Despite our best efforts the
Despite our best efforts, the cause of SCD in young individuals is sometimes not established; no cause is identified in up to 40% of cases. Importantly, whether a cause of death is established or not, the possibility of an underlying inherited cardiac disorder remains in many cases, including the possibility of a primary arrhythmogenic disease. Recent studies also suggest that in addition to true SADS cases, postmortem examinations may reveal some non-specific changes of uncertain clinical significance, such as unclassified “cardiomegaly” or minor cardiac histopathological changes. Importantly, the chance of finding an underlying primary arrhythmogenic syndrome in these uncertain “borderline” cases is as high as in those with true SADS .
While the conventional postmortem remains the cornerstone of the investigation of young SCD cases, there is emerging evidence that other imaging modalities may be helpful in diagnosing structural causes of SCD. Such non-invasive approaches may overcome some of the reservations that purchase KB SRC 4 have in proceeding with the traditional postmortem process for religious, logistic, personal, or cultural reasons. These modalities include computer tomography (CT) scanning and cardiovascular magnetic resonance (CMR) imaging . The majority of the studies to date examining the accuracy of postmortem CMR imaging have focused on fetal and neonatal deaths [29,30]. Two recent studies have shown great promise in terms of utilizing CT and CMR imaging in determining the cause of SCD in young adults [31,32]. Fig. 3 shows young SCD cases in which postmortem imaging identified the causes of death due to ARVC, HCM, and acute coronary occlusion . While the studies represent a small number of young SCD cases, the possibility of additional diagnostic tools to elucidate the cause of SCD at the postmortem now exists.
Genetic testing and the “molecular autopsy” The use of genetic testing in the setting of SCD cases was initiated over a decade ago . In SADS, where no cause of death is identified after a comprehensive postmortem examination, genetic testing of the decedent’s blood sample collected at postmortem may identify an underlying genetic cause of sudden death. This genetic testing process has been termed the “molecular autopsy”, and involves DNA extraction from postmortem blood, followed by DNA analysis of selected candidate genes responsible for the main inherited arrhythmogenic diseases (Fig. 4) [34,35].
Management of families following sudden cardiac death in the young Given the possibility of an inherited cardiac disease as a cause of SCD, appropriate evaluation and management of the surviving family is essential. Overall clinical management is guided by the goal of establishing a cause of death (the victim), and the clinical screening and management of the surviving family members (the family). The ultimate goal is prevention of SCD in any other family relatives. In SADS cases, underpinning the clinical evaluation and screening of family members is the presumption that the underlying cause was an inherited arrhythmogenic disorder such as LQTS, CPVT, or BrS. By definition, these SCD cases are unexplained at postmortem. Importantly however, over 95% of cardiac genetic disorders are inherited as an autosomal dominant trait such that first-degree relatives have a 1 in 2 (50%) chance of inheriting the same gene mutation [36,37]. Therefore, standard approaches for clinical evaluation of first-degree relatives are important, and may reveal disease in the family. Fig. 5 summarizes the basic clinical investigation of the family, including first-degree relatives, obligate carriers, and symptomatic relatives. This is largely based on the recent HRS/EHRA consensus document . Clinical investigation broadly involves two tiers of evaluation. All relatives should have a comprehensive medical and family history, physical examination, resting and exercise ECGs, and a standard transthoracic echocardiogram. Depending on the clinical situation, further second tier investigations may include CMR imaging, 24-h ECG monitoring and signal averaged ECG, and pharmacological challenge tests, such as an ajmaline challenge in suspected BrS patients. Clinical evaluation alone in families with a sudden unexplained death may identify an underlying cause in up to 50% of selected and comprehensively evaluated families in tertiary centers [51–53].