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An asymptomatic woman with no clinical history consulted for pneumonia-induced fever; she then presented episodes of syncope due to polymorphic ventricular tachycardia and ECG alterations compatible with Brugada syndrome. Genetic studies showed no alterations in the SCN5A gene but other polymorphisms were observed. Further genetic studies are required to elucidate the pathophysiological mechanisms of fever and the function of sodium channels., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Arrhythmogenic right ventricular cardiomyopathy is an inherited disease characterized by a progressive myocardium fibrofatty replacement. This abnormality disrupts electrical transmission causing ventricular arrhythmias and sudden cardiac death. This genetic disease is transmitted mainly with an autosomal dominant pattern. Our aim was to identify the genetic defect responsible for the pathology in a Spanish family, and to perform its phenotype connotations., Material and Methods: A total of 15 individuals in a three-generation Spanish family were screened after the sudden cardiac death of one family member. All they underwent a complete physical examination, 12-lead electrocardiogram, 2-dimensional echocardiography, magnetic resonance imaging, exercise stress test, 24-h Holter and genetic testing., Results: Autopsy revealed the presence of biventricular arrhythmogenic dysplasia in deceased member. Six family members showed clinical symptoms but only three of them fulfilled definite diagnostic criteria of the disease. Genetic analysis showed a novel nonsense genetic variation in nine family members. All family members with clinical symptoms carried the genetic variation., Conclusions: Genetic testing in families affected by arrhythmogenic right ventricular cardiomyopathy helps to identify the genetic cause responsible for the disease. The incomplete penetrance and variable phenotypic expression highlights the need of comprehensive genetic analysis and further phenotype implications of genetics to clarify the pathophysiology of the disease., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

There has been increased interest in a possible association between epilepsy channelopathies and cardiac arrhythmias, such as long QT syndrome (LQTS). We report a kindred that features LQTS, idiopathic epilepsy, and increased risk of sudden death. Genetic study showed a previously unreported heterozygous point mutation (c.246T>C) in the KCNH2 gene. Functional studies showed that the mutation induces severe loss of function. This observation provides further evidence for a possible link between idiopathic epilepsy and LQTS., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Cardiac arrhythmias are associated with abnormal channel function due to mutations in ion channel genes. Epilepsy is a disorder of neuronal function also involving abnormal channel function. It is increasingly demonstrated that the etiologies of long QT syndrome and epilepsy may partly overlap. However, only a few genetic studies have addressed a possible link between cardiac and neural channelopathies. We describe a family showing the association between Brugada syndrome and epilepsy in which a known mutation in the SCN5A gene (p.W1095X, c.3284G>A) was identified. We suggest that this mutation can be responsible for cardiac and brain involvement, probably at different developmental age in the same individual. This observation confirms the possibility that SCN5A mutations may confer susceptibility for recurrent seizure activity, supporting the emerging concept of a genetically determined cardiocerebral channelopathy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Brugada Syndrome (BrS) is a familial disease associated with sudden cardiac death. A 20%-25% of BrS patients carry genetic defects that cause loss-of-function of the voltage-gated cardiac sodium channel. Thus, 70%-75% of patients remain without a genetic diagnosis. In this work, we identified a novel missense mutation (p.Asp211Gly) in the sodium β2 subunit encoded by SCN2B, in a woman diagnosed with BrS. We studied the sodium current (INa ) from cells coexpressing Nav 1.5 and wild-type (β2WT) or mutant (β2D211G) β2 subunits. Our electrophysiological analysis showed a 39.4% reduction in INa density when Nav 1.5 was coexpressed with the β2D211G. Single channel analysis showed that the mutation did not affect the Nav 1.5 unitary channel conductance. Instead, protein membrane detection experiments suggested that β2D211G decreases Nav 1.5 cell surface expression. The effect of the mutant β2 subunit on the INa strongly suggests that SCN2B is a new candidate gene associated with BrS., (© 2013 WILEY PERIODICALS, INC.)

