular level the pathological link between CASQ2 mutations and the predisposition to adrenergically mediated arrhythmias observed in patients carrying CASQ2 defects.
Abstract: Among several conditions that can be responsible for sudden cardiac death (SCD), an important role is played by long QT syndrome (LQTS). LQTS is a congenital electric heart disease that can be asymptomatic or have very severe clinical manifestation, leading to cardiac arrest. In fact, the first manifestation of LQTS can be hyperkinetic ventricular arrhythmias. The presence of LQTS should be considered in all cases of SCD where autopsy is negative for anatomic and histopathological findings. In these cases, after an accurate anamnesis, a genetic screening should always be performed. The screening on LQTS genes is performed on DNA extracted from paraffin-embedded tissues. Making a proper diagnosis in such cases can help to find new affected subjects among the family members of SCD victims and treat them. In these cases, if the pathologist does not make a correct diagnosis, can he or she be sued for malpractice?
Abstract: The possibility of saving persons with sudden cardiac arrest (SCA) lowers of 10% every minute since the beginning of the event. The early defibrillation (within 4 min) of a person with SCA performed by first responders suitably trained increases the survival rate up to 50%. The basic aim is that early defibrillation is performed as soon as possible by the first responder.
Abstract: We identify a human mutation (E1053K) in the ankyrin-binding motif of Na(v)1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Na(v)1.5. The E1053K mutation abolishes binding of Na(v)1.5 to ankyrin-G, and also prevents accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. Ankyrin-G and Na(v)1.5 are both localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na(v)1.5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates from rat heart. These data suggest that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 localization at excitable membranes in cardiomyocytes. Together with previous work in neurons, these results in cardiomyocytes suggest that ankyrin-G participates in a common pathway for localization of voltage-gated Na(v) channels at sites of function in multiple excitable cell types.
Abstract: The aim of this study was to test the hypothesis that epinephrine test may have diagnostic value for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome (LQTS).
Abstract: 220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (InsP(3)) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome. Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes. The mutations are localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G in cardiomyocytes. All mutations abolish ability of ankyrin-B to restore abnormal Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes. This study, considered together with the first description of ankyrin-B mutation associated with cardiac dysfunction, supports a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP(3) receptor.
Abstract: Ca(V)1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.
Abstract: We sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1 channel in the LQT1 form of congenital long QT syndrome (LQTS).
Abstract: This presentation deals with the molecular substrates of the inherited diseases leading to genetically determined cardiac arrhythmias and sudden death. In the first part of this article the current knowledge concerning the molecular basis of cardiac arrhythmias will be summarized. Second, we will discuss the most recent evidence showing that the picture of the molecular bases of cardiac arrhythmias is becoming progressively more complex. Thanks to the contribution of molecular genetics, the genetic bases, pathogenesis, and genotype-phenotype correlation of diseases--such as the long QT syndrome, the Brugada syndrome, progressive cardiac conduction defect (Lenegre disease), catecholaminergic polymorphic ventricular tachycardia, and Andersen syndrome--have been progressively unveiled and shown to have an extremely high degree of genetic heterogeneity. The evidence supporting this concept is outlined, with particular emphasis on the growing complexity of the molecular pathways that may lead to arrhythmias and sudden death, in terms of the relationships between genetic defect(s) and genotype(s), as well as gene-to-gene interactions. The current knowledge is reviewed, focusing on the evidence that a single clinical phenotype may be caused by different genetic substrates and, conversely, a single gene may cause very different phenotypes acting through different pathways.
Abstract: Febrile illness has been rarely reported to modulate ST segment elevation in right precordial leads on ECG or even precipitate ventricular fibrillation in patients with Brugada syndrome. We report the case of a patient whose Brugada ECG pattern was unmasked by hyperthermia secondary to acute cholangitis. Serial ECGs showed progressive attenuation of ST segment elevation as body temperature gradually returned to normal. Structural heart disease was ruled out. Intravenous flecainide injection reproduced a less remarkable ST segment elevation. Genetic screening demonstrated a single amino acid substitution (H681P) in the SCN5A gene, thus confirming the diagnosis of Brugada syndrome. In vitro expression of this newly characterized genetic defect revealed novel biophysical abnormalities consisting of a shift in both steady-state activation and inactivation, resulting in a 60% reduction of sodium window current. Thus, SCN5A-H681P mutation induces a significant loss of transmembrane current and is clinically associated with a pathologic phenotype that is elicited by hyperthermia. Overall the observed clinical features are in agreement with previous observations and strongly suggest that fever may be an environmental modifier among Brugada syndrome patients with a detrimental (and possibly arrhythmogenic) effect on cardiac repolarization.
Abstract: In the last few years, a very active line of research took place after the first identification of SCN5A mutations associated with an inherited form of cardiac arrhythmias and sudden death, the LQT3 variant of the long QT syndrome. Subsequently, two allelic diseases additional to LQT3 were shown to be due to mutations in the same gene, the Brugada syndrome (BrS) and the Lev-Lenegre syndrome (progressive cardiac conduction defect). Genotype-phenotype correlation and in vitro expression studies provide evidence that structure-function relationships of the SCN5A protein are much more complex than initially anticipated. The biophysical characterization of the sodium channel defects associated with different phenotypes and the genotype-phenotype correlation studies brought to the attention of the scientific community a plethora of mechanisms by which even a single amino acid substitution may remarkably affect cardiac excitability. Finally, the evidence of patients harboring an SCN5A mutation and overlapping clinical presentations creates a need for a revision of the traditional classification of the above mentioned diseases. It is now appropriate to consider the "sodium channel syndrome" as a unique clinical entity that may manifest itself with a spectrum of possible phenotypes.
Abstract: Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca(2+) release and cardiac contractility. FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.
Abstract: We aimed to determine whether long QT syndrome (LQTS) genotype has a differential effect on clinical course of disease in male and female children and adults after adjustment for QTc duration.
Abstract: Mutations in potassium-channel genes KCNQ1 (LQT1 locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A (LQT3 locus) are the most common causes of the long-QT syndrome. We stratified risk according to the genotype, in conjunction with other clinical variables such as sex and the length of the QT interval.
Abstract: This study was designed to test the hypothesis that epinephrine infusion may be a provocative test able to unmask nonpenetrant KCNQ1 mutation carriers.
Abstract: The flecainide test is widely used in Brugada syndrome. However, its reproducibility and safety remain ill-defined. This study included 22 patients (18 men, mean age 34 years). Mutations in the SCN5A gene were found in eight patients. Two patients had aborted sudden cardiac death, 8 had syncope/presyncope, and 12 were asymptomatic. The ECG was diagnostic in 19 patients and suggestive in 3. At baseline, 21 of 22 patients underwent a flecainide test (2 mg/kg IV bolus over 10 minutes). In 21 of 21 patients the test was diagnostic or amplified the typical ECG pattern. At the end of drug infusion, sustained VT lasting 7-10 minutes developed in two patients. A second flecainide test was performed within 2 months in 20 patients. The test was not repeated in the two patients with prior development of VT. The flecainide test was diagnostic in 20 of 20 patients. Sustained VT occurred in one patient and recurrent VF in another. The reproducibility of the flecainide test was 100%. In 4 (18%) of 22 patients major VAs were documented after the end of flecainide infusion. VA occurred in 3 (43%) of 7 patients with, versus 1 (7%) 15 without SCN5A gene mutation (P < 0.05). No diagnostic ECG changes or arrhythmias developed in 25 control patients without structural heart disease who underwent the same study protocol. This study shows a high flecainide reproducibility, supporting its diagnostic value in Brugada syndrome. However, the occurrence of major VA, significantly higher in patients with documented SCN5A gene mutation, including in asymptomatic patients, mandates the performance under appropriate medical supervision. Whether a slower rate of drug infusion can lower the risk of VA induction, while maintaining the sensitivity of the test should be explored.
Abstract: Thanks to the contribution of molecular genetics, the genetic bases, the pathogenesis and genotype-phenotype correlation of diseases such as the Long QT syndrome, the Brugada Syndrome, the Progressive cardiac conduction defect (Lenegre disease), the Catecholaminergic Polymorphic Ventricular Tachycardia and Andersen Syndrome have been progressively unveiled and show an extremely high degree of genetic heterogeneity. The evidences supporting this concept are outlined with a particular emphasis on the growing complexity of the molecular pathways that may lead to arrhythmias and sudden death, in term of the relationships between genetic defect(s) and genotype(s) as well as gene-to gene interactions. The current knowledge is reviewed, focusing on the evidence that a single clinical phenotype may be caused by different genetic substrates and, conversely, a single gene may cause very different phenotypes acting through different pathways.
