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

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

Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: 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. METHODS AND RESULTS: Twelve patients presenting with typical catecholaminergic polymorphic ventricular tachycardia in the absence of structural heart abnormalities were identified. DNA was extracted from peripheral blood lymphocytes, and single-strand conformation polymorphism analysis was performed on polymerase chain reaction-amplified exons of the hRyR2 gene. Four single nucleotide substitutions leading to missense mutations were identified in 4 probands affected by the disease. Genetic analysis of the asymptomatic parents revealed that 3 probands carried de novo mutations. In 1 case, the identical twin of the proband died suddenly after having suffered syncopal episodes. The fourth mutation was identified in the proband, in 4 clinically affected family members, and in none of 3 nonaffected family members in a kindred with 2 sudden deaths that occurred at 16 and 14 years, respectively, in the sisters of the proband. CONCLUSIONS: We demonstrated that, in agreement with our hypothesis, hRyR2 is a gene responsible for catecholaminergic polymorphic ventricular tachycardia

Clinical phenotype and functional characterization of CASQ2 mutations associated with Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: 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. METHODS AND RESULTS: We identified a homozygous 16-bp deletion at position 339 to 354 leading to a frame shift and a stop codon after 5aa (CASQ2(G112+5X)) in a child with stress-induced ventricular tachycardia and cardiac arrest. The same deletion was also identified in association with a novel point mutation (CASQ2(L167H)) in a highly symptomatic CPVT child who is the first CPVT patient carrier of compound heterozygous CASQ2 mutations. We characterized in vitro the properties of CASQ2 mutants: CASQ2(G112+5X) did not bind Ca2+, whereas CASQ2(L167H) had normal calcium-binding properties. When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity and reduced the amplitude of I(Ca)-induced Ca2+ transients and of spontaneous Ca2+ sparks in permeabilized myocytes. Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2(G112+5X). CONCLUSIONS: CASQ2(L167H) and CASQ2(G112+5X) alter CASQ2 function in cardiac myocytes, which leads to reduction of active sarcoplasmic reticulum Ca2+ release and calcium content. In addition, CASQ2(G112+5X) displays altered calcium-binding properties and leads to delayed afterdepolarizations. We conclude that the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias

Risk of death in the long QT syndrome when a sibling has died

BACKGROUND: 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. OBJECTIVE: This study sought to test the hypothesis that sudden death of a sibling is a risk factor for death or aborted cardiac arrest (ACA) in patients with LQTS. METHODS: We examined all probands and first-degree and second-degree relatives in the International Long QT Registry from birth to age 40 years with QTc >/= 0.45 s. Covariates included sibling death, QTc, gender by age, syncope, and implantable cardioverter-defibrillator (ICD) and beta-blocker treatment. End points were (1) severe events (ACA, LQTS-related death) and (2) any cardiac event (syncope, ACA, or LQTS-related death). RESULTS: Of 1915 subjects, 270 had a sibling who died. There were 213 severe events and 829 total cardiac events. More subjects with history of sibling death received beta-blocker therapy. Sibling death was not significantly associated with risk of ACA or LQTS-related death, but was associated with increased risk of syncope. QTc >/= 0.53 s (hazard ratio 2.5, P <.01), history of syncope (hazard ratio 6.1, P <.01), and gender were strongly associated with risk of ACA or LQTS-related death. CONCLUSION: Sudden death of a sibling prompted more aggressive treatment but did not predict risk of death or ACA, whereas QTc >/= 0.53 s, gender, and syncope predicted this risk. All subjects should receive appropriate beta-blocker therapy. The decision to implant an ICD should be based on an individual's own risk characteristics (QTc, gender, and history of syncope)

FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.

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