Hallazgos histopatológicos en la disección y rotura de la aorta torácica. Estudio de 54 casos de autopsia / Histopathological findings in dissection and rupture of the thoracic aorta. Study of 54 autopsy cases

Introducción la disección/rotura de la aorta torácica tiene una alta mortalidad, constituyendo de 3,9 a 5,4% de las muertes súbitas en series forenses. Los hallazgos histopatológicos de la media asociados a estas entidades han recibido múltiples términos y definiciones. En 2016, la Asociación Europea de Patología Cardiovascular junto con la Sociedad de Patología Cardiovascular publicaron un documento de consenso, aplicado a muestras quirúrgicas, para unificar criterios. El objetivo de este trabajo es valorar su aplicación en las autopsias forenses. Un objetivo secundario es estudiar cambios inflamatorios útiles para la datación. Material y métodos se revisaron las preparaciones histológicas de aorta de 54 casos de muertes súbitas por rotura/disección aórtica estudiados entre 2019 y 2022. Resultados se observó degeneración de la media en 49 casos (90,8%) (severa en 42,9%). Por lesiones, el orden de frecuencia fue: fragmentación y/o pérdida de las fibras elásticas (74,1%); acúmulo de matriz mucoide extracelular (61,1%); pérdida de núcleos de células musculares lisas (48,1%) y colapso de la media (44,4%). Algunas lesiones del documento no pudieron ser valoradas. No se encontraron diferencias significativas por edad; presencia o no de colagenopatías; o válvulas aórticas bi/tricúspides. Se observó tejido de granulación o infiltrado neutrofílico en los fallecidos con dolor de varios días o <24 h antes de la muerte, respectivamente. Conclusión con la aplicación del documento se encuentran lesiones en la media en >90% de los casos y pueden estudiarse las lesiones fundamentales. La respuesta inflamatoria frente a la rotura/disección parece correlacionarse con el momento de la disección/rotura. (AU)

Introduction Thoracic aortic dissection/rupture has a high mortality, constituting 3.9-5.4% of sudden deaths in forensic series. Medial histopathological findings associated with these entities have received multiple terms and definitions. In 2016, the European Association for Cardiovascular Pathology and the Society for Cardiovascular Pathology published a consensus document, applied to surgical specimens, to unify criteria. The aim of this work is to assess its application in forensic autopsies. A secondary objective is to study inflammatory changes useful for dating. Material and methods Aortic histological preparations of the 54 cases of sudden deaths due to aortic rupture/dissection studied between 2019 and 2022 were reviewed. Results Medial degeneration was observed in 49 cases (90.8%) (severe in 42.9%). By lesions, the order of frequency was: fragmentation and/or loss of elastic fibers (74.1%); accumulation of extracellular mucoid matrix (61.1%); loss of smooth muscle cell nuclei (48.1%) and collapse of the media (44.4%). Some lesions of the consensus paper could not be assessed. No significant differences were found by age; presence or not of collagenopathies; or bi/tricuspid aortic valves. Granulation tissue or neutrophilic infiltrate was observed in those deceased with pain several days or <24 h before death, respectively. Conclusion With the application of the document, lesions in the media are found in >90% of cases and fundamental lesions can be studied. The inflammatory response to rupture/dissection appears to correlate with the timing of dissection/rupture. (AU)

Pathogenic truncating filamin C mutations presenting as acute myocarditis: a case series with insights from cardiac magnetic resonance and histological analysis.

Background: The exact mechanisms underlying the pathogenesis of myocarditis are not always understood, but there is emerging evidence to suggest that genetic factors may play a significant role. Case summary: Herein, we present six cases in which clinical, biochemical, and cardiovascular magnetic resonance data were consistent with myocarditis, and genetic testing subsequently revealed pathogenic filamin C (FLNC) mutations. Three patients presented with ventricular arrhythmias, two with severe biventricular dysfunction, and two suffered sudden cardiac arrest. Three received an implantable cardioverter defibrillator, and one underwent heart transplantation. Cascade testing was useful in identifying other relatives with FLNC mutation. We also present relevant histology results of myocardial specimens showing the presence of lymphocytic infiltration and inflammation, further supporting the potential association between FLNC mutations and a myocarditis phenotype. Discussion: Genetic testing of affected individuals for FLNC mutations and cascade screening in the setting of acute myocarditis may be considered in selected clinical context, such as in acute myocarditis accompanied by severe left ventricular systolic dysfunction, biventricular failure, significant ventricular arrhythmias, or right ventricular involvement.

Genetically determined cardiomyopathies at autopsy: the pivotal role of the pathologist in establishing the diagnosis and guiding family screening.