Abstract: Brugada syndrome is an inherited arrhythmogenic disease, that may cause syncope and sudden cardiac death in young individuals with a normal heart. It is characterized by a typical electrocardiographic pattern: complete or incomplete right bundle branch block and ST segment elevation in leads V1-V3. Thus far, the only gene linked to this syndrome is the gene SCN5A, the gene encoding for the cardiac sodium channel, that is also responsible of the LQT3 form of the Long QT syndrome. Mutations in SCN5A, responsible for Brugada syndrome, cause a functional reduction in the availability of cardiac sodium current. However, only 20-25% of patients affected by this syndrome have mutations on this gene. Therefore, the diagnosis of the syndrome is difficult, because it could manifest at first time as cardiac arrest without any previous symptom and the electrocardiographic pattern could be intermittent, thus a pharmacological challenge with antiarrhythmic class I drugs is required to unmask ST elevation. The clinical management is still empiricial because pharmacological therapies lack to show effectiveness and the only life-saving option is an implantable cardioverter defibrillator (ICD). So the identification of clinical parameters as predictors of adverse outcome for risk stratification has became of outmost importance for the clinical management of these patients, to discover which patients really need an ICD. This review presents clinical and genetic features of Brugada syndrome and the most recent diagnostic criteria. It will be discussed, therefore, the prognostic value of clinical tests, and especially of the programmed electrical stimulation, as prognostic predictors of sudden cardiac death to identify higher risk patients.
Abstract: Recent data showed that long QT syndrome (LQTS) patients with mutations in the pore region of the HERG (LQT2) gene have significantly higher risk of cardiac events than subjects with mutations in the non-pore region. The aim of this study was to determine whether there is an association between the location of mutations in the KCNQ1 gene and cardiac events in LQT1 patients.
Abstract: Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.
Abstract: Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.
Abstract: Pathogenesis of familial inherited arrhythmias is being progressively clarified thanks to the insights provided by molecular biology and by functional studies. Transmembrane or intracellular ion channel mutations have been identified in genetically determined forms of polymorphic ventricular tachycardia and sudden death such as catecholaminergic ventricular tachycardia, long QT syndrome, and Brugada syndrome. The role of molecular abnormalities in the genesis of monomorphic idiopathic ventricular tachycardias is less well defined, mainly because of the lack of a Mendelian pattern of inheritance. Interestingly, the presence of somatic mutations has been suggested as the mechanism for monomorphic ventricular tachycardia originating from the right ventricular outflow tract. The future goals for the application of molecular genetics to the management of cardiac arrhythmias will be to apply molecular genetics for a better risk stratification of affected individuals and to aim for the identification of gene-specific treatment of idiopathic ventricular tachycardia.
Abstract: Differences in the sensitivity of the genotype of the congenital long QT syndrome to sympathetic stimulation have been suggested. This study compared the influence of sympathetic stimulation on continuous corrected QT (QTc) intervals between LQT1, LQT2 and LQT3 forms of the congenital long QT syndrome.
Abstract: Molecular genetics applied to the study of inherited arrhythmogenic diseases has profoundly modified our understanding of cardiac electrophysiology providing new information on the crucial pathophysiological role of cardiac ion channels. These data are now putting forth innovative strategies for clinical management of the affected patients. Among these conditions, long QT syndrome (LQTS) was the first to enter the "genetic era", and nowadays the availability of large population of patients with known mutation allows to draw meaningful genotype-phenotype correlation and genetic-based risk stratification. However, despite the remarkable impact on knowledge, several still poorly defined issues limit the translation of such information into more effective therapeutic stratigies. As an example, despite the evidence of a significant QT shortening potential, the gene-specific therapy of LQTS has still to prove its impact upon the risk of cardiac events. The present article reviews the most critical findings obtained in the last decade in the field of genetic of LQTS in the attempt of underlying its current applicability, limitations and the future perspectives of this knowledge in the management of affected patients.
Abstract: This study compared the effects of beta-blockade on transmural and spatial dispersion of repolarization (TDR and SDR, respectively) between the LQT1 and LQT2 forms of congenital long QT syndrome (LQTS).
Abstract: The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go-related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I(Kr)). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder.
Abstract: The novel insights provided by the molecular genetic applied to the study of cardiac arrhythmias have just started to scratch the surface of the complex relationships between the genetic abnormalities of ion channel structure and the susceptibility to life threatening ventricular arrhythmias. These crucial pieces of information that are being gathered may have broader implications than those concerning the relatively restricted field of inherited arrhythmogenic diseases. An area of possible crucial application of the molecular genetic of cardiac ion channels, is the so-called drug-induced Torsade de Pointes (TdP) and acquired Long QT Syndrome. This condition is defined as an abnormal response to the administration of a variety of drugs which, in susceptible subjects, may induce an excessive QT interval prolongation and possibly lead to the onset of life-threatening ventricular tachyarrhythmias (drug-induced TdP). The "proof of concept" that sub-clinical variants of the inherited long QT syndrome may play a causative role has been recently brought to light. However, large population-based studies are still needed in order to quantify the epidemiological relevance of such findings. The future developments in this area of research will lead to the availability of pre-prescription genotyping for the identification of the susceptible subjects and to the development of safer drugs.
Abstract: The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Eleven RyR2 missense mutations have been linked to these diseases. All eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the three malignant hyperthermia (MH)/central core disease (CCD) mutation regions of the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 mutations have been shown to alter calcium-induced calcium release. Sympathetic nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A (PKA). PKA phosphorylation of RyR2 activates the channel. In conditions associated with high rates of SCD such as heart failure RyR2 is PKA hyperphosphorylated resulting in "leaky" channels. SR calcium leak during diastole can generate "delayed after depolarizations" that can trigger fatal cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic forms of catecholaminergic-induced SCD may alter the regulation of the channel resulting in increased SR calcium leak during sympathetic stimulation.
Abstract: The European Society of Cardiology has convened a Task Force on Sudden Cardiac Death in order to provide a comprehensive, educational document on this important topic. The main document has been published in the European Heart Journal in August 2001. The Task Force has now summarized the most important clinical issues on sudden cardiac death and provided tables with recommendations for risk stratification and for prophylaxis of sudden cardiac death. The present recommendations are specifically intended to encourage the development and revision of national guidelines on prevention of sudden cardiac death. The common challenge for cardiologists, physicians of other medical specialties and health professionals throughout Europe is to realize the potential for sudden cardiac death prevention and to contribute to public health efforts to reduce its burden.
Abstract: Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death.
Abstract: Brugada syndrome is an arrhythmogenic disease, characterized by syncope and sudden cardiac death, with a typical electrocardiographic pattern: right bundle branch block and ST segment elevation in the right precordial leads. Only recently, the first gene causing Brugada syndrome has been demonstrated by the identification of mutations in SCN5A, the gene encoding for the cardiac sodium channel, also responsible for the LQT3 subtype of long QT syndrome. Despite the knowledge on Brugada syndrome has dramatically improved in the recent years, the clinical management is still often empirical and limited by the lack of pharmacological therapies. Therefore, the implantable cardioverter-defibrillator (ICD) is the only life-saving option for high-risk patients. However, life-long implant in young individuals may have a major impact on the quality of life and it is not free from complications. Therefore, the identification of a robust risk stratification algorithm is of outmost importance to limit the use of ICD to the higher risk individuals. Programmed electrical stimulation has been proposed but this approach appears to have a low positive predictive value, thus leading to implants in many asymptomatic patients. Recently, we analyzed data from 200 Brugada syndrome patients, one of the largest groups so far reported, and we showed that the best predictor of cardiac events is the presence of a spontaneous abnormal ECG pattern associated with history of syncope. In the present article we will review the clinical characteristic of Brugada syndrome and point out a possible risk stratification scheme.
Abstract: Mutations in the cardiac ryanodine receptor gene (RyR2) underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disease occurring in the structurally intact heart. The proportion of patients with CPVT carrying RyR2 mutations is unknown, and the clinical features of RyR2-CPVT as compared with nongenotyped CPVT are undefined.
Abstract: A case of long QT syndrome diagnosed in the early neonatal period is described. A full-term male baby was delivered by cesarean section at 38 weeks of gestation. The indication to cesarean section was sudden marked fetal bradycardia. At birth, he presented the following rhythm disorders: a) an ectopic atrial rhythm with T wave alternans, and b) atrioventricular conduction disorders. Sinus rhythm, with a prolonged QT interval and T wave alternans, was recovered soon after birth, before starting beta-blocker therapy. The family history was negative for the long QT syndrome: sudden unexpected death and/or syncopal episodes and cases of congenital deafness have not been reported. Molecular screening of the five long QT syndrome-related genes did not reveal the presence of any mutation. At 3 years of follow-up, the child is well and he did not present with symptoms or arrhythmias during this period.
Abstract: Inducibility of ventricular arrhythmias at programmed electrical stimulation (PES) ranges between 50% and 80% of patients with Brugada syndrome. However, the variety of PES protocols and the lack of data relative to a control group or to ventricular arrhythmia reproducibility contribute to a still undefined interpretation of PES outcome in Brugada syndrome.
