Explaining the Unexplained

Applying Genetic Testing After Cardiac Arrest and Sudden Death

Elijah R. Behr

Disclosures

Eur Heart J. 2022;43(32):3082-3084. 

Graphical Abstract: The pathway for the application of genetic and clinical evaluation following cardiac arrest or sudden unexpected death. The broken arrow indicates weaker evidence. *Predictive genetic testing will identify family members for clinical evaluation who harbour a pathogenic or likely pathogenic variant when this has been identified in a family. Otherwise, all first-degree relatives should be offered clinical evaluation.[1] +Only genes with robust disease associations should be included.

An unexplained cardiac arrest (UCA) presents a significant diagnostic challenge to the clinical cardiologist; the underlying aetiology is critical for patient management and the potential for genetic heart disease raises concerns for relatives.[1] The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) has shown that 44% of out-of-hospital cardiac arrests without a clear presenting cause, such as ischaemia, structural heart disease, primary electrical disease, and/or metabolic abnormality, remained unexplained despite extensive investigations of the patient and their family members.[2] This is often also referred to as idiopathic ventricular fibrillation (IVF), defined as a resuscitated cardiac arrest (CA) survivor, with documentation of ventricular fibrillation (VF), in whom known cardiac, respiratory, metabolic, and toxicological causes have been excluded through clinical evaluation.[1] It is estimated to account for ~5–7% of all out-of-hospital cardiac arrests. More recent European data in 717 CA survivors identified diagnoses in most cases following a complete workup including pharmacological provocation tests, although 6.8% were still labelled as IVF.[1] These findings reflect the importance of comprehensive cardiac evaluation of CA survivors.[1]

While IVF may be considered a diagnosis of exclusion, some UCA patients share typical electrophysiological and clinical features that may be regarded as subphenotypes of IVF. Short-coupled 'Torsades de Pointes' or polymorphic VT/VF (SC-TDP/VF) is characterized by single premature ventricular contractions (PVCs) with an extremely short coupling interval (R-on-T phenomenon) that trigger the arrhythmia. Electro-anatomical mapping techniques have localized the site of origin of PVCs triggering VF to the specialized Purkinje system.[3] Early repolarization syndrome (ERS) has increasingly been used to describe UCA survivors with inferior ± lateral J point elevation: the early repolarization pattern (ERP).[4] An imbalance in myocyte currents in favour of enhanced outward currents (ITo and IK-ATP) during phase 2 of the action potential has been proposed to cause premature myocardial repolarization and variable loss of the action potential dome causing epicardial and transmural heterogeneity in the inferior left ventricular wall. However, high-density mapping studies have shown delayed, fragmented epi- and endocardial electrocardiograms (ECGs) in some ERS survivors, indicating local structural alterations in the inferior right and/or left ventricular walls coincident with the J wave. Ablation of these signals led to diminution of the J wave and reduced implantable-cardioverter defibrillator (ICD) shocks.[5] Importantly, similar abnormal epicardial signals have also been reported in a study of 24 UCA patients without any electrocardiographic phenotype. Localized areas of abnormal depolarization were identified in 62%, highlighting the role of conduction defects, with or without ECG manifestation, in the pathophysiology of UCA and IVF.[6]

Whether these conduction defects indicate concealed forms of cardiomyopathy is currently uncertain. Early genetic investigation of UCA survivors had focused on a mixture of cardiac gene panels and whole-exome sequencing (WES) in small case series, identifying a wide range of yield, from 2% to 27%, of rare putative cardiac disease causative variants.[7–9] The heterogeneity of study results probably reflected differences in genes studied, adjudication of variant pathogenicity, patient subphenotypes, and the thoroughness of clinical evaluation to exclude clinical diagnoses. There have, however, been some notable findings. A study of Finnish and Italian IVF survivors and a more recent analysis of UCA cases have detected a small proportion of cases with pathogenic and likely pathogenic RYR2 variants. Some exhibited gain-of-function pathophysiology and others loss of function, implying a role for concealed catecholaminergic polymorphic ventricular tachycardia (CPVT) and a novel syndrome of calcium release deficiency in UCA.[10,11] The most robust genetic finding in the subphenotype of SC-TDP/IVF has been a Dutch founder haplotype at the DPP6 gene.[12] Furthermore, a recent study in ERS probands has shown a 10% yield of SCN5A variants.[13] Importantly, and surprisingly, pathogenic variants in cardiomyopathy genes were detected in some UCA survivors.[9]