Arrhythmogenic right ventricular cardiomyopathy is a rare clinical entity characterised by fibro-fatty replacement of myocardium, mainly involving right ventricular free wall, leading to malignant electrical instability and sudden cardiac death. The disease is inherited in up to 50% of cases, with incomplete penetrance and variable phenotypic expression. To date, more than 300 pathogenic mutations have been identified in 12 genes, mainly with autosomal dominant inheritance. Here, we focus on recent advances in the genetics of arrhythmogenic right ventricular cardiomyopathy. Despite continuous improvements, current genotype-phenotype studies have not contributed yet to establish a genetic risk stratification of the disease.

Brugada syndrome (BrS) is a life-threatening, inherited arrhythmogenic syndrome associated with autosomal dominant mutations in SCN5A, the gene encoding the cardiac Na(+) channel alpha subunit (Na(v)1.5). The aim of this work was to characterize the functional alterations caused by a novel SCN5A mutation, I890T, and thus establish whether this mutation is associated with BrS. The mutation was identified by direct sequencing of SCN5A from the proband's DNA. Wild-type (WT) or I890T Na(v)1.5 channels were heterologously expressed in human embryonic kidney cells. Sodium currents were studied using standard whole cell patch-clamp protocols and immunodetection experiments were performed using an antibody against human Na(v)1.5 channel. A marked decrease in current density was observed in cells expressing the I890T channel (from -52.0 ± 6.5 pA/pF, n = 15 to -35.9 ± 3.4 pA/pF, n = 22, at -20 mV, WT and I890T, respectively). Moreover, a positive shift of the activation curve was identified (V(1/2) = -32.0 ± 0.3 mV, n = 18, and -27.3 ± 0.3 mV, n = 22, WT and I890T, respectively). No changes between WT and I890T currents were observed in steady-state inactivation, time course of inactivation, slow inactivation or recovery from inactivation parameters. Cell surface protein biotinylation analyses confirmed that Na(v)1.5 channel membrane expression levels were similar in WT and I890T cells. In summary, our data reveal that the I890T mutation, located within the pore of Na(v)1.5, causes an evident loss-of-function of the channel. Thus, the BrS phenotype observed in the proband is most likely due to this mutation.