Cardiomyopathies (CMP) comprise a heterogenous group of diseases affecting primarily the myocardium, either genetic and/or acquired in origin. While many classification systems have been proposed in the clinical setting, there is no internationally agreed pathological consensus concerning the diagnostic approach to inherited CMP at autopsy. A document on autopsy diagnosis of CMP is needed because the complexity of the pathologic backgrounds requires proper insight and expertise. In cases presenting with cardiac hypertrophy and/or dilatation/scarring with normal coronary arteries, a suspicion of inherited CMP must be considered, and a histological examination is essential. Establishing the actual cause of the disease may require a number of tissue-based and/or fluid-based investigations, be it histological, ultrastructural, or molecular. A history of illicit drug use must be looked for. Sudden death is frequently the first manifestation of disease in case of CMP, especially in the young. Also, during routine clinical or forensic autopsies, a suspicion of CMP may arise based on clinical data or pathological findings at autopsy. It is thus a challenge to make a diagnosis of a CMP at autopsy. The pathology report should provide the relevant data and a cardiac diagnosis which can help the family in furthering investigations, including genetic testing in case of genetic forms of CMP. With the explosion in molecular testing and the concept of the molecular autopsy, the pathologist should use strict criteria in the diagnosis of CMP, and helpful for clinical geneticists and cardiologists who advise the family as to the possibility of a genetic disease.

Muerte súbita relacionada con la actividad deportiva en España. Estudio poblacional multicéntrico forense de 288 casos / Sports-related sudden cardiac death in Spain. A multicenter, population-based, forensic study of 288 cases

Introducción y objetivos Conocer la incidencia, características clínico-patológicas, hábitos tóxicos y actividad deportiva relacionadas con la muerte súbita en la actividad deportiva en España.MétodosEstudio poblacional retrospectivo y multicéntrico, basado en autopsias forenses realizadas en 25 provincias durante 8 años (2010-2017).ResultadosSe investigaron 288 casos (el 98,6% varones; media de edad, 43,8±14,4 años). La incidencia fue de 0,38 casos/100.000 hab./año (0,82 entre deportistas habituales), la mayoría (54%) varones entre 35 y 54 años. Los deportes más frecuentes (el 96% recreativos) fueron ciclismo (28%), fútbol (18%) y carrera a pie (17%). La muerte fue de origen cardiovascular en el 99%: cardiopatía isquémica (63%), miocardiopatías (21%) y síndrome de muerte súbita arrítmica (6%). En los jóvenes, las miocardiopatías (38%) y la cardiopatía isquémica (30%), presente a partir de los 20 años, fueron las más prevalentes. La enfermedad se había diagnosticado en vida en 23 casos; se observaron antecedentes clínicos relevantes en 30 casos y factores de riesgo cardiovascular, principalmente obesidad, en 95. El análisis toxicológico detectó sustancias cardiotóxicas en el 7%, y destaca la relación entre cannabis y cardiopatía isquémica aguda.ConclusionesLa muerte súbita asociada a la actividad deportiva en España tiene una incidencia muy baja, afecta a varones de mediana edad que realizan deporte recreativo, principalmente ciclismo, fútbol y carrera, y es de origen cardiovascular, con aparición temprana de la cardiopatía isquémica. Los datos clínicos y los hábitos tóxicos deben tenerse en cuenta para desarrollar estrategias de prevención. (AU)

Introduction and objectives To determine the incidence of sports-related sudden cardiac death in Spain, and to identify the clinical-pathological characteristics, substance abuse, and sports activity associated with this entity.MethodsRetrospective, population-based, multicenter study of forensic autopsies conducted in 25 provinces during an 8-year period (2010-2017).ResultsWe investigated 288 cases (98.6% occurred in men with a mean age of 43.8±14.4 years). The incidence in the general population was 0.38 cases out of 100 000 inhabitants per year (0.82 among regular athletes), and most cases (54%) occurred in persons aged between 35 and 54 years. The most frequent sports (96% recreational) were cycling (28%), football (18%), and jogging (17%). Death was of cardiovascular origin in 99%. The main causes were ischemic heart disease (63%), cardiomyopathies (21%), and sudden arrhythmic death syndrome (6%). In young people, cardiomyopathies (38%) and ischemic heart disease (30%), present after the age of 20 years, were the most prevalent. The disease was diagnosed during life in 23 cases, relevant clinical antecedents were observed in 30 cases, and cardiovascular risk factors, mainly obesity, in 95 cases. Toxicological analysis detected cardiotoxic substances in 7%, highlighting the association between cannabis and acute ischemic heart disease.ConclusionsSports-related sudden cardiac death in Spain has a very low incidence and affects middle-aged men practicing recreational sports, mainly cycling, football, and jogging. This entity is of cardiovascular origin with early onset of ischemic heart disease. Clinical data and substance abuse should be taken into account to develop preventive strategies. (AU)

Sports-related sudden cardiac death in Spain. A multicenter, population-based, forensic study of 288 cases.

