Brugada syndrome

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

The long QT syndrome

Major progress has taken place, and at a very rapid pace, in the understanding of the congenital long QT syndrome (LQTS). This has been the direct consequence of the identification of several of the genes responsible for LQTS and of the studies that have followed, at both basic and clinical levels. A key issue is represented by the fact that all LQTS genes identified so far encode for ionic channels involved in the control of repolarization. The expression studies of the mutated genes have allowed identification of the specific electrophysiologic consequences of the specific mutations and have demonstrated alterations in the NA+ and in K+ currents sufficient to explain the prolongation of action potential duration and, hence, of the QT interval. Ongoing studies in the selected LQTS patients, for whom the specific mutations are known, are allowing a unique understanding of the complex genotype-phenotype correlation. These studies indicate the existence of what appear to be gene-specific patterns in many clinically important features such as the response to therapeutic interventions, the response to increases in heart rate, and in the factors that precipitate the life-threatening arrhythmias typical of this intriguing disease

When is genetic testing useful in patients suspected to have inherited cardiac arrhythmias?

PURPOSE OF REVIEW: 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. RECENT FINDINGS: Important advances have been made in the identification of new genes, associated mutations, and polymorphisms that modulate susceptibility of acquired arrhythmias. We will examine the most recent advances relevant to the rational application of genetic analysis, guided by genotype-phenotype correlations derived from disease and patient-specific evaluation, as well as discussing novel technologies and recently published cost-effectiveness data. SUMMARY: Genetic analysis can be performed to identify the molecular substrate in those patients suspected to be affected by an inherited arrhythmogenic disease; however, the clinical usefulness of this information is often not straightforward. We hope to emphasize the concept that there is a significant difference in the impact of genetic testing within the various arrhythmogenic disorders, and the benefit of accessing genetic testing is not the same in all patients. The resultant integration between the expected yield of genetic screening and cost may allow the formation of criteria to prioritize access for those who could derive the most clinical benefit

Letter regarding article by Coronel et al, ''right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study''

Letter regarding article by Coronel et al, ''right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study'

Ryanodine receptor and calsequestrin in arrhythmogenesis: What we have learnt from genetic diseases and transgenic mice

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 disease

Inherited calcium channelopathies in the pathophysiology of arrhythmias.

Regulation of calcium flux in the heart is a key process that affects cardiac excitability and contractility. Degenerative diseases, such as coronary artery disease, have long been recognized to alter the physiology of intracellular calcium regulation, leading to contractile dysfunction or arrhythmias. Since the discovery of the first gene mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2001, a new area of interest in this field has emerged-the genetic abnormalities of key components of the calcium regulatory system. Such anomalies cause a variety of genetic diseases characterized by the development of life-threatening arrhythmias in young individuals. In this Review, we provide an overview of the structural organization and the function of calcium-handling proteins and describe the mechanisms by which mutations determine the clinical phenotype. Firstly, we discuss mutations in the genes encoding the ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2). These proteins are pivotal to the regulation of calcium release from the sarcoplasmic reticulum, and mutations can cause CPVT. Secondly, we review defects in genes encoding proteins that form the voltage-dependent L-type calcium channel, which regulates calcium entry into myocytes. Mutations in these genes cause various phenotypes, including Timothy syndrome, Brugada syndrome, and early repolarization syndrome. The identification of mutations associated with 'calcium-handling diseases' has led to an improved understanding of the role of calcium in cardiac physiology

Role of the JP45-Calsequestrin Complex on Calcium Entry in Slow Twitch Skeletal Muscles

We exploited a variety of mouse models to assess the roles of JP45-CASQ1 (CASQ, calsequestrin) and JP45-CASQ2 on calcium entry in slow twitch muscles. In flexor digitorum brevis (FDB) fibers isolated from JP45-CASQ1-CASQ2 triple KO mice, calcium transients induced by tetanic stimulation rely on calcium entry via La3+- and nifedipine-sensitive calcium channels. The comparison of excitation-coupled calcium entry (ECCE) between FDB fibers from WT, JP45KO, CASQ1KO, CASQ2KO, JP45-CASQ1 double KO, JP45-CASQ2 double KO, and JP45-CASQ1-CASQ2 triple KO shows that ECCE enhancement requires ablation of both CASQs and JP45. Calcium entry activated by ablation of both JP45-CASQ1 and JP45-CASQ2 complexes supports tetanic force development in slow twitch soleus muscles. In addition, we show that CASQs interact with JP45 at Ca2+ concentrations similar to those present in the lumen of the sarcoplasmic reticulum at rest, whereas Ca2+ concentrations similar to those present in the SR lumen after depolarization-induced calcium release cause the dissociation of JP45 from CASQs. Our results show that the complex JP45-CASQs is a negative regulator of ECCE and that tetanic force development in slow twitch muscles is supported by the dynamic interaction between JP45 and CASQs

Arrhythmogenic Mechanism of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly lethal form of inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic VT. The identification of the genetic substrate of the disease has allowed to achieve important milestones in the understanding of the arrhythmogenic mechanisms of the disease. Abnormal calcium leak from the mutant cardiac ryanodine receptor has been associated with the induction of delayed afterdepolarization suggesting that arrhythmogenesis in CPVT is likely to be induced by triggered activity. Here we review the current knowledge and some controversial issues about the molecular mechanism of arrhythmias initiation in CPVT and we discuss their implications for the development of novel therapeutic strategies in CPVT

Current Strategies to Diminish the Impact of Cardiovascular Diseases in Women

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

An ICT infrastructure to integrate clinical and molecular data in oncology research

<p>Abstract</p> <p>Background</p> <p>The ONCO-i2b2 platform is a bioinformatics tool designed to integrate clinical and research data and support translational research in oncology. It is implemented by the University of Pavia and the IRCCS Fondazione Maugeri hospital (FSM), and grounded on the software developed by the Informatics for Integrating Biology and the Bedside (i2b2) research center. I2b2 has delivered an open source suite based on a data warehouse, which is efficiently interrogated to find sets of interesting patients through a query tool interface.</p> <p>Methods</p> <p>Onco-i2b2 integrates data coming from multiple sources and allows the users to jointly query them. I2b2 data are then stored in a data warehouse, where facts are hierarchically structured as ontologies. Onco-i2b2 gathers data from the FSM pathology unit (PU) database and from the hospital biobank and merges them with the clinical information from the hospital information system.</p> <p>Our main effort was to provide a robust integrated research environment, giving a particular emphasis to the integration process and facing different challenges, consecutively listed: biospecimen samples privacy and anonymization; synchronization of the biobank database with the i2b2 data warehouse through a series of Extract, Transform, Load (ETL) operations; development and integration of a Natural Language Processing (NLP) module, to retrieve coded information, such as SNOMED terms and malignant tumors (TNM) classifications, and clinical tests results from unstructured medical records. Furthermore, we have developed an internal SNOMED ontology rested on the NCBO BioPortal web services.</p> <p>Results</p> <p>Onco-i2b2 manages data of more than 6,500 patients with breast cancer diagnosis collected between 2001 and 2011 (over 390 of them have at least one biological sample in the cancer biobank), more than 47,000 visits and 96,000 observations over 960 medical concepts.</p> <p>Conclusions</p> <p>Onco-i2b2 is a concrete example of how integrated Information and Communication Technology architecture can be implemented to support translational research. The next steps of our project will involve the extension of its capabilities by implementing new plug-in devoted to bioinformatics data analysis as well as a temporal query module.</p