Abstract: Mutations in the gene (SCN5A) encoding the alpha-subunit of the cardiac Na+ channel cause congenital long QT syndrome (LQT-3). Here we describe a novel LQT-3 mutation I1768V (I1768V) located in the sixth transmembrane spanning segment of domain IV. This mutation is unusual in that it is located within a transmembrane spanning domain and does not promote the typically observed sustained inward current corresponding to a gain of channel function (bursting). Rather, I1768V increases the rate of recovery from inactivation and increases the channel availability, observed as a positive shift of the steady-state inactivation curve (+7.6 mV). Using a Markovian model of the cardiac Na+ channel, we simulated these changes in gating behavior and demonstrated that a small increase in the rate of recovery from inactivation is sufficient to explain all of the experimentally observed current changes. The effect of these alterations in channel gating results in an increase in window current that may act to disrupt cardiac repolarization.
Abstract: The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.
Abstract: Cardiac dysfunction including arrhythmias and myocardial ischemia have often been reported in carbon monoxide poisoning; scattered punctiform hemorrhages throughout the heart have been documented in autopsy samples. An appropriate diagnostic approach is crucial to assess carbon monoxide cardiac damage. This evaluation may be confounded by several factors, including the absence of overt symptoms and of specific ischemic changes in the electrocardiogram. In experimental studies, laboratory animals can develop cardiac changes similar to those seen in humans and therefore proved to be useful models to study the effects and the mechanisms of cardiac damage due to carbon monoxide. These investigations, as well as others performed in vitro, provide support for a direct action of carbon monoxide on the heart, in addition to systemic hypoxia produced by carboxyhemoglobin formation. This review focuses on the diagnostic aspects of carbon monoxide cardiotoxicity. Experimental results obtained in animals and in vitro models are also discussed.
Abstract: Cardiovascular disorders including myocardial ischemia and heart failure have been described in both laboratory animals and humans following carbon monoxide poisoning. Carbon monoxide cardiotoxicity may be clinically occult and often remains undiagnosed because of the lack of overt symptoms and specific ischemic changes in the electrocardiogram. Routine myocardial necrosis markers have low diagnostic efficiency, particularly in patients with concomitant skeletal muscle necrosis or multiple organ failure complicating carbon monoxide poisoning. Carbon monoxide-induced cardiotoxicity has been investigated rarely in children.
Abstract: Previous studies showed that diagnosing congenital long QT syndrome (LQTS) is difficult due to variable penetrance and genetic heterogeneity, especially when subjects from multiple families with diverse mutations are combined. We hypothesized that a combination of clinical and ECG techniques could identify gene carriers within a single family with congenital LQTS.
Abstract: In clinical cardiology, resort has recently been made to molecular genetics in order to explain some mechanisms that underlie sudden cardiac death in young people with structurally normal hearts. It has become evident that genetic mutations regarding cardiac ion channels may disrupt the delicate balance of currents in the action potential, thus inducing malignant ventricular tachyarrhythmias. The cardiac sodium channel gene, SCN5A, is involved in two of such arrhythmogenic diseases, the Brugada syndrome and one form of the long QT syndrome (LQT3). It is believed that these syndromes result from opposite molecular effects: Brugada syndrome mutations cause a reduced sodium current, while LQT3 mutations are associated with a gain of function. The effects of class I antiarrhythmic drugs have been used to differentiate these diseases. Intravenous flecainide is used as a highly specific test to unmask the electrocardiographic phenotype of the Brugada syndrome. On the other hand, on the basis of experimental and clinical studies, the possibility that the same drugs act as a gene-specific therapy in this disorder by contrasting the effect of mutations in LQT3 has been explored. Recent evidence shows that phenotypic overlap may exist between the Brugada syndrome and LQT3. One large family with a SCN5A mutation and a "mixed" electrocardiographic pattern (prolonged QT interval and ST-segment elevation) has been reported. Moreover, our recent data showed that flecainide challenge may elicit ST-segment elevation in some LQT3 patients. The presence of "intermediate" phenotypes highlights a remarkable heterogeneity suggesting that clinical features may depend upon the single mutation. Only deepened understanding of the genotype-phenotype correlation will allow the definition of the individual patient's risk and the development of guidelines for clinical management.
Abstract: Catecholaminergic polymorphic ventricular tachycardia is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. The electrocardiographic pattern of this ventricular tachycardia closely resembles the arrhythmias associated with calcium overload and the delayed afterdepolarizations observed during digitalis toxicity. We speculated that a genetically determined abnormality of intracellular calcium handling might be the substrate of the disease; therefore, we considered the human cardiac ryanodine receptor gene (hRyR2) a likely candidate for this genetically transmitted arrhythmic disorder.
Abstract: The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific.
Abstract: Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V(1/2)) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na(+) channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na(+) channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K(+) channels that underlie the plateau and terminal repolarization phases of the action potential. Na(+) channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K(+) channel conductance is low than at more negative potentials (wild-type channels), where total K(+) channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.
Abstract: In approximately 6--10% of survivors of cardiac arrest no cardiac abnormality can be identified despite extensive clinical evaluation. Autopsy data confirm that in a similar percentage of victims of sudden death no structural heart disease can be identified at post mortem evaluation. Occurrence of cardiac arrest in the absence of a substrate is defined 'idiopathic ventricular fibrillation' thus admitting that the cause for the arrhythmic event has remained unknown. We present data supporting the hypothesis that incompletely penetrant genetic defects may underlie at least some of these unexplained deaths.
Abstract: Defects of the SCN5A gene encoding the cardiac sodium channel alpha-subunit are associated with both the long QT-3 (LQT-3) subtype of long-QT syndrome and Brugada syndrome (BrS). One previously described SCN5A mutation (1795insD) in the C terminus results in a clinical phenotype combining QT prolongation and ST segment elevation, indicating a close interrelationship between the two disorders. Here we provide additional evidence that these two disorders are closely related. We report the analysis of two novel mutations on the same codon, Y1795C (LQT-3) and Y1795H (BrS), expressed in HEK 293 cells and characterized using whole-cell patch clamp procedures. We find marked and opposing effects on channel gating consistent with activity associated with the cellular basis of each clinical disorder. Y1795H speeds and Y1795C slows the onset of inactivation. The Y1795H, but not the Y1795C, mutation causes a marked negative shift in the voltage dependence of inactivation, and neither mutation affects the kinetics of the recovery from inactivation. Interestingly, both mutations increase the expression of sustained Na+ channel activity compared with wild type (WT) channels, although this effect is most pronounced for the Y1795C mutation, and both mutations promote entrance into an intermediate or a slowly developing inactivated state. These data confirm the key role of the C-terminal tail of the cardiac Na+ channel in the control of channel gating, illustrate how subtle changes in channel biophysics can have significant and distinct effects in human disease, and, additionally, provide further evidence of the close interrelationship between BrS and LQT-3 at the molecular level.
Abstract: Although sudden infant death syndrome (SIDS) has been associated with long QT syndrome-a genetic disorder that causes arrhythmia-a causal link has not been shown. We screened genomic DNA from a child who died of SIDS and identified a de-novo mutation in KVLQT1, the gene most frequently associated with long QT syndrome. This mutation (C350T) had already been identified in an unrelated family that was affected by long QT syndrome. These results confirm the hypothesis that some deaths from SIDS are caused by long QT syndrome and support implementation of neonatal electrocardiographic screening.
Abstract: The study compared the influence of sympathetic stimulation on transmural and spatial dispersion of repolarization between LQT1 and LQT2 forms of congenital long QT sYndrome (LQTS).
Abstract: Whenever a proband is identified with long-QT syndrome (LQTS), his or her parents and siblings should be evaluated regarding the possibility of carrying the disorder. In the majority of cases, one of the proband's parents and one or more siblings are affected. The aim of this study was (1) to determine whether the clinical severity of LQTS in the proband is useful in identifying first-degree family members at high risk for cardiac events, and (2) to evaluate the clinical course of affected parents and siblings of LQTS probands.
Abstract: The aim of this study was to test the hypothesis that some cases of drug-induced arrhythmias depend on genetic predisposition. Excessive prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some drug-induced arrhythmias might represent cases of "forme fruste" of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of drug-induced QT prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause drug-induced life-threatening arrhythmias and allow early identification of individuals at risk.
Abstract: Defects of the SCN5A gene encoding the cardiac sodium channel are associated with both the LQT3 subtype of long-QT syndrome and Brugada syndrome (BS). The typical manifestations of long-QT syndrome (QT interval prolongation) and BS (ST segment elevation in leads V1 through V3) may coexist in the same patients, which raises questions about the actual differences between LQT3 and BS. Intravenous flecainide is the standard provocative test used to unmask BS in individuals with concealed forms of the disease, and oral flecainide has been proposed as a treatment option for LQT3 patients because it may shorten their QT interval.
Abstract: In the long QT syndrome (LQTS) most life-threatening cardiac events occur in association with physical or emotional stress. However, a minority of patients dies suddenly during sleep; intriguingly, these sleep-related sudden deaths tend to cluster in families. The mechanism(s) underlying this phenomenon and the reason why it occurs in few selected families are unknown. Recently, some of the LQTS genes have been identified leading to three main subgroups (LQT1, LQT2, LQT3) associated respectively with mutations affecting the following ionic currents involved in the control of ventricular repolarization: I(Ks), I(Kr), I(Na). We have recently observed that cardiac events nighttime are rare in LQT1 and frequent in LQT3 patients.