INTRODUCTION AND OBJECTIVES: To determine the incidence of sports-related sudden cardiac death in Spain, and to identify the clinical-pathological characteristics, substance abuse, and sports activity associated with this entity. METHODS: Retrospective, population-based, multicenter study of forensic autopsies conducted in 25 provinces during an 8-year period (2010-2017). RESULTS: We investigated 288 cases (98.6% occurred in men with a mean age of 43.8±14.4 years). The incidence in the general population was 0.38 cases out of 100 000 inhabitants per year (0.82 among regular athletes), and most cases (54%) occurred in persons aged between 35 and 54 years. The most frequent sports (96% recreational) were cycling (28%), football (18%), and jogging (17%). Death was of cardiovascular origin in 99%. The main causes were ischemic heart disease (63%), cardiomyopathies (21%), and sudden arrhythmic death syndrome (6%). In young people, cardiomyopathies (38%) and ischemic heart disease (30%), present after the age of 20 years, were the most prevalent. The disease was diagnosed during life in 23 cases, relevant clinical antecedents were observed in 30 cases, and cardiovascular risk factors, mainly obesity, in 95 cases. Toxicological analysis detected cardiotoxic substances in 7%, highlighting the association between cannabis and acute ischemic heart disease. CONCLUSIONS: Sports-related sudden cardiac death in Spain has a very low incidence and affects middle-aged men practicing recreational sports, mainly cycling, football, and jogging. This entity is of cardiovascular origin with early onset of ischemic heart disease. Clinical data and substance abuse should be taken into account to develop preventive strategies.

Autopsias en casos sospechosos de SARS-CoV-2 / Autopsies of suspected SARS-CoV-2 cases

La medicina forense debe contemplar la posibilidad de que fallecidos por causas violentas o desconocidas puedan estar infectados por el virus SARS-CoV-2, o que el diagnóstico de la enfermedad tenga implicaciones legales, lo que exige un conocimiento adecuado de la epidemiología de la enfermedad, de las medidas de protección, de la toma de muestras y de las características anatomopatológicas. La práctica de autopsias en fallecidos por COVID-19 se ha visto limitada por las obligadas medidas preventivas frente al contagio y por la necesidad de disponer de instalaciones con nivel de protección frente a riesgos biológicos de nivel 3, de modo que las series publicadas hasta la fecha son escasas, y parciales, con abordajes limitados (autopsia mínimamente invasiva o biopsia con aguja gruesa). En este artículo se hace una revisión de los aspectos de la fisiopatología de la enfermedad que tienen repercusión en la infectividad de los tejidos y fluidos del cadáver, de las medidas de prevención del riesgo biológico, de la toma de muestras y de los hallazgos patológicos, tanto macroscópicos como microscópicos, asociados a la muerte provocada por la infección por el virus SARS-CoV-2

Forensic physicians should consider the possibility that people who have died from violent or unknown causes may be infected by the virus SARS-CoV-2, or that the diagnosis of the disease has legal implications, which requires adequate knowledge of the epidemiology of the disease, protective measures, adequate sampling and the pathological characteristics. The practice of autopsies on people who have died from COVID-19 has been limited by the mandatory preventive measures against contagion and by the need for facilities with a level of protection against level-3 biological risk, and therefore series published to date are scarce and partial,with limited approaches (minimally invasive autopsy or needle biopsy). This article reviews the aspects of the pathophysiology of the disease that have an impact on the infectivity of the body's tissues and fluids, measures for preventing biological risk, taking samples and pathological findings, both macroscopic and microscopic, associated with death caused by infection with the SARS-CoV-2 virus

Sports-related sudden cardiac death due to myocardial diseases on a population from 1-35 years: a multicentre forensic study in Spain.

