Browsing by Subject "Sudden death"

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    A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain.
    (Elsevier, 2016-10-28) Sabater Molina, María; Saura, Daniel; García Molina Sáez, Esperanza; González Carrillo, Josefa; Polo, Luis; Pérez Sánchez, Inmaculada; Olmo, María Carmen; Oliva Sandoval, María José; Barriales Villa, Roberto; Carbonell, Pablo; Pascual Figal, Domingo A.; Gimeno, Juan Ramón; Ciencias Sociosanitarias
    Introducción y objetivos: Las mutaciones en MYBPC3 son causa de miocardiopatía hipertrófica (MCH). A pesar de que la mayorı´a de ellas producen una proteína truncada, la gravedad del fenotipo es diversa. Se describe el fenotipo clínico de una nueva mutación en MYBPC3, p.Pro108Alafs*9, presente en 13 familias del sur de España, y se compara con la mutación de MYBPC3 con mayor prevalencia en dicha región (c.2308 + 1 G > A). Métodos: Se estudió a 107 familiares de 13 casos índice que tenían diagnóstico de MCH y portaban la mutación p.Pro108Alafs*9. Se realizó un anélisis del árbol genealógico, junto con una evaluación clínica y determinación del genotipo. Resultados: Se identificó en total a 54 portadores de la mutación p.Pro108Alafs*9, de los que 39 tenían MCH. Hubo 5 casos de muerte súbita en las 13 familias. La penetrancia de la enfermedad aumentaba a medida que se incrementaba la edad, y los pacientes con MCH fueron con más frecuencia varones, y estos contrajeron la enfermedad más precozmente que las mujeres. El fenotipo fue similar en la p.Pro108Alafs*9 y la c.2308 + 1 G > A, pero se observaron diferencias en varios factores de riesgo y en la supervivencia. Hubo tendencia a mayor masa ventricular izquierda en la p.Pro108Alafs*9 que en la c.2308 + 1G > A. La resonancia magnética cardiaca reveló una extensión y un patrón de fibrosis similares en ambas. Conclusiones: La mutación p.Pro108Alafs*9 se asoció a MCH, alta penetrancia y aparición de la enfermedad a mediana edad.
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    Characteristics of sudden death in inherited heart disease
    (Elsevier, 2009-09-17) Gimeno, Juan Ramón; Oliva, María José; Lacunza, Javier; García Alberola, Arcadio; Sabater Molina, María; Martínez Sánchez, Juan José; Saura, Daniel; Romero, Antonio; Valdés, Mariano; Ciencias Sociosanitarias
    Introduction and objectives Cardiomyopathy and channelopathy are major causes of sudden death (SD). The little information available on the context in which SD occurs has come from only a few referral centers. The objective was to investigate the circumstances surrounding SD in families with inherited heart disease.. Methods. The study included 152 SD patients (mean age, 43[19] years) from 103 families. The reasons for inclusion were resuscitated SD in 7%, recent SD in 8%, and a diagnosis of cardiomyopathy or channelopathy in a living relative in 72%. Also, 13% were athletes. Family trees were constructed and each death’s circumstances were recorded. Autopsy and medical records were reviewed. Results. Overall, 18% of SDs occurred during physical exercise, 32% during normal daily activities, and 37% during rest or sleep. There was a significant association between male sex and SD: 111 males (73.0%) versus 41 females (27.0%; P=.03). Exercise-related SD was associated with young age (P=.01). The percentage of SDs associated with exercise, stress, or normal daily activities was significantly greater with cardiomyopathy than channelopathy (61% vs 41%, P=.057). All athletes were male and the majority died during exercise (50% vs 11% of non-athletes; P=.0002). Patients with Brugada syndrome had the highest percentage of SDs during rest or sleep (ie, 47%). No clear trigger could be identified in 33%. Conclusions. SD was common in inherited heart disease, which accounted for a significant number of cases. Males clearly predominated over females (ratio, 3:1) among SD cases (irrespective of pathological type). Most SDs occurred during exercise or normal daily activities in cardiomyopathies and during rest or sleep in channelopathies. The percentage of exercise-related SDs (i.e. 18%) was higher than expected.
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    Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype
    (Oxford University Press, 2014-06-17) López Ayala-José María; Gómez-Milanés, Iván; Sánchez Muñoz, Juan José; Ruiz Espejo, Francisco; Ortíz, Martín; González-Carrillo, Josefa; López-Cuenca, David; Monserrat, Lorenzo; Valdés, Mariano; Gimeno Blanes, Juan Ramón; Medicina; Facultad de Medicina
    Aims: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype–phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations. Methods and results: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging. Conclusion: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.