Abstract: In five children from the same family who died after unexplained cardiac arrest, Brugada syndrome syndrome was suspected based on the transient manifestation of the typical electrocardiogram pattern in one of them. A mutation in the cardiac sodium-channel confirmed the diagnosis of Brugada syndrome, which suggests that this disease may cause sudden death in children.
Abstract: Congenital long-QT syndrome (LQTS) is caused by mutations of genes encoding the slow component of the delayed rectifier current (LQT1, LQT5), the rapid component of the delayed rectifier current (LQT2, LQT6), or the Na(+) current (LQT3), resulting in ST-T-wave abnormalities on the ECG. This study evaluated the spectrum of ST-T-wave patterns and repolarization parameters by genotype and determined whether genotype could be identified by ECG.
Abstract: beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated.
Abstract: Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.
Abstract: In patients with the long QT syndrome (LQTS), the occurrence of cardiac events (syncope or cardiac arrest) is frequently associated with acute arousal caused by exercise, swimming, emotion, or noise. However, cardiac events may also occur during sleep or with ordinary daily activities. The purpose of this study was to determine whether there are differential clinical, electrocardiographic, and genetic features among LQTS patients who experienced cardiac events with and without acute arousal. We identified 1,325 patients with cardiac events from the International LQTS Registry. Based on the precipitating conditions of the first event, 427 patients were classified as arousal, 345 as nonarousal, and the remaining 553 were unknown (not classifiable). Gene linkage was known in 78 of the 772 patients with classifiable first events. The age at first cardiac event was significantly younger in the arousal than the nonarousal group (11.7 vs. 15.5 years, respectively; p<0.001). The arousal-type patients had a higher rate of subsequent cardiac events during follow-up after the index event than the nonarousal-type patients (p = 0.02). Arousal-related cardiac events occurred in 85% of LQT1, 67% of LQT2, and 33% of LQT3 patients (p = 0.008). This study provides evidence that the genotype is an important determinant of the LQTS phenotype in terms of arousal and nonarousal-related cardiac events.
Abstract: The long QT syndrome (LQTS) has often been considered as a model to study the abnormalities of cardiac repolarization in humans because it represents a pure electrical disease with no evidence of cardiac structural abnormalities. The arrhythmogenic potential of prolonged ventricular repolarization has been extensively studied both in experimental models and at the clinical level in LQTS patients, and many studies pointed to the pathogenetic role of the dispersion of ventricular recovery times (i.e., dispersion of ventricular repolarization). In the last few years, a new critical knowledge has been achieved thanks to the molecular biology techniques that are unveiling the genetic bases of LQTS. Indeed, the understanding of the genes and mutations that may cause the LQTS opened the way to understanding the molecular determinants of the altered ventricular repolarization that can be found in LQTS patients. From the clinical standpoint, the traditional tools applied for the detection and quantification of the dispersion of ventricular repolarization (monophasic action potential, QT dispersion) showed their effectiveness but also their limitations. More recently, the availability of new algorithms and the development of powerful computerized supports allowed the evaluation of innovative techniques, which now represent possible attractive alternatives intended to quantify the degree of repolarization abnormalities in LQTS patients and possibly to noninvasively quantify the risk of cardiac events.
Abstract: The ICD is an important treatment option in adults and children with life-threatening tachyarrhythmias. The possibility of lead displacement caused by growth and the lack of dedicated leads and devices poses special problems in pediatric ICD implantation. We describe our experience in three children in whom we left a redundant lead loop within the inferior vena cava (IVC) is allow for further growth. Since February 1998, three children underwent ICD implantation at our institution. A lead (screw-in) was advanced into the right ventricular apex, and a loop was created in the IVC by progressively withdrawing the stylet and pushing in the lead. Satisfactory sensing and pacing threshold values were obtained and a successful single 16-J defibrillation test was performed. No complications were encountered. After a mean follow-up of 16 months, with a mean increase in body weight and height of 4.1 +/- 0.5 Kg and 6.3 +/- 0.4 cm, respectively, chest X ray showed some release of additional lead length, in the absence of dislodgments, while significant changes in pacing/sensing parameters were not found. In conclusion, the creation of a loop within the IVC allows the lead to adjust for growth in children receiving an ICD. This approach is feasible and safe.
Abstract: Drug-induced long QT syndrome (LQTS) is a prevalent disorder of uncertain etiology that predisposes to sudden death. KCNE2 encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel I(Kr) that has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in approximately 1.6% of the general population. While mutant channels showed diminished potassium flux at baseline and wild-type drug sensitivity, channels with the SNP were normal at baseline but inhibited by sulfamethoxazole at therapeutic levels that did not affect wild-type channels. We conclude that allelic variants of MiRP1 contribute to a significant fraction of cases of drug-induced LQTS through multiple mechanisms and that common sequence variations that increase the risk of life-threatening drug reactions can be clinically silent before drug exposure.
Abstract: The ECG pattern of right bundle branch block and ST-segment elevation in leads V(1) to V(3) (Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups.
Abstract: Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K(+) channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K(+) current (I(Ks) )], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I(Ks) currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I(Ks) current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Delta544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.
Abstract: Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease characterized by prolonged QT interval in the electrocardiogram, recurrent syncope, and sudden cardiac death. Mutations in the cardiac potassium channel HERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K(+) currents, thereby prolonging repolarization. We studied a novel COOH-terminal missense mutation, HERG R752W, which segregated with the disease in a family of 101 genotyped individuals. When the mutant cRNA was expressed in Xenopus oocytes it produced enhanced rather than reduced currents. Simulations using the Luo-Rudy model predicted minimal shortening rather than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT observed clinically. This anomaly was resolved by our observation that the mutant protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was corrected at lower incubation temperatures and that functional channels were now delivered to the plasma membrane. However, trafficking could not be restored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQTS. The occurrence of different classes of misprocessed channels suggests that a unified therapeutic approach for altering HERG trafficking will not be possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants.
Abstract: It is still currently held that most patients affected by the long-QT syndrome (LQTS) show QT interval prolongation or clinical symptoms. This is reflected by the assumption in linkage studies of a penetrance of 90%. We had previously suggested that a larger-than-anticipated number of LQTS patients might be affected without showing clinical signs. We have now exploited the availability of molecular diagnosis to test this hypothesis.
Abstract: Genetic approaches have succeeded in defining the molecular basis of an increasing array of heart diseases, such as hypertrophic cardiomyopathy and the long-QT syndromes, associated with serious arrhythmias. Importantly, the way in which this new knowledge can be applied to managing patients and to the development of syndrome-specific antiarrhythmic strategies is evolving rapidly because of these recent advances. In addition, the extent to which new knowledge represents a purely research tool versus the extent to which it can be applied clinically is also evolving. The present article represents a consensus report of a meeting of the European Working Group on Arrhythmias. The current state of the art of the molecular and genetic basis of inherited arrhythmias is first reviewed, followed by practical advice on the role of genetic testing in these and other syndromes and the way in which new findings have influenced current understanding of the molecular and biophysical basis of arrhythmogenesis.
Abstract: Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes, KVLQT1, KCNE1 (minK), and HERG, and the cardiac sodium channel gene SCN5A cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in KVLQT1 and KCNE1 in JLNS families in which QTc prolongation was inherited as a dominant trait.
Abstract: Acute auditory stimuli and swimming activities are frequently associated with syncope, aborted cardiac arrest, and death in the long QT syndrome (LQTS). We investigated the clinical and genetic findings associated with cardiac events precipitated by these arousal factors. The study population involved 195 patients with an index cardiac event associated with a loud noise (n = 77) or swimming activity (n = 118). Patients with events associated with loud auditory stimuli were older at their index event and were more likely to be women than patients who experienced events during swimming-related activities. Patients with an index event associated with loud noise were likely to have subsequent events related to auditory stimuli; patients with an index event associated with swimming were likely to have recurrent events related to swimming or physical activities. Family patterning of auditory and swimming and/or physical activity-related events was evident. Genotype analyses in 25 patients revealed a significant difference in the distribution of index cardiac events by genotype (p <0.001), with all 19 patients with swimming-related episodes associated with LQT1 genotype and 5 of 6 patients with auditory-related events associated with LQT2 genotype. The clinical profile and genotype findings of patients with LQTS who experience cardiac events related to acute auditory stimuli are quite different from those who experience events accompanying swimming activities.
Abstract: Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed rectifier K+ current IKs and may assemble with HERG to modulate the rapid delayed rectifier IKr. We used electrophysiological and immunocytochemical methods to compare the cellular phenotypes of wild-type minK and four LQT5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one mutant, L51H, was not. Co-expression of V47F and W87R with KvLQT1 produced IKs currents having altered gating and reduced amplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 current rather than IKs and co-expression with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG current markedly. Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel. We conclude that minK is a co-factor in the expression of both IKs and IKr and propose that clinical manifestations of LQT5 may be complicated by differing effects of minK mutations on KvLQT1 and HERG.