This is a multicentre forensic study that identifies all sports-related sudden deaths (SRSDs) in young people, due to myocardial diseases (MDs) that occurred in a large area of Spain. The aim of the study is to assess the epidemiology, causes of death, and sport activities associated with these fatalities. This is a retrospective study based on forensic autopsies performed in the provinces of Biscay, Seville, Valencia and in the jurisdiction covered by the National Institute of Toxicology and Forensic Sciences in Madrid (Spain). The retrospective study encompasses from 2010 to 2017. All sudden cardiac deaths (SCDs) in persons 1-35 years old were selected. The total number of SCDs were divided into death occurred during exercise (SRSD) and death during rest, sleep or normal activities (non-SRSD). Each of these two groups was subdivided according to the cause of death into MD (primary cardiomyopathies and myocarditis) and non-MD. Clinic-pathological, toxicological and genetic characteristics of SRSD due to MD were analysed. Over the 8-year study period, we identified 645 cases of SCD in the young: 75 SRSD (11.6%) and 570 non-SRSD (88.4%). MD was diagnosed in 33 (44.0%) of the SRSD and in 112 (19.6%) of the non-SRSD cases. All cases of SRSD due to MD were males (mean age (24.0 ± 7.6) years) practicing recreational sports (85%). SRSDs were more frequent in arrhythmogenic cardiomyopathy (ACM) (37%) and hypertrophic cardiomyopathy (HCM) (24%), followed by myocarditis (15%) and idiopathic left ventricular hypertrophy (ILVH) (9%). Only in five cases of SRSD the MD responsible of death (HCM) had been diagnosed in life. Cardiovascular symptoms related to the disease were present in other seven patients (six of them with ACM). Postmortem genetic studies were performed in 15/28 (54%) primary cardiomyopathies with positive results in 12 (80%) cases. The most frequent sports disciplines were football (49%) followed by gymnastics (15%) and running (12%). In Spain, SRSD in young people due to MDs occurs in males who perform a recreational activity. Compared with control group we observed a strong association between MDs and exertion. One in three SRSDs are due to cardiomyopathy, especially ACM, which reinforces the need for preparticipation screening to detect these pathologies in recreational sport athletes. Further studies are warranted to understand the causes and circumstances of sudden death to facilitate the development of preventive strategies.

Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.

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.

Técnica de electrólisis para el estudio histopatológico de stents coronarios / Electrolysis technique for the histopathological study of stented coronaries

Introducción. El uso generalizado de stents coronarios para el tratamiento de la cardiopatía isquémica hace que con frecuencia se encuentren en los corazones de autopsia. Al ser metálicos, las coronarias no pueden procesarse de forma convencional y su estudio requiere la extracción manual previa, o la inclusión en resinas sintéticas, que es un método caro y lento. En 2009, Bradshaw et al. describieron un método para la disolución de stents mediante electrólisis. El objetivo de este trabajo es presentar esta técnica y los resultados obtenidos en nuestro laboratorio. Material y método. Se requiere fuente de alimentación para crear un campo eléctrico, vaso de precipitados con solución electrolítica, cables eléctricos, anilla metálica, tapadera, muelle de acero inoxidable y grasa industrial. La técnica se basa en una reacción electroquímica, de manera que se crea una corriente eléctrica continua en una solución salina entre un metal (stent) más electropositivo que se oxida (se disuelve) y un metal (anilla) más electronegativo que se reduce. Tras la disolución del stent la coronaria se secciona e incluye en parafina. Hemos estudiado 60 segmentos coronarios con stents de 54 corazones. Resultados. La disolución del metal se ha conseguido en todos los casos excepto en uno. En 54 se observó neoíntima con orificios vacíos dejados por el metal; en 6 se observó la impronta dejada por el stent en la íntima y en 3 de estos, trombosis oclusiva. Conclusión. La electrólisis de stents coronarios es una técnica sencilla, económica y segura accesible a cualquier laboratorio de Anatomía Patológica (AU)

Introduction. Coronary stenting for the treatment of ischemic heart disease is widespread and thus stents are frequently found in hearts at autopsy. Conventional methods of histological preparation cannot be used in stented coronaries and embedding in synthetic resins is required, which is expensive and time-consuming. In 2009, Bradshaw et al. described a method to dissolve metallic stents by electrolysis. The aim of this work is to present this method and the results obtained in our laboratory. Material and method. A power supply, a beaker with electrolytic solution, electrical wires, a metal ring, a stopper, a stainless steel spring and industrial grease are required. The method is based on an electrochemical reaction so that an electric current is created in a saline solution between a more electropositive metal (stent), which is oxidized (dissolves), and a more electronegative metal (ring), which is reduced. After dissolution the stented coronary is cut and embedded in paraffin. We have studied 60 stented coronaries from 54 hearts. Results. Metal dissolution was accomplished in all cases but one. In 54 a neointima was observed with empty holes left by the metal; in six, the stent imprint was observed in the intima and 3 showed occlusive thrombus. Conclusion. Stented coronary electrolysis is a simple, cheap and safe technique accessible to any Pathology Laboratory (AU)

Hallazgo casual de un quiste aracnoideo intracraneal / Incidental intracraneal arachnoid cyst

No disponible

Rasgos no ventriculares, clínicos y funcionales de la mutación RyR2 R420Q causante de taquicardia ventricular polimórfica catecolaminérgica / Non-ventricular, clinical, and functional features of the ryr2 r420q mutation causing catecholaminergic polymorphic ventricular tachycardia