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    Exercise-induced ventricular arrhythmias and risk of sudden cardiac death in patients with hypertrophic cardiomyopathy
    (Oxford University Press, European Society of Cardiology, 2009-08-17) Gimeno Blanes, Juan Ramón; Tomé-Esteban, Maite; Lofiego, Carla; Hurtado, José; Pantazis, Antonios; Mist, Bryan; Lambiase, Pier; McKenna, William J.; Elliot, Perry M.; Medicina; Facultad de Medicina
    Background: Non-sustained ventricular tachycardia (NSVT) during ambulatory electrocardiographic monitoring (typically occurring at rest or during sleep) is associated with an increased risk of sudden cardiac death in patients with hypertrophic cardiomyopathy. The prevalence and prognostic significance of ventricular arrhythmias during exercise is unknown. Methods and results: This was a cohort study, with prospective data collection. We studied 1380 patients, referred to a cardiomyopathy clinic in London, UK [mean age 42 years (SD 15); 62% male; mean follow-up 54 (SD 49) months]. Patients underwent two-dimensional and Doppler echocardiography, upright exercise testing, and Holter monitoring. Twenty-seven patients [mean age 40 (SD 14) years (18–64); 22 (81.5%) male] had NSVT (24) or ventricular fibrillation (VF) (3) during exercise. During exercise, 13 (54.2%) had more than one run of NSVT (maximum 5) with a mean heart rate of 221 (SD 48) b.p.m. Patients with exercise NSVT/VF had more severe hypertrophy (22.6 vs. 19.5 mm, P = 0.009) and larger left atria (47.3 vs. 43.7 mm, P = 0.03). Male gender was significantly associated with exercise NSVT/VF [22 (81.5%) vs. 832 (61.5%), P = 0.03]. Eight (29.6%) of the exercise NSVT/VF patients died or had a cardiac event (SD/ICD discharge/transplant) compared with 150 (11.1%) patients without exercise NSVT/VF, P = 0.008. Patients with NSVT/VF had a 3.73-fold increase in risk of SD/ICD discharge (HR 95% CI: 1.61–8.63, P = 0.002). Exercise NSVT alone was associated with a 2.82-fold increased risk (HR 95% CI: 1.02–7.75, P = 0.049). In multivariable analysis with other risk markers, exercise NSVT/VF (but not NSVT alone) was independently associated with an increased risk of SD/ICD [HR 3.14 (95% CI: 1.29–7.61, P = 0.01)]. Conclusion: Ventricular arrhythmia during symptom limited exercise is rare in patients with hypertrophic cardiomyopathy, but is associated with an increased risk of sudden cardiac death.
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    Genetics of hypertrophic cardiomyopathy: A review of current state.
    (Wiley, 2017-03-21) Sabater Molina, María; Pérez Sánchez, Inmaculada; Gimeno, Juan Ramón; Hernández del Rincón, Juan Pedro; Ciencias Sociosanitarias
    Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease. HCM is a highly complex and heterogeneous disease regarding not only the number of associated mutations but also the severity of phenotype, symptom burden, and the risk of complications, such as heart failure and sudden death. The penetrance is incomplete and it is age and gender dependent. It is accepted as a disease of the sarcomere. Sixty percent of HCM cases carry mutations in 1 of 8 sarcomere protein genes, mainly non-sense MYBPC3 and missense MYH7 variants. Young patients with severe phenotype and other clinical features are included in proposed scores for prediction of high positive genetic result. The number of genes reported as disease-causing has increased in the last few years, in some cases without robust evidence. Currently available in silico tools are not always useful for differentiation between benign and deleterious variants. There is enough information on genotypephenotype correlations to start understanding the mechanisms of the disease. Genetic and environmental modifiers have been explored with some interesting insights from miRNA studies with potential as biomarkers and therapeutic agents. There is an additional value of genetic testing in HCM for prognosis. Knowledge about genetics and functional studies are the basis of near future therapies.
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    Impact of the Human Microbiome in Forensic Sciences: a Systematic Review
    (American Society for Microbiology, 2020-10-28) García, Manuel G.; Pérez Cárceles, María Dolores; Osuna, Eduardo; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    Numerous studies relate differences in microbial communities to human health and disease; however, little is known about microbial changes that occur postmortem or the possible applications of microbiome analysis in the field of forensic science. The aim of this review was to study the microbiome and its applications in forensic sciences and to determine the main lines of investigation that are emerging, as well as its possible contributions to the forensic field. A systematic review of the human microbiome in relation to forensic science was carried out by following PRISMA guidelines. This study sheds light on the role of microbiome research in the postmortem interval during the process of decomposition, identifying death caused by drowning or sudden death, locating the geographical location of death, establishing a connection between the human microbiome and personal items, sexual contact, and the identification of individuals. Actinomycetaceae, Bacteroidaceae, Alcaligenaceae, and Bacilli play an important role in determining the postmortem interval. Aeromonas can be used to determine the cause of death, and Corynebacterium or Helicobacter pylori can be used to ascertain personal identity or geographical location. Several studies point to a promising future for microbiome analysis in the different fields of forensic science, opening up an important new area of research.
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    Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies
    (Elsevier, American College of Cardiology, 2016-11-28) Ortiz-Genga, Martín F.; Cuenca, Sofía; Dal Ferro, Matteo; Zorio, Esther; Zorio, Esther; Climent, Vicente; Padrón-Barthe, Laura; Duro-Aguado, Iria; Jiménez-Jáimez, Juan; Hidalgo-Olivares, Victor M.; García-Campo, Enrique; Lanzillo, Chiara; Suárez-Mier, M. Paz; Yonath, Hagith; Marcos-Alonso, Sonia; Ochoa, Juan P.; Santomé, José L.; García-Giustiniani, Diego; Rodríguez-Garrido, Jorge L.; Domínguez, Fernando; Merlo, Marco; Palomino, Julián; Peña, María L.; Trujillo, Juan P.; Martín-Vila, Alicia; Stolfo, Davide; Molina, Pilar; Lara-Pezzi, Enrique; Calvo-Iglesias, Francisco E.; Nof, Eyal; Calò, Leonardo; Barriales-Villa, Roberto; Gimeno Blanes, Juan Ramón; Arad, Michael; García-Pavía, Pablo; Monserrat, Lorenzo; Medicina; Facultad de Medicina
    BACKGROUND: Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES: The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS: FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS: Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS: Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.