Grondin et al., in their manuscript published in this issue of the European Heart Journal, studied the largest cohort to date of 228 initially unexplained CA patients from the CASPER employing systematically an initial protocol of investigations followed by physician-specified advanced clinical evaluation and a 'virtual' genetic testing panel of cardiac disease-related genes derived from WES data.[14] They found a 10% yield of pathogenic and likely pathogenic variants (indicating disease causation according to internationally accepted guidelines) in the overall UCA group. On a cautionary note, however, the number of variants of uncertain significance (VUS) was much higher than the yield of pathogenic and likely pathogenic variants, and increased with very little additional pathogenic yield the more genes that were added to the virtual panel analysis. A VUS can cause confusion and distress for the patient and family whilst adding no diagnostic advantage. Nonetheless, while further advanced clinical assessment had a diagnostic yield of 9%, the addition of virtual gene panels increased it further to 17%. In addition, genetic testing increased the accuracy of clinical diagnoses; for example, clinical diagnoses of CPVT were found to be in part due to subclinical cardiomyopathy. Molecular testing also enhanced the diagnostic yield even in those cases that remained unexplained after advanced phenotypic assessment. Cases not reaching diagnostic thresholds for long QT syndrome and CPVT were diagnosed by genetic results, whilst a case of calcium release deficiency syndrome, due to a loss-of-function RYR2 variant, was now recognizable. Furthermore, loss-of function variants in SCN5A supportive of underlying Brugada syndrome (or potentially ERS) were picked up in cases with negative procainamide challenge. Given that the diagnostic yield of SCN5A variants in Brugada syndrome is usually only 20%, a more diagnostically potent sodium channel blocker challenge such as ajmaline would have probably resulted in a significantly higher diagnostic yield of Brugada syndrome from clinical evaluation.[15] As in the prior smaller studies, amongst the cases remaining unexplained after advanced evaluation, i.e. IVF, there was also a significant yield of pathogenic and likely pathogenic variants in cardiomyopathy genes, despite the absence of any significant structural findings. This included patients harbouring both hypertrophic and arrhythmogenic cardiomyopathy variants, some of whom subsequently developed a demonstrable phenotype during follow-up including one with Noonan syndrome.

A parallel phenomenon has been illustrated in another unexplained phenotype: autopsy-negative sudden death or sudden arrhythmic death syndrome (SADS).[1] In the absence of an antecedent illness, SADS describes either a witnessed sudden death or a death where the decedent has been found with no suspicious circumstances, and no cause can be identified despite a full autopsy and toxicology. Post-mortem genetic testing in >300 cases of SADS gave a yield of 13% for pathogenic and likely pathogenic variants in cardiac disease-related genes, similar to that described for UCA.[14] When combined with comprehensive cardiac evaluation of relatives (the equivalent of advanced assessment described by Grondin et al.[14]) it led to an increase in diagnostic yield of genetic heart disease by half from 26% to 39%.[16] Of these diagnoses, 4% were cardiomyopathy despite the absence of structural disease at autopsy.

These data, taken together, suggest that an underlying concealed cardiomyopathy, sufficient to cause CA or sudden death, can be undetectable either by conventional clinical methods or by autopsy but may only potentially be distinguished as a substrate by genetic testing or by the invasive mapping studies described above. This hypothesis of a distinct and genetically mediated structural disorder underlying UCA (including ERS and IVF) and SADS needs to be explored further. In the meantime, there are clinical implications for the use of genetic testing. The most recent international expert consensus statement proposed that arrythmia syndrome-focused post-mortem genetic testing 'can be useful' following a SADS death (Class 2a) while genetic evaluation of CA survivors without a distinct phenotype for genetic cardiac disease 'may be considered' in select circumstances (Class 2b). The work from Grondin et al. coupled with others further promotes the role for genetic testing, implying that cardiomyopathy genes with robust disease associations should be included in gene panels, albeit with careful adjudication of variant pathogenicity. Furthermore, the systematic application of genetic testing in patients suffering UCA can be useful and could therefore be upgraded to Class 2a. Ultimately their further utility will be realized when a pathogenic or likely pathogenic variant is detected in the index case which can then be applied for predictive testing for diagnosis in family members and then their subsequent management (Graphical Abstract). If genetic testing does not return such a finding, then clinical evaluation should still proceed in first-degree relatives of SADS decedents.[1] The evidence supporting a role for clinal evaluation of relatives of an UCA survivor without signs of genetic heart disease is, however, weaker.[17]

The challenge that awaits is to determine the causation of cases of UCA and SADS that remain unexplained despite the aforementioned clinical and genetic investigations. If there is a genetic basis, could it be polygenic and how much risk is environmentally determined? This will require even larger cohorts with extensive genomic and clinical characterization to tease out further and will be addressed by a unique European and International collaboration: the GenUCA Investigators (https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2020/august/bhf-dzhk-dhf-4-million-euros-funding-for-heart-research; https://dzhk.de/en/news/latest-news/article/working-together-to-strengthen-cardiovascular-research-in-europe/; https://professionals.hartstichting.nl/actualiteiten/internationale-financiering-toegekend).

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