Introducción y objetivos: La taquicardia ventricular polimórfica catecolaminérgica es una enfermedad maligna que se debe a mutaciones en las proteínas que controlan la homeostasis del Ca2+. Aunque el fenotipo se caracteriza por arritmias ventriculares polimórficas desencadenadas por el estrés, no se han caracterizado plenamente las arritmias supraventriculares que en ocasiones las acompañan. Métodos: Veinticinco miembros de una familia española en la que había habido varias muertes súbitas fueron evaluados mediante electrocardiograma, pruebas de esfuerzo y prueba de desenmascaramiento con adrenalina opcionalmente. Se realizó secuenciación selectiva deRyR2 en un miembro afectado y un cribado en cascada al resto de la familia. Se generó la mutación RyR2R420Q en células HEK-293 mediante mutagénesis dirigida, con objeto de realizar estudios funcionales in vitro. Resultados: Las pruebas de esfuerzo desenmascararon taquicardia ventricular polimórfica catecolaminérgica en 8 familiares (sensibilidad del 89%; valor predictivo positivo del 100%; valor predictivo negativo del 93%), todos ellos portadores de una mutación heterocigota RyR2R420Q, que estaba presente también en el caso probando y en una chica joven sin prueba de esfuerzo, lo que corresponde a una penetrancia del 91% al final del seguimiento. Es de destacar que en los pacientes se identificó bradicardia sinusal, arritmias auriculares y de la unión y/u ondas U gigantes tras esfuerzo. Tras la permeabilización y en las células intactas, las células que expresaban RyR2R420Q mostraron un pico de liberación de Ca2+ menor que el de las célulasRyR2 no mutado o wild-type. Sin embargo, a una concentración de Ca2+ intracelular fisiológica, equivalente a la concentración citosólica diastólica, las células RyR2R420Q liberaban más Ca2+ y oscilaban con mayor rapidez que las células con RyR2 no mutado o wild-type. Conclusiones: La mutación missense RyR2R420Q se identificó en el extremo aminoterminal del gen RyR2 en esta familia muy sintomática. Es de destacar que esta mutación se asocia a bradicardia sinusal, arritmias auriculares y de la unión y ondas U gigantes. En conjunto, los estudios de expresión heteróloga funcional indican que la mutación RyR2R420Q causa un comportamiento aberrante del canal, con pérdida o ganancia de función, según cuál sea la concentración de Ca2+ intracelular citosólica

Introduction and objectives: Catecholaminergic polymorphic ventricular tachycardia is a malignant disease, due to mutations in proteins controlling Ca2+ homeostasis. While the phenotype is characterized by polymorphic ventricular arrhythmias under stress, supraventricular arrhythmias may occur and are not fully characterized. Methods: Twenty-five relatives from a Spanish family with several sudden deaths were evaluated with electrocardiogram, exercise testing, and optional epinephrine challenge. Selective RyR2 sequencing in an affected individual and cascade screening in the rest of the family was offered. The RyR2R420Q mutation was generated in HEK-293 cells using site-directed mutagenesis to conduct in vitro functional studies. Results: The exercise testing unmasked catecholaminergic polymorphic ventricular tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; negative predictive value = 93%), all of them carrying the heterozygous RyR2R420Q mutation, which was also present in the proband and a young girl without exercise testing, a 91% penetrance at the end of the follow-up. Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant post-effort U-waves were identified in patients. Upon permeabilization and in intact cells, the RyR2R420Q expressing cells showed a smaller peak of Ca2+ release than RyR2 wild-type cells. However, at physiologic intracellular Ca2+ concentration, equivalent to the diastolic cytosolic concentration, the RyR2R420Q released more Ca2+ and oscillated faster than RyR2 wild-type cells. Conclusions The missense RyR2R420Q mutation was identified in the N-terminus of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is associated with sinus bradycardia, atrial and junctional arrhythmias, and giant U-waves. Collectively, functional heterologous expression studies suggest that the RyR2R420Q behaves as an aberrant channel, as a loss- or gain-of-function mutation depending on cytosolic intracellular Ca2+ concentration

Non-ventricular, Clinical, and Functional Features of the RyR2(R420Q) Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia.