In developed countries, sudden infant death syndrome (SIDS) represents the most prevalent cause of death in children between 1 month and 1 year of age. SIDS is a diagnosis of exclusion, a negative autopsy which requires the absence of structural organ disease. Although investigators have confirmed that a significant percentage of SIDS cases are actually channelopathies, no data have been made available as to whether other sudden cardiac death-associated diseases, such as hypertrophic cardiomyopathy (HCM), could be responsible for some cases of SIDS. The presence of a genetic mutation in the sarcomeric protein usually affects the force of contraction of the myocyte, whose weakness is compensated with progressive hypertrophy and disarray. However, it is unclear whether in the most incipient forms, that is, first years of life, the lack of these phenotypes still confers a risk of arrhythmogenesis. The main goal of the present study is to wonder whether genetic defects in the sarcomeric proteins, previously associated with HCM, could be responsible for SIDS. We have analysed 286 SIDS cases for the most common genes implicated in HCM in adults. A total of 680 mutations localised in 16 genes were analysed by semi-automated matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDITOF-MS) using the Sequenom MassARRAY(®) System. Ten subjects with completely normal hearts showed mutated alleles at nine of the genetic variants analysed, and one additional novel mutation was detected by conventional sequencing. Therefore, a genetic mutation associated with HCM may cause sudden cardiac death in the absence of an identifiable phenotype., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Brain aging is associated to several morphological and functional alterations that influence the evolution and outcome of CNS damage. Acute brain injury such as an excitotoxic insult induces initial tissue damage followed by associated inflammation and oxidative stress, partly attributed to neutrophil recruitment and the expression of oxidative enzymes such as myeloperoxidase (MPO), among others. However, to date, very few studies have focused on how age can influence neutrophil infiltration after acute brain damage. Therefore, to evaluate the age-dependent pattern of neutrophil cell infiltration following an excitotoxic injury, intrastriatal injection of N-methyl-d-aspartate was performed in young and aged male Wistar rats. Animals were sacrificed at different times between 12h post-lesion (hpl) to 14 days post-lesion (dpl). Cryostat sections were processed for myeloperoxidase (MPO) immunohistochemistry, and double labeling for either neuronal cells (NeuN), astrocytes (GFAP), perivascular macrophages (ED-2), or microglia/macrophages (tomato lectin histochemistry). Our observations showed that MPO + cells were observed in the injured striatum from 12 hpl (when maximum values were found) until 7 dpl, when cell density was strongly diminished. However, at all survival times analyzed, the overall density of MPO + cells was lower in the aged versus the adult injured striatum. MPO + cells were mainly identified as neutrophils (especially at 12 hpl and 1 dpl), but it should be noted that MPO + neurons and microglia/macrophages were also found. MPO + neurons were most commonly observed at 12 hpl and reduced in the aged. MPO + microglia/macrophages were the main population expressing MPO from 3 dpl, when density was also reduced in aged subjects. These results point to neutrophil infiltration as another important factor contributing to the different responses of the adult and aged brain to damage, highlighting the need of using aged animals for the study of acute age-related brain insults., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Each year, 1.2 million people die worldwide as a result of motor-vehicle accidents (MVA), representing a tremendous burden to healthcare. The aim of this study was to define the prevalence of coronary disease and its possible role in motor-vehicle accidents., Methods and Results: We examined consecutive cases of non-hospital sudden death autopsies in the area of West Quebec during the period of 2002-2006, and we focused on those victims of MVA. Severe coronary artery disease (CAD) was defined as a narrowing of ≥ 75% of a cross-sectional area or the presence of acute plaque events in major epicardial coronary arteries. From a total cohort of 1260 autopsies, MVA were responsible for 123 deaths, 100 of whom were men and 23 were women. Significant CAD was documented in approximately 37% of these cases. In individuals older than 60 years, the prevalence of significant CAD and ischemia were 86.2% and 19.8%, respectively. A percentage of 40% of the coronary patients showed erratic driving before the accident, as observed by witnesses. Statistical analysis showed that an individual affected by CAD has 9% probability of suffering a motor-vehicle accident., Conclusions: The prevalence of severe CAD and acute myocardial ischemia is very high among individuals who have suffered a MVA. Our data suggest the hypothesis that acute CAD could be the cause of accidents in a large group of the drivers affected by coronary disease. For these reasons CAD could be investigated in drivers above 50 years old, as a possible preventive measure and determinant of individual risk stratification., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Sudden cardiac death is a major contributor to mortality in industrialized nations; in fact, it is the cause of more deaths than acquired immune deficiency syndrome, lung and breast cancer, and stroke together. Frequently, the autopsy becomes the principal diagnostic tool because macroscopic and microscopic analyses reveal the underlying cause of death. However, a significant number of sudden cardiac deaths remain unexplained. These cases are referred to as "natural" or arrhythmogenic. In the young, in up to 50% of sudden cardiac death cases, sudden death is the first and only clinical manifestation of an inherited cardiac disease that had remained undetected by conventional clinical investigations. To improve diagnosis, genetic testing has recently been added to these clinical tools. During the last two decades, there has been considerable progress in the understanding about genetics of sudden cardiac death. With that new information, the probands and their family members can make an informed decision regarding their care and know whether and to what extent they are at risk of suffering from the disease. Thus, genetic technology and expertise have become essential for the diagnosis of some forms of inherited cardiac diseases and to provide a basis for subsequent prevention strategies. This review focuses on recent advances in the understanding of cardiopathies owing to genetic investigations.

The remarkable advances that have taken place in biomedicine over the past 50 years have resulted in dramatic improvements in the prevention, diagnosis and treatment of many diseases. Although cardiology has adopted these advances at a relatively slow pace, today it is fully immersed in this revolution and has become one of the most innovative medical specialties. Research is continuing to give rise to new developments in genetics and molecular biology that lead, almost daily, to innovative ways of preventing, diagnosing and treating the most severe forms of heart disease. Consequently, it is essential that clinical cardiologists have some basic knowledge of genetics and molecular biology as these disciplines are having an increasing influence on clinical practice.