Abstract: Reports of serious cardiac arrhythmia associated with some second-generation antihistamines have prompted concern for their prescription. This article reviews the nature of the adverse events reported and concludes that the blockade of potassium channels, particularly the subtype responsible for the rapid component of the delayed rectifier current (IKr), is largely responsible for such adverse cardiac events. Consequently, antihistamines with little or no interaction with these channels are expected to have the greatest safety margin. The main cardiac arrhythmia of concern is that of torsades de pointes, a potentially fatal phenomenon characterized by prolonged ventricular depolarization that manifests as a prolonged QT interval and polymorphic ventricular tachycardia, with twisting of the QRS complexes. Based on pre-clinical and clinical evidence, it appears that loratadine, cetirizine, and fexofenadine are safe from cardiac arrhythmia via the IKr channel, whereas astemizole and terfenadine have a propensity to cause ventricular tachyarrhythmias.
Abstract: Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry.
Abstract: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A).
Abstract: The congenital long-QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged ventricular repolarization and life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac potassium channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a dominant trait, and the Jervell and Lange-Nielsen syndrome, inherited as an autosomal recessive trait.
Abstract: Molecular genetics is progressively entering clinical practice. This new approach is modifying medical thinking as it becomes possible to diagnose diseases in their presymptomatic phase. It is therefore important for physicians to become acquainted with the "language" and the "methodology" of molecular biologists in order to balance opposite attitudes of the novice, i.e. skepticism and over-expectation, and to establish a fruitful interaction with the molecular diagnostic laboratories. Long QT syndrome is an inherited disease that few years ago was still called "idiopathic" as the underlying causes were unknown. Clinicians are now becoming aware that what was considered as one disease is actually the common phenotype of defects in at least five different LQT-related genes and that therefore clinical heterogeneity is likely to parallel genetic heterogeneity. The first steps have been undertaken to define the relative prevalence of the molecular variants of LQTS, to develop gene-specific therapy and to perform risk stratification based on the molecular defect. In this article, current knowledge of the molecular bases of LQTS is reviewed and criteria are proposed to help defining 1) when it is appropriate to attempt molecular diagnosis, 2) how to interpret results of the diagnostic laboratory and 3) how molecular diagnosis may affect patients management.
Abstract: The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease.
Abstract: The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions of adrenergic activation. Recently, the genes for the LQTS inked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQT1) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQT1 potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na+ channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na+ channel blocker such as mexiletine for LQT3 patients and of interventions such as K+ channel openers or increases in the extracellular concentration of potassium for LQT1 and LQT2 patients.
Abstract: The duration of the QT interval is only a gross estimate of repolarization. Besides its limited accuracy and reproducibility, it does not provide information on the morphology of the T wave; thus, morphologic alterations such as notches can be only qualitatively described but not objectively quantified.
Abstract: The long QT syndrome (LQTS) is a familial disease characterized by abnormally prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmia. Recently, molecular biology studies brought major advancements in the understanding of the pathophysiologic mechanisms of this disease. The genes for the LQTS linked to chromosomes 3 (LQT3). 7 (LQT2) and 11 (LQT1) were identified as SCNSA, the cardiac sodium channel gene and as HERG and KVLQT1 potassium channel genes. We developed a cellular model in which ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. The effects of sodium channel blockade and rapid pacing were then studied showing a pronounced action potential shortening in response to mexlietine and during rapid pacing only in antopleurin-treated cells but no in dofetilide-treated cells. On this experimental basis, we tested the hypothesis that QT interval would behave differently during similar intervention in LQT3 and LQT2 patients. Results showed that 1) mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients and 2) LQT3 patients shortened their QT interal in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. They also suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cathecolamines with the insufficient adaptation of their QT interval when heart rate increases.
Abstract: The long-QT syndrome (LQTS) is a hereditary disorder characterized by an abnormally prolonged QT interval and by life-threatening arrhythmias. Recently, two of the genes responsible for LQTS have been identified: SCN5A, a voltage-dependent Na+ channel on chromosome 3 (LQT3), and HERG, responsible for the rapid component of the delayed rectifier current (IKr), on chromosome 7 (LQT2). We developed an in vitro model to attempt reproduction of the expected alterations in LQT3 and LQT2 patients. Guinea pig ventricular myocytes were exposed to anthopleura toxin A (anthopleurin), an inhibitor of the inactivation of the Na+ current, and to dofetilide, a selective blocker of IKr. Both interventions significantly prolonged action potential duration (APD), by 54 +/- 13 and 62 +/- 16 ms, respectively. Cells pretreated with anthopleurin significantly shortened APD in response to mexiletine, isoproterenol, and rapid pacing (from 264 +/- 38 to 226 +/- 32 ms after mexiletine, P < .001). On the contrary, cells exposed to dofetilide did not shorten the APD after mexiletine and even prolonged it after initial exposure to isoproterenol (from 280 +/- 25 to 313 +/- 20 ms, P < .001); during rapid pacing, APD was shortened but less (38 +/- 9 versus 60 +/- 11 ms, P < .05) than in anthopleurin-treated cells. This study shows that a cellular model for LQTS, based on the recent advances in molecular genetics, can provide adequate "phenotypes" of prolonged repolarization amenable to the testing of interventions of potential clinical relevance. We found differential responses to Na+ channel blockade, to beta-adrenergic stimulation, and to rapid pacing according to specific pretreatment with either anthopleurin (to mimic LQT3) or dofetilide (to mimic LQT2). These different responses in myocytes bear striking similarities with the differential response to analogous interventions in LQTS patients with mutations on the SCN5A and HERG genes.
Abstract: The idiopathic long QT syndrome is a congenital disease characterized by prolongation of the QT interval and by stress-induced syncopal episodes caused by the development of "torsades de pointes". Over the last decade, the great advances in the field of molecular biology have made it possible to elucidate the genetic causes of the disease. In particular, three genes have been implicated in the pathogenesis of the disease: SCN5A (LQT3), encoding for the cardiac sodium channel and located on chromosome 3, HERG (LQT2), encoding for a cardiac potassium channel (Ikr) and located on chromosome 7 and KVLQT1 (LQT1), located on chromosome 11 and encoding for a cardiac potassium channel whose electrophysiologic profile is still undefined. Within each of these genes several different mutations have been identified and subsequently expressed to determine the electrophysiological changes induced by the mutation in the normal function of the channels. These studies have suggested that LQT3 is caused by alterations in the inactivation of cardiac sodium channels while LQT2 is caused by a reduction in the delayed rectifier potassium current. Based on this evidence, we developed the first cellular model for LQTS in order to provide a mean of assessing the effect of different interventions in two different forms of disease, LQT2 and LQT3. We exposed guinea pig ventricular myocytes to anthopleurin, a toxin that interferes with the inactivation of INa, and to dofetilide, a selective blocker of Ikr, obtaining a prolongation of cellular repolarization with both drugs. We then exposed cells to a Na+ channel blocker, mexiletine, which significantly reduced APD in cells treated with anthopleurin while it did not modify the prolongation induced by dofetilide. In addition, anthopleurin-treated cells demonstrated a greater shortening of APD to rapid pacing than both control and dofetilide-treated cells. Based on this experimental evidence, we tested the same therapeutic interventions, mexiletine and pacing, in fifteen genetically characterized LQTS patients. Mexiletine significantly shortened the QT interval in LQT3 patients but not in LQT2 patients. When we examined the response to an increase in heart rate, we found that LQT3 patients had a more shortened QT interval in response to heart rate changes than LQT2 patients and than healthy controls.
Abstract: The aim of the present study was to test, in vivo and in vitro, the influence of adrenergic activation on action potential prolongation induced by the potassium channel blocking agent d-sotalol.
Abstract: The primary aim of U-CARE (Unexplained Cardiac Arrest Registry of Europe) is to collect clinical information on survivors about a documented episode of idiopathic ventricular fibrillation (IVF) and to follow these patients (pts) prospectively to acquire information on 1) recurrence of malignant arrhythmias or cardiac arrest, 2) development of a previously non obvious organic heart disease, 3) potential difference in outcome in pts treated with different drugs or devices.
Abstract: Long QT syndrome (LQT) is an inherited cardiac disorder that causes syncope, seizures and sudden death from ventricular tachyarrhythmias. We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families. These mutations include two identical intragenic deletions and two missense mutations. These data suggest that SCN5A mutations cause LQT. The location and character of these mutations suggest that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.
Abstract: The idiopathic long QT syndrome (LQTS) is an unusual clinical disorder characterized by a prolongation of the QT interval and by syncopal episodes occurring among young subjects, most often during exercise, stress, or other conditions of increased sympathetic activity. Both an imbalance in sympathetic innervation and an intracardiac defect in membrane currents have been proposed as pathogenetic mechanisms. The latter appears substantiated by recent advances in molecular genetics showing a linkage on chromosomes 11, 3, 7, and 4, with identification of the genes for chromosomes 3 and 7. For symptomatic patients with the long QT syndrome, beta-adrenergic blockade, with efficacy in approximately 80% of patients, currently remains the therapy of first choice. For the patients who continue to suffer syncope or cardiac arrest despite beta blockade, evidence has been provided that left cardiac sympathetic denervation represents a very effective treatment. The improvement in the understanding of the molecular mechanisms involved may soon lead to gene specific therapy in most long QT patients.
