This study sought to determine the burden of genetic disease in community adult presumed sudden cardiac deaths (SCDs). We first used autopsy to determine underlying cause of sudden death and identify cases with “high suspicion” for inherited disease. Two-thirds of cases were autopsy-confirmed SCDs, while one-third died of a noncardiac cause. A panel of genes associated with sudden death (cardiac and non-cardiac conditions) were tested, and the genetic testing results were correlated with cause of sudden death and autopsy findings. Furthermore, family history in high-suspicion cases was obtained. Genetic testing results were positive in 4.6% of all sudden death cases, but half of these (53%) were “false positives” and were not related to cause of death or autopsy findings. Thus, final analysis showed that only 2% of total sudden deaths, 2.5% of confirmed SCDs, and 2.7% of even high suspicion cases had identifiable genetic cause. Of the high suspicion cases that underwent family screening, half of cases (56%) had family history of a related condition, much higher than the results of genetic testing alone (5.9%). Overall, these results do not support the common practice of routine genetic testing for community sudden deaths, particularly without autopsy.
Next, this study sought to define the cardiac gene expression profile of autopsy-defined sudden arrhythmic deaths, compared to non-arrhythmic sudden deaths and trauma deaths, to determine the vulnerable state of the heart in the hours to days before SCD. We evaluated gene expression in heart tissue sampled at the time of SCD using a curated panel of genes with known or hypothesized association with SCD. This identified the active fibrosis in the presence of fixed scar and selected ion-channel dysregulation (more pronounced among female cases) as an acute vulnerable substrate for fatal arrhythmias. These findings may represent novel directions to identify patients at elevated near-term risk for SCD and critical pathways for intervention to reduce acute lethal arrhythmias.
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