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Catecholaminergic Polymorphic Ventricular Tachycardia

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Catecholaminergic Polymorphic Ventricular Tachycardia 2011/2012 Lídia Sousa Catecholaminergic Polymorphic Ventricular Tachycardia Março, 2012 Lídia Sousa Catecholaminergic Polymorphic Ventricular Tachycardia Mestrado Integrado em Medicina Área: Cardiologia Trabalho efectuado sob a Orientação de: Doutor Manuel Joaquim Lopes Vaz da silva Março 2012 MESTRADO INTEGRADO EM MEDICINA Ano letivo: 2011/2012 Nome do Estudante: Lídia Sousa Orientador : Doutor Manuel Joaquim Lopes Vaz da Silva Área do Projeto: Cardiologia Título do Projeto: Catecholaminergic Polymorphic Ventricular Tachycardia Resumo: A Taquicardia Ventricular Polimórfica Catecolaminérgica é uma doença hereditária arritmogénica rara, mas altamente letal quando não tratada. Constitui um problema de saúde importante, pois pode causar morte súbita em indivíduos jovens e aparentemente saudáveis. Caracteristicamente é induzida pelo exercício físico ou stress emocional e manifesta-se geralmente como uma síncope acompanhada de taquicardia ventricular, polimórfica, bidireccional. Nas últimas décadas tem havido uma crescente consciencialização sobre distintas canalopatias hereditárias, que são potencialmente letais, o que levou a um desabrochar da investigação neste campo. O objetivo principal desta revisão é resumir o conhecimento atual e destacar as novas descobertas sobre as características clínicas, o diagnóstico, as bases genéticas e fisiopatológicas, a terapêutica e o prognóstico da Taquicardia Ventricular Polimórfica Catecolaminérgica. Catecholaminergic Polymorphic Ventricular Tachycardia Sousa, Lídia Aluna da Faculdade de Medicina da Universidade do Porto Contact: [email protected] Faculdade de Medicina da Universidade do Porto Al. Prof. Hernâni Monteiro P- 4200 Porto Index List of Abbreviations ............................................................................................................. 2 List of Figures ........................................................................................................................ 3 List of Tables ......................................................................................................................... 3 Abstract ................................................................................................................................. 4 Keywords............................................................................................................................... 4 Resumo .................................................................................................................................. 5 Palavras-chave ....................................................................................................................... 5 Introduction ........................................................................................................................... 6 Material and Methods ............................................................................................................ 7 Clinical Manifestations .......................................................................................................... 8 Diagnosis and ECG Pattern .................................................................................................... 9 Pathophysiology of Arrhythmias ......................................................................................... 11 Genetic Basis ................................................................................................................... 11 RyR2 Mutations ........................................................................................................... 11 CASQ2 Mutations ........................................................................................................ 13 Ionic and Cellular Mechanisms ........................................................................................ 15 RyR2 Mutations and CPVT .......................................................................................... 17 CASQ2 Mutations and CPVT....................................................................................... 18 Effects of ß -Adrenergic Stimulation ............................................................................ 19 Current and Future Therapies for CPVT ............................................................................... 20 Acute Treatment............................................................................................................... 20 Chronic Treatment ........................................................................................................... 21 ß- Blocker Therapy....................................................................................................... 21 Other Options for Chronic Treatment ........................................................................... 21 Future Developments ....................................................................................................... 24 Genetic Testing .................................................................................................................... 26 Conclusions ......................................................................................................................... 27 Acknowledgements .............................................................................................................. 29 Conflicts of Interest.............................................................................................................. 29 References ........................................................................................................................... 30 List of Abbreviations ACC-American College of Cardiology AHA-American Heart Association CAMKII- Calmodulin Kinase II CASQ2- Calsequestrin 2 CPVT- Catecholaminergic Polymorphic Ventricular Tachycardia DADs- Delayed Afterdepolarizations ECG- Electrocardiogram ESC-European Society of Cardiology HRS-Heart Rhythm Society ICD- Implantable Cardioverter Defibrillators LSD- Left Sympathetic Denervation LTCC-L-Type Calcium Channels PKA- Phospho- Kinase A RyR2- Ryanodine Receptor 2 SCD- Sudden Cardiac Death SR- Sarcoplasmatic Reticulum VF- Ventricular Fibrillation VT- Ventricular Tachycardia 2 List of Figures Figure 1- Typical ECG of a patient with CPVT. Figure 2- Transmenbranar structure of the RyR2 channel, with localization of a new mutation. Figure 3- CASQ2 gene sequentiation. Figure 4- Excitation-contraction coupling mechanism. Figure 5- Schematic sequence: Cytoplasmatic calcium overload- Delayed Afterdepolarizations- Polymorphic Ventricular Tachycardia. List of Tables Table 1- RyR2 mutations. Table 2- CASQ2 mutations. 3 Abstract Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare, although highly lethal, inherited arrhythmogenic disease. It constitutes an important health burden as may cause sudden cardiac death in young otherwise healthy subjects. Characteristically it manifests as exercise or emotion-induced syncopal events and a distinctive pattern of reproducible, stress- related, bi-directional ventricular tachycardia. Clinical evaluation by exercise stress testing and holter monitoring can facilitate early identification, even though molecular genetic screening is critical to confirm uncertain diagnosis of CPVT. An autossomal-dominant form (related to mutations in the gene that codifies the Ryanodine Receptor 2) and an autossomal- recessive form (related to mutations on the cardiac isoform of calsequestrin 2) have been well described, and a mutation on either of these genes is found in 50 to 70% of patients with this syndrome. The basic arrhythmogenic mechanism of CPVT is thought to be deregulated leak of calcium from the sarcoplasmatic reticulum causing intracytoplasmatic overload and thus potentiating delayed afterdepolarizations and triggered activity. It is generally accepted that ß-blocker agents are the cornerstone of chronic CPVT therapy, nonetheless, many patients still remain symptomatic; recurrence and mortality remain high and many patients require an implantable cardioverter defibrillator. A great number of innovative therapeutic options have been described and seem promising but more investigation is still warranted. In the past decade there has been an increasing awareness of distinct, potentially lethal, heritable channelopathic syndromes, which led to a boom of investigation in this field. The main objective of this review is to summarize the current knowledge and highlight the new discoveries on the clinical characteristics, diagnostic, genetics, pathophysiologic mechanisms, therapeutic and prognostic features of CPVT. Keywords Catecholaminergic Polymorphic Ventricular Tachycardia; Delayed afterdepolarizations; Lethal arrhythmias; RyR2 Mutation; CASQ2 Mutation; Treatment 4 Resumo A Taquicardia Ventricular Polimórfica Catecolaminérgica (TVPC) é uma doença hereditária arritmogénica rara, mas altamente letal quando não tratada. Constitui um problema de saúde importante, pois pode causar morte súbita em indivíduos jovens e aparentemente saudáveis. Caracteristicamente é induzida pelo exercício físico ou stress emocional e manifesta-se geralmente como uma síncope acompanhada de taquicardia ventricular, polimórfica, bidireccional. A avaliação clínica através de um teste de stress ou monitorização com Holter pode facilitar a identificação precoce, ainda que uma investigação genética molecular seja fundamental para confirmar diagnósticos incertos. Estão descritas duas variantes desta doença, uma forma autossómica dominante que se deve a mutações no Receptor Rianodínico Tipo 2, e uma forma autossómica
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