Sudden cardiac arrest (SCA) is frequent in elderly patients as a consequence of coronary artery disease and other acquired structural heart diseases. However, inherited cardiac conditions represent a significant cause of SCA in young patients and when coronary ischaemia has been excluded. Elucidating the etiology of a SCA is often only the beginning of a diagnostic odyssey for both patients and their family, allowing risk stratification beyond the diagnosis. In the era of next-generation sequencing, with reduced costs and exponentially increasing efficiency, together with a rapidly growing knowledge on the genetic base of diseases and normal variation, genetic testing in the management of SCA enters the clinical reality.
Current guidelines recommend targeted genetic testing only for SCA survivors if a specific genetic condition is suspected. Addressing the role of genetic testing in idiopathic SCA, Isbister et al conducted a study analysing the output of broad genetic testing in clinically idiopathic SCA survivors in order to evaluate the prospective diagnostic utility of such multi-phenotype testing in this group.
The authors reported a single-centre study of clinically idiopathic SCA survivors referred to the Genetic Heart Disease multidisciplinary clinic at Royal Prince Alfred Hospital in Sydney, Australia between 1997 and 2019 for either a clinical evaluation and/or consideration of genetic testing (genes known to be correlated with either cardiomyopathy or primary arrhythmia syndromes) following SCA. Eligible patients had suffered an out-of-hospital cardiac arrest defined by circulatory collapse requiring cardio-pulmonary resuscitation, with or without defibrillation, to restore spontaneous circulation and had no cause identified on clinical investigation. Patients of all ages were included if the results of broad, multi-phenotype genetic testing were available for analysis.
Of the total 36 idiopathic SCA survivors, 61% patients were male. 21 (58%) SCA survivors were aged ≤35 years at the time of their arrest and the mean age over the group was 36.9 ± 16.9 years. Arrests most frequently aroused at home (37%, n=13) and nearly two thirds of incidents occurred at rest or during sleep (65%, n = 22). 22% (8/36) of the clinically idiopathic SCA survivors showed a disease-causing variant identified on broad genetic testing. Interestingly, 7 (88%) disease-causing variants identified were in cardiomyopathy-associated genes (MYH7, MYBPC3, ACTN2, PKP2, DES) despite the absence of diagnostic structural changes on imaging. Only one SCA survivor showed a variant recognized in a channelopathy correlated gene (SCN5A).
As always there are some limitations regarding this study. The cohort was enriched for genetic heart disease due to the nature of referrals to a tertiary center. Clinical evaluation across the cohort was not standardised, with investigations directed by the attending clinician and reflective of the evolving diagnostic landscape over the study period. As the authors said the numbers in their study were small and may account for the lack of a correlation between clinical features such as a family history of sudden death or syncope and the identification of a genetic cause which as has been described previously. More comprehensive cascade testing and longer follow-up of probands as well as genotype-positive relatives will be useful to better understand the natural history of concealed cardiomyopathy and identify factors that affect disease progression.
Thus, it was concluded that genetic testing can identify a potential etiology of cardiac arrest in 22% of SCA survivors when clinical investigations failed to reveal a diagnosis. The majority of causative variants were found in cardiomyopathy-associated genes even in the absence of structural disease, allowing the authors to highlight that a concealed cardiomyopathy could be an under-recognized cause of clinically idiopathic SCA which can be detected with a broad genetic analysis. Furthermore the authors reported at the 70th Annual Scientific Meeting of the Cardiac Society of Australia and New Zeeland another cohort comprised of 93 sudden cardiac death victims where no cause was identified on autopsy with a disease-causing variant being identified in 18% of them (65% in cardiomyopathy genes: MYH7, ACTN2, TTN, NKX2.5, RIT1, DSP, FLNC, PKP2 and 29% in arrhythmia-syndrome genes: CASQ2, KCNH2, KCNQ1, SCN5A) concluding that extended genetic testing may improve the diagnostic rate following sudden cardiac death by uncovering concealed cardiomyopathy. Although broad, multi-phenotype genetic testing is not yet ready for primetime, the authors presented early evidence that it may be useful in identifying concealed cardiomyopathy which can impact patient and relatives management.