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Basi genetiche della morte cardiaca improvvisa
No full textArticolo sulle base genetiche della morte improvvisa e delle malattie aritmogene ereditari
Test diagnostici in cardiologia
No full textGli incredibili sviluppi degli ultimi dieci anni nel campo della genetica umana, hanno avuto un importante impatto nell’ambito della cardiologia. Dopo l’identificazione delle basi di alcune malattie genetiche con coinvolgimento cardiaco, l'interesse dei cardiologi si è rivolto alla genetica molecolare. Rapidamente test genetici, terapie gene-specifiche e stratificazioni del rischio basate sul tipo di difetto genetico, stanno entrando a far parte della pratica clinica.
E' fondamentale ricordare la classificazione delle malattie geneticamente determinate in tre categorie:
• Malattie cromosomiche, che derivano dall'acquisto o dalla perdita di un intero cromosoma o da parti di esso (es: Sindrome di Down)
• Malattie monogeniche, malattie causate da singoli geni mutati che hanno notevole effetto sulla salute del paziente (es: fibrosi cistica, Sindrome del QT Lungo)
• Malattie multifattoriali, malattie che derivano dall'interazione di più geni, che hanno effetto additivo o interattivo come responsabili alla predisposizione alla malattia, che a sua volta compare solo in presenza di appropriati fattori ambientali scatenanti (es: ipertensione, diabe mellito).
Patologie quali la Sindrome del QT Lungo, la Sindrome di Brugada, la Cardiomiopatia Ipertrofica, la Cardiomiopatia Aritmogena del Ventricolo Destro, la Tachicardia Ventricolare Polimorfa Catecolaminergica alcune varianti di Cardiomiopatia Dilatativa, sono esempi ben noti di patologie cardiache monogeniche (1) (Tabella 1). E’ tuttavia fondamentale ricordare che tra i fattori che causano malattia cardiaca, ciò che più frequentemente è geneticamente trasmesso non è una variante rara dell’assetto del DNA, ma sono varianti comuni (polimorfismi) che possono essere presenti in un’ampia parte della popolazione creando uno svantaggio in termini di suscettibilita
Gene-specific therapy for inherited arrhythmogenic diseases
Full text linkIn 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 therapie
Romano-Ward and other congenital long QT syndromes
Full text linkMolecular 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
Tachicardia Ventricolare Polimorfa Catecolaminergica
No full textIn questo capitolo si trova la definizione, la presentazione clinica e diagnosi, la aritmie, basi genetiche e fisiopatalogia, storia naturale e risposta alla terapia delle CPV
Clinical utility gene card for: Catecholaminergic polymorphic ventricular tachycardia (CPVT).
No full textRationale: The recessive form of catecholaminergic polymorphic ventricular tachycardia is caused by mutations in the cardiac calsequestrin-2 gene; this variant of catecholaminergic polymorphic ventricular tachycardia is less well characterized than the autosomal-dominant form caused by mutations in the ryanodine receptor-2 gene. Objective: We characterized the intracellular Ca(2+) homeostasis, electrophysiological properties, and ultrastructural features of the Ca(2+) release units in the homozygous calsequestrin 2-R33Q knock-in mouse model (R33Q) R33Q knock-in mouse model. Methods and Results: We studied isolated R33Q and wild-type ventricular myocytes and observed properties not previously identified in a catecholaminergic polymorphic ventricular tachycardia model. As compared with wild-type cells, R33Q myocytes (1) show spontaneous Ca(2+) waves unable to propagate as cell-wide waves; (2) show smaller Ca(2+)sparks with shortened coupling intervals, suggesting a reduced refractoriness of Ca(2+) release events; (3) have a reduction of the area of membrane contact, of the junctions between junctional sarcoplasmic reticulum and T tubules (couplons), and of junctional sarcoplasmic reticulum volume; (4) have a propensity to develop phase 2 to 4 afterdepolarizations that can elicit triggered beats; and (5) involve viral gene transfer with wild-type cardiac calsequestrin-2 that is able to normalize structural abnormalities and to restore cell-wide calcium wave propagation. Conclusions: Our data show that homozygous cardiac calsequestrin-2-R33Q myocytes develop spontaneous Ca(2+) release events with a broad range of intervals coupled to preceding beats, leading to the formation of early and delayed afterdepolarizations. They also display a major disruption of the Ca(2+) release unit architecture that leads to fragmentation of spontaneous Ca(2+) waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia
La tachicardia ventricolare polimorfa catecolaminergica
No full textArticle summarizing the current state of the art in diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardi
Postmortem molecular analysis in victims of sudden unexplained death
No full textAmong 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
La sindrome di Brugada: epidemiologia, stratificazione del rischio e management clinico.
No full textBrugada 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
Sudden Cardiac Death and Genetic Ion Channelopathies: Long QT, Brugada, Short QT, Catecholaminergic Polymorphic Ventricular Tachycardia, and Idiopathic Ventricular Fibrillation
No full textThis article provides a timely review of the most recent advancements in the field of inherited arrhythmogenic diseases both form the clinical and the basic sience point of vie
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