Abstract: The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate.
Abstract: Torsade de pointes is a polymorphic ventricular tachycardia showing a peculiar electrocardiographic pattern characterised by a continuous twisting in QRS axis around an imaginary baseline. An abnormally prolonged QT interval is actually associated with torsade de pointes and it is constantly observed in the sinus beats preceding the onset of the arrhythmic event. Prolongation of ventricular repolarisation associated with the development of torsade de pointes can be observed in many clinical conditions, commonly referred to as prolonged QT syndromes, which can be divided into two major groups: (a) idiopathic long QT syndrome (LQTS), which include the Jervell-Lange-Nielsen and the Romano-Ward syndromes; and (b) acquired prolonged QT syndromes, which are largely iatrogenic and may follow treatment with antiarrhythmic drugs, tricyclic antidepressants, phenothiazines or macrolide antibiotics, and may be associated with metabolic disturbances (hypokalaemia, hypocalcaemia and hypomagnesaemia). Clinical studies have provided criteria for the definition and guidelines for the management of torsade de pointes, while the electrophysiological mechanisms responsible for its onset are still unclear. Two pathogenetic hypotheses have been proposed to account for the electrophysiological mechanisms underlying the condition: (a) re-entry due to a dispersion of refractory periods; and (b) triggered activity initiated by either early or delayed after-depolarisations. Both mechanisms are supported by clinical and experimental observations but a conclusive answer is not yet available.
Abstract: QT interval dispersion, measured as interlead variability of QT, is a marker of dispersion of ventricular repolarization and, hence, of cardiac electrical instability. We tested the hypothesis that dispersion of ventricular repolarization may be differently affected by interventions destined to provide complete or incomplete protection against malignant arrhythmias in patients with long QT syndrome (LQTS). Twenty-eight patients affected by the Romano Ward form of LQTS entered the study and were divided into three groups: LQTS patients before institution of therapy, patients who did respond to beta-blocker therapy, and patients who continued to have syncope and cardiac arrest despite beta-blockade and who underwent left cardiac sympathetic denervation. A group of 15 healthy volunteers served as control subjects.
Abstract: This paper describes a compact, low-profile patch radiator which is the base element for efficient, small-size applicators suitable for superficial hyperthermia. The design criteria and the technological processes involved are presented. The electromagnetic characteristics of the patch element are outlined, and possible application of the radiator are discussed.
Abstract: New evidence has been accumulated allowing a better understanding of the physiology and pathophysiology of receptors in the heart. Three major receptor systems influence electrophysiological characteristics of myocardial cells and are critical in the development and prevention of cardiac arrhythmias: the adrenergic, the muscarinic and the adenosine systems. Although it has long been recognized that beta adrenergic stimulation is arrhythmogenic, only recently have the mechanisms of this arrhythmogenic effect been clarified. In addition, the contribution to arrhythmogenesis of alpha receptor stimulation, which has been overlooked for many years, has been recognized as an important accompaniment to the beta component, especially during hypoxia-ischaemia. On the other hand, it has been demonstrated that although direct electrophysiological effects of acetylcholine on the ventricle remain controversial, the antagonism of sympathetic activation by cholinergic stimulation may be important in preventing arrhythmias induced by a high sympathetic tone in the presence of myocardial ischaemia. More recently, the importance of the adenosine system has been better appreciated. Experimental studies have shown that adenosine receptor activation inhibits the adenylyl cyclase system by activating the Gi regulatory proteins. Activation of this pathway inhibits the development of adrenergic-dependent triggered activity in isolated cells and these have also been confirmed in man. It is likely that this effect is specific against triggered rhythms induced by adrenergic activation. Even though further research is needed to clarify fully the interaction of these three systems at the subcellular level, the pharmacological modulation of these cardiac receptors appears as a rational approach for refining the treatment of arrhythmias.
Abstract: Several studies have demonstrated that focal mechanisms contribute to arrhythmogenesis during acute myocardial ischemia in vivo. However, the biochemical derangements during ischemia may either potentiate or depress the electrophysiological mechanisms leading to focal arrhythmias. In the study presented here we have characterized the consequences of various levels of cellular depression and of alterations in the extracellular environment on the development of early (EADs) and delayed (DADs) afterdepolarizations induced by catecholamines. Adult canine myocytes were exposed to: normoxia; hypoxia (pO2 less than 10 mmHg); hypoxia + high K+ or cyanide infusion. Early and delayed afterdepolarizations were induced by alpha or beta adrenergic stimulation in the different experimental conditions by infusing isoproterenol (10(-8)-10(-6) M) or phenylephrine (10(-7)-10(-5) M) + the betablocker nadolol. Hypoxia did not modify EADs or DADs induced by beta stimulation and potentiated DADs induced by alpha stimulation; hypoxia + high K+ blunted DADs induced by both types of stimulation and cyanide infusion completely prevented and suppressed them. Thus, triggered arrhythmias dependent upon adrenergic stimulation can either be potentiated or inhibited by the biochemical derangements of acute ischemia. Focal arrhythmias are more likely to occur in the borderline ischemic cells where cellular depression and extracellular K+ accumulation are less marked.
Abstract: To investigate the potential influence on one analogue of carnitine on the electrophysiologic derangements elicited by myocardial ischemia and subsequent reperfusion, we evaluated whether increasing concentrations of propionylcarnitine would interact with carnitine acyltransferase I and thereby decrease the accumulation of long-chain acylcarnitines during hypoxia in isolated adult canine myocytes. Propionylcarnitine (1-100 microM) did not alter the sixfold reversible increase in long-chain acylcarnitines elicited by 10 minutes of hypoxia. Likewise, propionylcarnitine did not alter the reversal of the accumulation of long-chain acylcarnitines associated with reoxygenation of hypoxic myocytes. To assess whether analogues of carnitine could influence the development or reversal of the electrophysiologic derangements induced by hypoxia in adult canine epicardial tissue, selected concentrations of propionylcarnitine (1 microM to 10 mM) were administered prior to and during 15 minutes of hypoxic perfusion at 35 degrees C followed by 5-20 minutes of reoxygenation. Continuous intracellular transmembrane action potentials were recorded with glass microelectrodes. Administration of propionylcarnitine prior to and during hypoxia did not alter the electrophysiologic derangements elicited by hypoxia or subsequent reoxygenation. Therefore, propionylcarnitine does not influence the activity of carnitine acyltransferase I and does not alter the accumulation of long-chain acylcarnitines during hypoxia. Although propionylcarnitine may protect ischemic myocardium by enhancing the recovery of contractile function during reperfusion, propionylcarnitine does not attenuate any of the electrophysiologic alterations observed during hypoxia or subsequent reoxygenation in isolated tissue.
Abstract: Although findings from several reports suggest that nonreentrant or focal mechanisms contribute to the genesis of arrhythmias during early ischemia, the contribution of triggered activity arising from early or delayed afterdepolarizations has not been resolved. We have previously demonstrated that beta- but not alpha-adrenergic stimulation induces afterdepolarizations and triggered activity in isolated normoxic myocytes. In the present study, the influence of the extent of cellular derangements as well as increases in [K+]o on alpha- and beta-adrenergic-mediated afterdepolarizations and triggered activity was evaluated. Adult canine myocytes were exposed to one of the following experimental conditions with simultaneous intracellular transmembrane action potential recordings: 1) low PO2 (less than 10 mm Hg, obtained using a specially designed hypoxic chamber) and low (6.8) pH; 2) low PO2, low pH, and high extracellular potassium ([K+]o) (10 mM); or 3) severe metabolic inhibition with cyanide (10(-6) M). Cells from each group were superfused with either the alpha-agonist phenylephrine (10(-5) or 10(-7) M, with 10(-5) M nadolol) or the beta-agonist isoproterenol (10(-6) M). Moderate changes in the action potentials were observed under conditions 1 and 2 (moderate hypoxia), whereas marked but reversible changes were observed with cyanide (severe metabolic inhibition). During moderate hypoxia in normal [K+]o, delayed afterdepolarizations or triggered activity were elicited by both alpha- (12 of 13 cells) and beta-adrenergic (five of five cells) stimulation. Increasing [K+]o during moderate hypoxia completely abolished the afterdepolarizations induced by alpha-adrenergic stimulation and prevented the occurrence of triggered activity. In contrast, the influence of beta-adrenergic stimulation was only attenuated by an increase in [K+]o. Exposure to cyanide completely prevented the induction of afterdepolarizations and triggered activity by both alpha- and beta-adrenergic stimulation. Our findings indicate that moderate hypoxia in normal [K+]o is associated with the development of adrenergic-mediated afterdepolarizations and triggered activity. In contrast, accumulation of [K+]o or severe impairment of cellular metabolism is accompanied by inhibition of adrenergic-mediated afterdepolarizations and triggered activity.