INTRODUCTION AND OBJECTIVES: Catecholaminergic polymorphic ventricular tachycardia is a malignant disease, due to mutations in proteins controlling Ca(2+) homeostasis. While the phenotype is characterized by polymorphic ventricular arrhythmias under stress, supraventricular arrhythmias may occur and are not fully characterized. METHODS: Twenty-five relatives from a Spanish family with several sudden deaths were evaluated with electrocardiogram, exercise testing, and optional epinephrine challenge. Selective RyR2 sequencing in an affected individual and cascade screening in the rest of the family was offered. The RyR2(R420Q) mutation was generated in HEK-293 cells using site-directed mutagenesis to conduct in vitro functional studies. RESULTS: The exercise testing unmasked catecholaminergic polymorphic ventricular tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; negative predictive value = 93%), all of them carrying the heterozygous RyR2(R420Q) mutation, which was also present in the proband and a young girl without exercise testing, a 91% penetrance at the end of the follow-up. Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant post-effort U-waves were identified in patients. Upon permeabilization and in intact cells, the RyR2(R420Q) expressing cells showed a smaller peak of Ca(2+) release than RyR2 wild-type cells. However, at physiologic intracellular Ca(2+) concentration, equivalent to the diastolic cytosolic concentration, the RyR2(R420Q) released more Ca(2+) and oscillated faster than RyR2 wild-type cells. CONCLUSIONS: The missense RyR2(R420Q) mutation was identified in the N-terminus of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is associated with sinus bradycardia, atrial and junctional arrhythmias, and giant U-waves. Collectively, functional heterologous expression studies suggest that the RyR2(R420Q) behaves as an aberrant channel, as a loss- or gain-of-function mutation depending on cytosolic intracellular Ca(2+) concentration.

Pathology of sudden death during recreational sports in Spain.

BACKGROUND: Most sudden deaths during sports occur in general population practising recreational sports and according to legislation, a forensic autopsy is required. Most are sudden cardiac deaths but the incidence of specific pathologies differs in reported series according to autopsy methods or diagnostic criteria. The purpose of this work is to analyse the pathology of sports-related sudden deaths in a large forensic series from Spain studied according with cardiovascular pathology criteria. MATERIALS AND RESULTS: We have reviewed the sudden deaths occurred during sports studied at our institution between 1995 and 2010 in which a complete autopsy was performed with exhaustive cardiac examination and toxicological analysis. Out of 8862 sudden deaths studied, 168 (1.8%) were related to sports; age was between 9 and 69 (average 36.6 ± 15.6 y); 163 were males and 5 females. Only 3 were professional athletes. Most frequent sports associated to sudden death were cycling (29%), soccer (25.5%), running (8.9%) and gymnastics (6.5%). In 49 cases (29.1%) there were some personal pathological antecedents or familial sudden deaths. Causes of death were: coronary atherosclerotic disease, 85 (50.5%) (74 over 35 years old); arrhythmogenic cardiomyopathy, 13 (7.7%); hypertrophic cardiomyopathy, 12 (7.1%); idiopathic left ventricular hypertrophy, 7 (4.1%); congenital coronary anomalies, 7 (4.1%); myocarditis, 6 (3.5%); aortic stenosis, 5 (2.9%); and other, 11 (6.5%). Myocardial diseases were the most frequent under 35 years old. No cause of death was found in 19 (11.3%) (all under 30 years old) what stresses the necessity of including molecular techniques in forensic autopsies.

False lumen stent placement during iatrogenic coronary dissection.

A 38-year-old woman without significant cardiovascular risk factors was admitted in the coronary care unit with the diagnosis of acute coronary syndrome without ST-segment elevation. In coronary angiography, left coronary artery system was normal in the first contrast injection, but acute occlusion of the left main coronary trunk (LCT) due to iatrogenic dissection was observed in the following. The patient presented marked ST elevation, severe hypotension, hemodynamic collapse, and loss of consciousness. Cardiopulmonary resuscitation (CPR) was initiated, and two drug-eluting stents were consecutively placed in the LCT and the left anterior descending coronary (LAD), but the patient died after 60 min of continuous CPR. The autopsy showed dissection of the LCT and LAD coronaries with both stents placed in the false lumen and hyperacute myocardial infarction in the anterior left ventricular free wall. This case underlines the importance of careful indication of invasive procedures and of taking in consideration their potential risks.

Clinicopathological features of sudden unexpected infectious death: population-based study in children and young adults.

