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    • The main inherited arrhythmogenic causes of SCD in the young

    2019-04-18

    The main inherited arrhythmogenic causes of SCD in the young are summarized in Fig. 1. These arrhythmogenic disorders include familial long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), idiopathic ventricular fibrillation, early repolarization syndromes, and short QT syndrome. Since these E-64 disorders rarely cause any structural changes to the heart, the postmortem is often “negative” (no cause of death is identified), including normal histopathology and toxicology analyses (key features are summarized in Table 1). Such cases in which no abnormalities are found at the postmortem examination occur in up to 40% of SCD cases in young populations [7,8,12,16–18]. This strongly suggests an underlying arrhythmogenic cause (Fig. 1). Sudden unexplained deaths are often referred to as sudden arrhythmic death syndrome (SADS) with “young” defined as 1–40 years old (excluding sudden unexplained death in infancy from 0 to 1 years, referred to as SIDS) [19]. The true overall incidence of SCD is likely to be an underestimate, since primary arrhythmogenic disorders can predispose people to more overt causes of death, such as drowning and motor vehicle accidents. Such overt causes may be caused by ventricular arrhythmias in patients with LQTS and CPVT [20–22].
    Role of the postmortem in the investigation of sudden cardiac death in the young Establishing a definitive cause of death in a young SCD case is of major importance, and so the postmortem evaluation is a critical first step in all cases (Fig. 2). Important aspects of the postmortem include the proper and detailed conduct of the postmortem examination itself, collection of appropriate samples for subsequent analysis (including DNA analysis), careful evaluation of the findings, and a precise and accurate final conclusion are important aspects of the role of the postmortem. A comprehensive and detailed postmortem process can not only define the exact cause of death in a young SCD case, but the results also have far-reaching effects in identifying at-risk relatives of the decedent. This information can thereby provide a therapeutic window for disease and sudden death prevention in at-risk relatives (Fig. 2). The key aspects of the postmortem evaluation are summarized in Table 2, and are modified from the Best Practice Guidelines of the Royal Australasian College of Pathologists implemented in Australia in 2008 [23]. A comprehensive postmortem by an experienced forensic pathologist should be performed in all SCD cases in the young (0–40 years) [19,23,24]. A complete premorbid medical history should be sought, including a history of syncopal episodes, exertional symptoms, intercurrent illnesses, recent pharmacological therapies, previous ECGs, and other relevant studies. The investigation should also include a comprehensive, 3-generation family pedigree focused on identifying any family history of cardiac disease, premature sudden death, or suspicious deaths (e.g. SIDS cases or drowning). Other relevant family history information can include family members with epilepsy, identifying “fainters”, and any other unusual symptoms or clinical presentations. The circumstances of SCD need to be established when possible, including activity at the time of death, the level of physical activity, and the symptoms immediately preceding the death. This often relies on obtaining information from available ambulance and police reports, as well as talking to witnesses or those who found the deceased. The postmortem examination should include a detailed macroscopic and histological evaluation of the heart, as well as other key organs such as the brain, with the purpose of identifying any non-cardiac causes of death (e.g. pulmonary embolism or cerebral aneurysm), before focusing on specific cardiac pathologies. In all SCD cases in the young, a 5–10mL blood sample should be collected for subsequent DNA extraction and analysis. In addition, frozen sections of the liver or spleen, which are highly cellular and therefore rich in DNA, should also be collected and stored when possible. Of note, paraffin-embedded tissues are not suitable for DNA studies, as the quality of the DNA is significantly diminished [25,26]. Obtaining a postmortem blood sample in young SCD cases is now recommended by the HRS/EHRA guidelines [24], and is mandated in several countries, including Australia and New Zealand [23]. A representative best practice document entitled “Postmortem in sudden unexpected death in the young: guidelines on autopsy practice” and endorsed by the Royal College of Pathologists of Australasia is detailed in Supplementary File 1.