Abstract: Torsades de pointes (TDP) is a polymorphic ventricular tachycardia with a peculiar electrocardiographic pattern of continuously changing morphology of the QRS complex twisting around an imaginary baseline. The clinical setting under which TDP develops covers many clinico-pathologic conditions, including the long QT syndrome (LQTS). In the present review, we analyze the evolution of the hypotheses for the mechanisms underlying TDP and we discuss some of the experimental models used and their related clinico-pathologic counterparts. Together with the hypothesis that TDP represents a form of reentrant arrhythmia, recent evidence has suggested the possibility that triggered activity may indeed be responsible for TDP. Data collected in vitro are presented that demonstrate a role for catecholamines in the development of afterpotentials in ventricular tissue. Whether adrenergic-mediated afterdepolarizations are the mechanism responsible for TDP in the clinical setting of LQTS has not yet been proven and remains an important area of investigation.
Abstract: The relative influence of alpha- and beta-adrenergic receptor activation in eliciting early (EADs) and delayed (DADs) after depolarizations was assessed using intracellular microelectrode recordings in isolated adult canine ventricular myocytes. Normoxic myocytes were exposed to the alpha-adrenergic agonist phenylephrine (10(-8)-10(-6) M) or the beta-adrenergic agonist isoproterenol (10(-9)-10(-6) M) during pacing at different frequencies (0.5-4 Hz). alpha-Adrenergic stimulation resulted in a dose-dependent prolongation of action potential duration but failed to induce either EADs or DADs. beta-Adrenergic stimulation with isoproterenol at low concentrations (10(-9)-10(-8) M) induced a prolongation of the action potential, whereas higher concentrations (10(-7) and 10(-6) M) resulted in a marked shortening. Isoproterenol elicited single or multiple (2-5) DADs at concentrations from 10(-8) to 10(-6) M, with a corresponding increase in the amplitude of the DADs and decrease in the coupling interval as cells were paced at increasing rates. DADs often initiated and maintained sustained triggered rhythms that spontaneously terminated. Isoproterenol (10(-8)-10(-6) M) also elicited EADs in 80% of cells at the highest concentration utilized (10(-6) M) and at intermediate pacing frequencies (1-2 Hz). EADs often occurred with a 2:1 or 3:1 pattern. EADs and DADs induced by isoproterenol were reversibly abolished by low extracellular sodium, ryanodine (10(-6) M), or benzamil (10(-4) M), thus indicating that Ca2+ release from the sarcoplasmic reticulum and extracellular Na+ concentration are two major factors in the development of both types of afterdepolarizations. The demonstration that EADs can be induced by isoproterenol in ventricular muscle suggest a novel pathway for beta-adrenergic receptors to mediate arrhythmogenesis in the intact heart.
Abstract: Recent studies in vitro have shown that afterdepolarizations may develop during reperfusion after hypoxia, thus suggesting that these afterdepolarizations may contribute to the genesis of reperfusion arrhythmias. We recorded monophasic action potentials (MAPs) during myocardial ischemia and reperfusion to investigate whether afterdepolarizations develop in vivo when reperfusion arrhythmias occur. In 15 anesthetized cats, 24 trials of 10 minutes of occlusion of the left anterior descending coronary artery were followed by reperfusion. In 13 of 24 (54%) trials, afterdepolarizations developed at the moment of reperfusion, with a mean amplitude of 2.4 +/- 1.1 mV (13 +/- 8% of MAP amplitude). When cycle length was either increased by vagal stimulation or decreased by atrial pacing, early afterdepolarization (EAD) amplitude was modified, according to what has been described for EAD in vitro, with a positive linear correlation between cycle length and EAD amplitude (r = 0.91, p less than 0.0001). The occurrence of EAD was not related to rapid changes in left ventricular pressure. In the eight of 13 (62%) cases in which EAD development was associated with reperfusion arrhythmias, the coupling interval of the EAD and of premature ventricular contractions showed a significant correlation (r = 0.86, p less than 0.0001). However, in five of 13 (38%) cases, occurrence of reperfusion arrhythmias was not accompanied by the presence of EAD on the MAP recording. In two animals, a 2:1 block of EAD conduction was observed, and this was reflected on the intracavitary electrocardiogram as T wave alternans. Thus, EADs occur frequently after reperfusion in vivo, with a time course that parallels the onset of reperfusion arrhythmias. This finding further supports the role of triggered activity in the genesis of reperfusion arrhythmias in vivo.
Abstract: The long-term efficacy and safety of flecainide (100 to 200 mg twice a day) were evaluated in 21 patients with high-grade, chronic ventricular arrhythmias who responded to and tolerated flecainide at a preliminary evaluation (200 mg, single oral dose). Antiarrhythmic response was evaluated at 3 days and 3, 6, 12, 18, and 24 months. The mean follow-up was 25 +/- 14 months (range 3 to 52). Four patients (19%) were excluded from efficacy analysis because of spontaneous decrease in baseline arrhythmia observed after 12 months of therapy. Effective arrhythmia suppression at both Holter monitoring and during exercise stress testing was maintained in 14 of 17 patients (82%). Mean frequency of premature ventricular contractions remained reduced by more than 95% throughout the follow-up. Five patients discontinued therapy between 3 and 18 months because of drug ineffectiveness (three patients, 18%) or side effects (two patients, 12%). In 12 patients (71%) long-term efficacy and tolerance were demonstrated. In no case was aggravation of arrhythmia or adverse cardiac effects observed. Side effects (5% to 29% of patients during follow-up) were usually minor and easily abolished by dosage reduction. In patients with chronic ventricular arrhythmias, flecainide maintained a favorable ratio between efficacy and side effects during a 2-year follow-up.
Abstract: This study addresses the question of the choice of treatment for the individual patient with chronic ventricular arrhythmias. Acute oral drug testing offers a pragmatic approach to the rapid selection of the drug with the best efficacy/side-effect ratio by allowing multiple comparisons within the same patient. Forty patients with chronic ventricular arrhythmias received a single oral dose of the following antiarrhythmic drugs: flecainide 200 mg, propafenone 450 mg, disopyramide 300 mg, mexiletine 400 mg, tocainide 800 mg, verapamil 160 mg, propranolol 120 mg. Criteria for efficacy were suppression of complex ventricular arrhythmias and a greater than 90% reduction in premature ventricular beats lasting for at least 2 h. An antiarrhythmic effect was achieved with each of the drugs in the following percentages of patients: flecainide 69.4%, propafenone 67.5%, disopyramide 54.8%, mexiletine 45.2%, tocainide 31.3%, verapamil 31.3%, propranolol 12.5%. In no case was worsening of arrhythmia observed. At the end of the acute testing phase, the drug that had proved most effective in each patient was administered at a full dosage for 72 h. A concordant response between the two phases was observed in 80% of patients and was as high as 89% when the analysis was limited to flecainide and propafenone. This study shows the feasibility and practical advantages for patient management of a multiple comparison of antiarrhythmic drugs by acute oral drug testing. It also provides, in a non-invasive cost-effective manner, unique insights into the complex relationship between drug characteristics, individual responses and clinical efficacy.
Abstract: Sympathetic hyperactivity plays a major role in the genesis of malignant arrhythmias during acute myocardial ischemia. An experimental model in which life-threatening arrhythmias are specifically and consistently induced by the interaction between acute myocardial ischemia and left stellate ganglion stimulation has been developed in alpha-chloralose anesthetized cats. In this preparation, drugs that share antiischemic, antiadrenergic, and specific electrophysiologic effects, such as verapamil, diltiazem, and amiodarone, were most effective. To evaluate the relative role of these different properties in mediating the effect of antiarrhythmic drugs, we used this same model to test nifedipine, a calcium channel blocker that is able to counteract the consequences of sympathetic stimulation on coronary circulation but has no electrophysiologic properties at concentrations relevant in the clinical setting. Nifedipine (15 micrograms/kg) prevented the occurrence of ventricular fibrillation in 10 of 13 animals (77%). Its efficacy was independent of changes in the peripheral hemodynamics. Plasma concentrations of nifedipine were within the therapeutic range in humans. To evaluate if this rather striking protective effect was specifically related to the prevention of the deleterious consequences of sympathetic stimulation, the effect of nifedipine on ventricular fibrillation threshold was studied in an additional group of 13 cats in the nonischemic state, during acute myocardial ischemia and during ischemia plus sympathetic stimulation. Nifedipine did not modify ventricular fibrillation threshold in nonischemic or in ischemic conditions. However, nifedipine specifically prevented the further reduction in ventricular fibrillation threshold occurring when sympathetic stimulation was superimposed on acute ischemia. These data suggest that the extension of ischemic damage by sympathetic stimulation is an important progenitor of arrhythmogenic action during acute ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Activation of cardiac sympathetic nerves is recognized as a triggering factor for cardiac arrhythmias. However, the mechanisms involved have only been speculated. Because evidence from studies in vitro has established a relation between catecholamines, delayed afterdepolarizations (DAD), and triggered rhythms, it seemed possible that in vivo adrenergic activation also might lead to the development of DAD. Because very little evidence was available for DAD in vivo, we have evaluated whether monophasic action potential (MAP) recording with a contact electrode could be a suitable technique for the detection of DAD from the endocardium of anesthetized cats. In six animals, atrial pacing and graded aortic constriction were performed during MAP recording to assess MAP stability during hemodynamic changes, and in no cases were modifications of the baseline observed. In 11 cats, calcium gluconate (0.5 g) and G-strophanthin (100 micrograms) were administered. Action potential duration at 50% (APD50) and 90% (APD90) repolarization were reduced (from 138 +/- 16 to 122 +/- 18 msec, p less than 0.02, and from 163 +/- 23 to 149 +/- 20 msec, p less than 0.025, respectively). In eight of 11 (73%) animals, DAD were elicited with a mean amplitude of 1.2 +/- 0.4 mV. In 14 cats, the left stellate ganglion was stimulated for 45 seconds. APD50 and APD90 decreased (from 153 +/- 15 to 145 +/- 16 msec, p less than 0.005, and from 176 +/- 18 to 165 +/- 13 msec, p less than 0.001, respectively). DAD were induced in 10 of 14 animals (71%) with a mean amplitude of 1.2 +/- 0.3 mV. These results show that DAD can be induced in vivo by administration of calcium and digitalis and by activation of the cardiac sympathetic nerves. This latter finding further strengthens the existing link between adrenergic activation and ventricular arrhythmogenesis and suggests triggered activity as a likely mechanism.