INTRODUCTION AND OBJECTIVES: Infectious diseases are one of the major causes of sudden death, but data of sudden unexpected death from infectious diseases (SUDID) are sparse in children and young people. The aim of this study is to analyse their epidemiological, clinical, pathological and microbiological characteristics. METHODS: Population observational study of all deaths due to infectious diseases in people aged 0-34 years in Biscay between 1991 and 2010. The data of Mortality Register and Forensic Pathology Service were analysed. The SUDID cases in which a forensic autopsy was performed were identified. RESULTS: There were 56 SUDID cases (16% of the all sudden deaths). Myocarditis (n=20) and acute bacterial bronchopneumonia/pneumonia (n=18) were the most frequent causes, followed by meningococcemia (n=5) and viral pneumonia (n=4). A chronic co-morbid condition (mainly drug abuse in young people and moderate low birth weight in infants) was recorded in one-third and prodromal symptoms in two-thirds. Seventeen young people had consumed illegal drugs and/or methadone. In 17 of the 23 autopsies where microbiological analyses were performed, the organism responsible was identified. The incidence of SUDID was 0.6/100000 inhabitants/year, representing 5% of all deaths from infectious diseases. SUDID rate was 1.87 times higher in males than in females. The highest incidence occurred in infants (3.7). CONCLUSIONS: SUDID is infrequent, but it represents a significant proportion of all sudden deaths in children and young people. The relationship between methadone and bronchopneumonia is noticeable. This article stresses the importance of microbiological analyses in SUDID. Investigation based on forensic pathology provides useful epidemiologic, clinico-pathological and microbiological information for prevention of infectious diseases.

[Myocardial disease mortality in children and young adults. A population-based observational study]. / Mortalidad por enfermedades del miocardio en niños y jóvenes. Estudio observacional de base poblacional.

INTRODUCTION AND OBJECTIVES: Few studies have investigated death due to myocardial disease in children and young adults. The aim of this study was to analyze the epidemiological, clinical, and pathologic characteristics of death in these cases. PATIENTS AND METHOD: Population-based observational study of all deaths in individuals aged 1-35 years in the Spanish province of Biscay over a period of 12 years. RESULTS: Forty deaths from myocardial disease occurred in 29 males and 11 females (mean age 25.3 years): 30 sudden and 10 non-sudden deaths. The mortality rate was 0.64 per 100,000 persons-year. The relative risk of sudden death was significantly greater than that of non-sudden death, particularly in adolescents and young males. The cause of death was myocarditis in 12 cases (83.3% sudden death), dilated cardiomyopathy in 10 (80% non-sudden death), arrhythmogenic cardiomyopathy in seven, hypertrophic cardiomyopathy in six, and idiopathic concentric left ventricular hypertrophy in five (100% sudden death). Myocardial disease was diagnosed before sudden death in only three cases. Ten subjects had symptoms and electrocardiogram abnormalities but their cardiomyopathy had not been diagnosed. Six individuals had a comorbid condition (morbid obesity in four), six had prodromal symptoms, and 11 had arrhythmic triggering factors (sporting activity in seven). Ventricular fibrillation was frequently observed during cardiopulmonary resuscitation. CONCLUSIONS: Mortality due to myocardial disease in children and young adults is uncommon. Most deaths are sudden. However, some may be preventable. Preventative measures should be aimed at sudden death in adolescents and young males. There was a noticeable association between arrhythmogenic cardiomyopathy and sporting activity.

Mortalidad por enfermedades del miocardio en niños y jóvenes. Estudio observacional de base poblacional / Myocardial disease mortality in children and young adults. A population-based observational study

Introducción y objetivos. Hay pocos estudios sobre la mortalidad por enfermedades del miocardio en niños y jóvenes. El objetivo de este estudio es analizar sus características epidemiológicas y clinicopatológicas. Pacientes y método. Estudio observacional sobre la población general de todas las muertes en personas de 1-35 años de edad en Bizkaia durante 12 años. Resultados. Hubo 40 fallecimientos por enfermedades del miocardio: 30 muertes súbitas y 10 no súbitas; 29 varones y 11 mujeres (edad media, 25,3 años). La tasa de mortalidad fue de 0,64/100.000 habitantes/año. El riesgo relativo de muerte súbita fue significativamente más alto que el de muerte no súbita, en particular entre adolescentes y varones jóvenes. Las causas de muerte fueron: miocarditis en 12 casos (el 83,3% por muerte súbita), miocardiopatía dilatada en 10 (el 80% por muerte no súbita), miocardiopatía arritmogénica en 7, miocardiopatía hipertrófica en 6 e hipertrofia ventricular izquierda concéntrica idiopática en 5 (el 100% por muerte súbita). Sólo en 3 casos de muerte súbita la enfermedad se diagnosticó en vida. Diez sujetos presentaron en vida síntomas o anomalías electrocardiográficas, pero sin diagnóstico de la enfermedad. Se detectaron condiciones comórbidas en 6 casos (obesidad mórbida en 4), síntomas prodrómicos en 6 y factores desencadenantes de la arritmia letal en 11 (deporte en 7). Durante la reanimación cardiopulmonar se observó con frecuencia fibrilación ventricular. Conclusiones. La mortalidad por enfermedades del miocardio en niños y jóvenes es infrecuente y la mayoría son muertes súbitas. Algunos casos podrían ser potencialmente previsibles. Los principales esfuerzos de prevención deberían orientarse al grupo de varones adolescentes y jóvenes Es destacable la relación entre miocardiopatía arritmogénica y deporte

