Muerte súbita cardiaca de origen arrítmico: valor del análisis genético post mortem / Sudden cardiac death of arrhythmic origin: value of post-mortem genetic analysis

La muerte súbita inexplicada hace referencia a los fallecimientos repentinos que quedan sin causa concluyente del episodio letal tras realizarse una autopsia completa. Estos casos se catalogan como fallecimientos de origen arrítmico, sin alteración estructural cardiaca. En los últimos años, los avances biomédicos han permitido la progresiva interacción entre la investigación genética y el campo forense para realizar análisis genéticos post mortem, la llamada autopsia molecular. Estos estudios ponen de manifiesto alteraciones genéticas familiares causantes de patologías cardiacas asociadas a eventos arrítmicos y muerte súbita. Estudios recientes post mortem identifican alteraciones genéticas como causa más probable del fallecimiento en alrededor de un 30% de los casos. Los resultados obtenidos tras estos análisis permiten también realizar una traslación al ámbito clínico focalizada en la identificación precoz de familiares a riesgo de síncope, así como la adopción de medidas terapéuticas para la prevención y el tratamiento personalizado (AU)

Sudden unexplained death refers to sudden deaths that remain without a conclusive cause of death after a complete autopsy has been performed. These cases are classified as deaths of arrhythmic origin, without any alterations in cardiac structure. In recent years, biomedical advances have allowed progressive interaction between genetic research and the forensic field to perform post-mortem genetic analyses, the so-called molecular autopsy. These studies reveal familial genetic alterations that cause heart diseases associated with arrhythmic events and sudden death. Recent post-mortem studies identify genetic alterations as the most probable cause of death in approximately 30% of cases. The results obtained after these analyses also allow for a translation into the clinical field to be made, focused on the early identification of relatives at risk of syncope, as well as the adoption of therapeutic measures for prevention and personalised treatment (AU)

Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis.

BACKGROUND: Sudden cardiac death is a natural and unexpected death that occurs within 1 h of the first symptom. Most sudden cardiac deaths occur during exercise, mostly as a result of myocardial infarction. After autopsy, some cases, especially in the young, are diagnosed as cardiomyopathies or remain without a conclusive cause of death. In both situations, genetic alterations may explain the arrhythmia. OBJECTIVE: Our aim was to identify a genetic predisposition to sudden cardiac death in a cohort of post-mortem cases of individuals who died during exercise, with a structurally normal heart, and were classified as arrhythmogenic death. METHODS: We analyzed a cohort of 52 post-mortem samples from individuals <50 years old who had a negative autopsy. Next-generation sequencing technology was used to screen genes associated with sudden cardiac death. RESULTS: Our cohort showed a male prevalence (12:1). Half of the deaths occurred in individuals 41-50 years of age. Running was the most common exercise activity during the fatal event, accounting for 46.15% of cases. Genetic analysis identified 83 rare variants in 37 samples (71.15% of all samples). Of all rare variants, 36.14% were classified as deleterious, being present in 53.84% of all cases. CONCLUSIONS: A comprehensive analysis of sudden cardiac death-related genes in individuals who died suddenly while exercising enabled the identification of potentially causative variants. However, many genetic variants remain of indeterminate significance, thus further work is needed before clinical translation. Nonetheless, comprehensive genetic analysis of individuals who died during exercise enables the detection of potentially causative variants and helps to identify at-risk relatives.

Genetic analysis in post-mortem samples with micro-ischemic alterations.

Sudden cardiac arrest is a leading cause of death worldwide. Most cardiac arrests happen in patients who have previously suffered a myocardial infarct. The risk of sudden death after infarction may increase in people who carry a pathogenic genetic alteration in cardiac ion channels. We hypothesized that micro-ischemia could trigger lethal arrhythmogenesis, thus we sought to identify genetic alterations in cardiac ion channels in patients with micro-ischemic disease. We studied a cohort of 56 post-mortem samples. Autopsy studies identified myocardial infarction as the cause of death in each case. We used both Sanger sequencing and next-generation sequencing to screen candidate genes associated with sudden cardiac death. We identified six rare missense genetic variations in five unrelated patients. Two variants have been previously reported; one is associated with atrial fibrillation (SCN5A_p.H445D), and the other is predicted to be benign (ANK2_p.T2059M). The novel variants were predicted in silico as benign, except for one (RyR2_p.M4019T), which was classified as deleterious. Our post-mortem, micro-infarction cohort displayed a rate of nearly 10% non-common genetic variants. However, the clinical significance of most of the identified variants remains unknown due to lack of family assessment. Further analyses should be performed in large cohorts to clarify the role of ion-channel gene analysis in samples showing microscopic ischemic alterations.

Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death.

A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death.

Post-mortem genetic analysis in juvenile cases of sudden cardiac death.

BACKGROUND: The reason behind a sudden death of a young individual remains unknown in up to 50% of postmortem cases. Pathogenic mutations in genes encoding heart proteins are known to cause sudden cardiac death. OBJECTIVE: The aim of our study was to ascertain whether genetic alterations could provide an explanation for sudden cardiac death in a juvenile cohort with no-conclusive cause of death after comprehensive autopsy. METHODS: Twenty-nine cases <15 years showing no-conclusive cause of death after a complete autopsy were studied. Genetic analysis of 7 main genes associated with sudden cardiac death was performed using Sanger technology in low quality DNA cases, while in good quality cases the analysis of 55 genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. RESULTS: Thirty-five genetic variants were identified in 12 cases (41.37%). Ten genetic/variants in genes encoding cardiac ion channels were identified in 8 cases (27.58%). We also identified 9 cases (31.03%) carrying 25 genetic variants in genes encoding structural cardiac proteins. Nine cases carried more than one genetic variation, 5 of them combining structural and non-structural genes. CONCLUSIONS: Our study supports the inclusion of molecular autopsy in forensic routine protocols when no conclusive cause of death is identified. Around 40% of sudden cardiac death young cases carry a genetic variant that could provide an explanation for the cause of death. Because relatives could be at risk of sudden cardiac death, our data reinforce their need of clinical assessment and, if indicated, of genetic analysis.

Capacity planning in hospital nursing: a model for minimum staff calculation.

An aging population, emerging technology, heightening patient expectations, rising health care costs, shorter patient stays, and growing pressure to improve quality have made the management of nursing resources even more critical today. While approaching a model for staffing levels, the authors considered factors such as patient acuity, work redesign, and minimum quality standards. The methodology for analysis included estimating the time needed to complete nursing tasks and calculating the average number of tasks per patient. With respect to nursing quality measures, the study examined the adequacy of nursing documentation including admission history, assessments, nursing procedures, and discharge report as well as nursing-driven outcomes such as fall and phlebitis rates. Lastly, the authors determined the theoretical number of staff needed to provide nursing care according to quality standards.