Abstract: The role of the autonomic nervous system in modulating reperfusion arrhythmias is still unclear. Experiments with sympathetic denervation or alpha- and beta-adrenergic blocking agents have provided mixed results, while the effect of parasympathetic activation has not been investigated extensively. The effect of bilateral vagotomy and of vagal stimulation was studied, with and without attendant bradycardia, on the incidence of reperfusion arrhythmias in alpha-chloralose anesthetized cats. The left anterior descending coronary artery was occluded for 20 minutes, followed by reperfusion in 105 animals. The incidence and severity of reperfusion arrhythmias was compared in 1) neurally intact animals (heart rate 208 +/- 24 beats/min), 2) animals with acute bilateral vagotomy (heart rate 233 +/- 25 beats/min), 3) animals with vagal stimulation adjusted to maintain heart rate at 90-100 beats/min, and 4) animals with vagal stimulation + ventricular pacing to maintain heart rate at prestimulation values. All the neurally intact and vagotomized animals developed complex reperfusion arrhythmias, but these arrhythmias occurred in only 60 and 72%, respectively, of the animals with vagal stimulation and vagal stimulation + pacing (p less than 0.005 vs. neurally intact and p less than 0.02 vs. vagotomy). The incidence of ventricular fibrillation was similar in neurally intact (62%) and vagotomized (58%) animals; it was strikingly lower (7%, p less than 0.01) in animals with vagal stimulation when heart rate was allowed to decrease, and it was 48% when heart rate was kept constant during vagal stimulation. A selective protection from sustained (greater than 30 seconds duration) ventricular tachycardia was observed in animals with vagal stimulation independent of heart rate changes.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The antiarrhythmic efficacy of a new class I agent, penticainide, was evaluated by acute oral drug testing and compared in the same patient population with the efficacy of disopyramide, flecainide, mexiletine and propafenone. Twenty-five patients with high-grade chronic ventricular arrhythmias entered the study. During acute oral drug testing, penticainide (7 mg/kg) was effective (more than 90% reduction in ventricular premature complexes and complete abolition of class 4A and 4B arrhythmias) in 17 of 25 subjects (68%). The mean plasma level of the drug at 90 minutes was 4.4 +/- 1.9 micrograms/ml; at the same time increases in the PQ interval (from 168 +/- 27 to 189 +/- 31 ms, p less than 0.0001) and QRS duration (from 89 +/- 14 to 96 +/- 18 ms, p less than 0.001) were observed. The QTc was slightly but not significantly shortened in the overall population; however, in the subgroup with a basally prolonged QTc (n = 8), a significant reduction was observed (from 456 +/- 8 to 440 +/- 18 ms, p less than 0.02). No adverse effects were reported. The antiarrhythmic efficacy of the other drugs tested in the same population was: disopyramide, 12 of 19 (63%); flecainide, 13 of 24 (54%); propafenone, 13 of 24 (54%); and mexiletine, 7 of 20 (35%). Penticainide appears to be a well-tolerated and effective compound of potential value for treatment of ventricular arrhythmias.
Abstract: The potential role of calcium entry blockers in the prevention of life-threatening arrhythmias associated with acute myocardial ischemia and reperfusion is still controversial. In 98 anesthetized cats, the effect of diltiazem was examined in two experimental models. In protocol I, ventricular tachycardia or fibrillation was consistently induced by the interaction between a 2 minute coronary artery occlusion and a 30 second left stellate ganglion stimulation. After three trials under control conditions, if the same pattern of arrhythmia was induced, the drug under study was administered and three additional trials were performed. In 16 animals the administration of saline solution did not modify the pattern of arrhythmias. In contrast, diltiazem (0.1 mg/kg body weight plus 0.2 mg/kg per h) abolished both ventricular tachycardia and fibrillation that had occurred in 64 and 36%, respectively, of the cats in the control state. In protocol II, a 20 minute coronary artery occlusion was released in three groups; one served as the control group, one received diltiazem 15 minutes before occlusion and one received diltiazem 3 minutes before reperfusion. The incidence of reperfusion ventricular fibrillation was 62% (16 of 26) in the control group. It was significantly (p less than 0.05) reduced by diltiazem administered before the occlusion to 25% (4 of 16), whereas it was not affected when diltiazem was administered just before reperfusion (7 [47%] of 15). These results indicate that diltiazem exerts a striking protective effect against the malignant arrhythmias induced by the combination of acute myocardial ischemia and sympathetic hyperactivity. Diltiazem was also effective in reducing the incidence of life-threatening reperfusion arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The efficacy of the new class Ic anti-arrhythmic (aa) drug, Flecainide, has been evaluated in patients (pts) affected by frequent and/or severe chronic ventricular arrhythmias (VA), as assessed by 24 hours Holter monitoring and maximal exercise stress testing. The protocol consisted in a preliminary screening with multiple aa drugs (average 6.0 per pt) using the acute oral drug testing. The most effective drug was then given for 72 hours and 24 hours Holter monitoring and exercise stress testing repeated; if the efficacy was confirmed, chronic treatment was initiated and control visits were repeated after 3, 6 and 12 months. The study population consisted of 27 pts; 22 (81%) were in Lown class 4A (18%) or 4B (63%). Eight pts (30%) had a previous (greater than 1 year) myocardial infarction, while in 14 (52%) no evidence of cardiac disease was found. During acute oral drug testing a positive response (reduction of PVC's greater than 90% and abolition of grades 4A and 4B) was obtained with Flecainide, 200 mg, in 20 pts (74%). In 6 pts (22%) no effect was observed, while a possible proarrhythmic effect was observed in 1 pt (4%). Eighteen pts entered the second phase of the study with an average dose of Flecainide of 175 mg b.i.d. In 83% of the pts there was a positive concordance between the acute oral testing and the 72 hours treatment, as in 15 out of 18 pts grades 4A and 4B were totally abolished and the mean frequency of PVC's was reduced by 99%. In 3 pts (17%) no response was observed. Flecainide increased significantly PR (37 msec), QRS (20 msec) and QTc (28 msec). The plasma levels attained with chronic therapy (846 ng/ml) were higher than those achieved with the acute oral testing (372 ng/ml). Mild side effects (dizziness, tremor and headache) were observed in 33% of the pts and were all eliminated by a 100 mg reduction in Flecainide dose. Fifteen pts entered the third phase (long term treatment): in this group there was a 93.3% correlation with phase two, as in 14 out of 15 pts there was a complete abolition of grade 4B arrhythmias, a 98.8% reduction of couplets and a reduction in the number of PVC's greater than 85%. This study shows that Flecainide is a quite powerful aa drug with modest side effects. Its efficacy against chronic VA is high, also when compared to the most effective and available aa drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Recently it has been stated that in dogs absence of arrhythmias during coronary artery occlusion identifies a subgroup at almost no risk for developing ventricular fibrillation (VF) during reperfusion. A potential implication would be that prevention of ischemic arrhythmias may also prevent the most severe reperfusion arrhythmias. This concept is at variance with available clinical evidence. In order to reexamine this problem the left anterior descending coronary artery was occluded for 20 minutes in 41 anesthetized cats; the incidence and type of arrhythmias during occlusion and during the first minute of reperfusion were analyzed. Five animals had VF during occlusion and were not resuscitated. Twenty animals had ischemic arrhythmias, and among them the incidence of reperfusion VF was 50%. Sixteen animals did not have ischemic arrhythmias, but they did have a very similar incidence of reperfusion VF (44%). Thus, in this feline preparation, absence of ischemic arrhythmias did not help to predict a favorable outcome at the moment of reperfusion. This disparity with previous studies does not depend on the protocol used, but it may be partly due to species difference. These results demonstrate a lack of correlation between reperfusion VF and ischemic arrhythmias and provide further support for the concept of different mechanisms involved in occlusion and reperfusion arrhythmias.