Introduction and objectives. Few studies have investigated death due to myocardial disease in children and young adults. The aim of this study was to analyze the epidemiological, clinical, and pathologic characteristics of death in these cases. Patients and method. Population-based observational study of all deaths in individuals aged 1-35 years in the Spanish province of Biscay over a period of 12 years. Results. Forty deaths from myocardial disease occurred in 29 males and 11 females (mean age 25.3 years): 30 sudden and 10 non-sudden deaths. The mortality rate was 0.64 per 100,000 persons-year. The relative risk of sudden death was significantly greater than that of non-sudden death, particularly in adolescents and young males. The cause of death was myocarditis in 12 cases (83.3% sudden death), dilated cardiomyopathy in 10 (80% non-sudden death), arrhythmogenic cardiomyopathy in seven, hypertrophic cardiomyopathy in six, and idiopathic concentric left ventricular hypertrophy in five (100% sudden death). Myocardial disease was diagnosed before sudden death in only three cases. Ten subjects had symptoms and electrocardiogram abnormalities but their cardiomyopathy had not been diagnosed. Six individuals had a comorbid condition (morbid obesity in four), six had prodromal symptoms, and 11 had arrhythmic triggering factors (sporting activity in seven). Ventricular fibrillation was frequently observed during cardiopulmonary resuscitation. Conclusions. Mortality due to myocardial disease in children and young adults is uncommon. Most deaths are sudden. However, some may be preventable. Preventative measures should be aimed at sudden death in adolescents and young males. There was a noticeable association between arrhythmogenic cardiomyopathy and sporting activity

Cardiac arteriovenous malformation causing sudden death.

Cardiac vascular malformations are rare. We report a subendocardial arteriovenous malformation (AVM), associated with extensive myocardial fibrosis, causing sudden death in a 25-year-old woman. To our knowledge, this is the first autopsy case reported.

Muerte súbita inexplicada. En busca de la "autopsia molecular" / Unexplained sudden death. Searching into "molecular autopsy"

Se revisa el concepto de muerte súbita cardiaca y de muerte súbita arrítmica con corazón estructuralmente normal, así como la metódica de estudio recomendada para poder llegar a este diagnóstico. Se describen las entidades conocidas hasta el momento y que se deben a alteraciones en los canales iónicos cardiacos como son el síndrome de QT largo, el síndrome de Brugada y la Taquicardia Ventricular Polimórfica Catecolaminérgica. Se destaca la labor de prevención que puede hacer el patólogo al tratarse de síndromes que pueden ser familiares y que pueden debutar con muerte súbita, así como la necesidad de incorporar el análisis molecular al estudio autópsico para establecer el diagnóstico y dar el oportuno consejo genético a la familia del fallecido (AU)

Sudden death resulting from lesions of the cardiac conduction system.

Sudden unexpected deaths in young persons with noncontributory histories, autopsy results, and drug screen results are a common problem in forensic pathology. As part of the evaluation of such cases, the cardiac conduction system (CCS) should be studied. To determine the type and incidence of lethal CCS lesions, the authors reviewed their files of sudden unexpected cardiac deaths with particular attention to cases with causes of death in the conduction system. Cases of sudden cardiac death in patients aged < or=40 years during a 10-year period (Michigan) and a 4 year-period (Spain) were selected from the files. From this group, cases were identified in which the cause of death was a lethal change in the CCS. The portions of the heart containing the CCS were excised, and at least one hematoxylin and eosin slide and at least one trichrome or elastic trichrome slide per block were studied. In the two centers, 381 cases of sudden cardiac death were identified. The most common causes of sudden cardiac death were arteriosclerotic narrowing of the coronary arteries, cardiomyopathy, and myocarditis. In 82 cases, there was no identifiable cause of death even after complete gross and microscopic autopsy was performed, a medical history was obtained, and a drug screen was performed. In 11 cases, the CCS contained lesions that were considered lethal: narrowing of the atrioventricular node artery by fibromuscular hyperplasia (7 cases) and atrioventricular node tumors (4 cases). The 11 cases accounted for 2.9% of the 381 cases of sudden cardiac death and 11.8% of the indeterminable cases. It was concluded that examination of the CCS in deaths in which the gross and microscopic autopsy, history, and drug screen fail to provide a cause of death can yield a cause of death in a significant percentage of cases. If heart block was not documented during life and no explanatory lesions were found during routine cardiac examination, examination of the CCS can yield valuable information.