“Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest

doi:10.1016/j.ijcard.2020.09.031

International Journal of Cardiology

Volume 324, 1 February 2021, Pages 96-101

https://doi.org/10.1016/j.ijcard.2020.09.031 Get rights and content

Highlights

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Current guidelines do not recommend genetic testing in clinically-idiopathic sudden cardiac arrest (SCA) survivors.

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22% of clinically-idiopathic SCA survivors carry a disease-causing variant most commonly in cardiomyopathy-associated genes.

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Multi-phenotype genetic testing can identify “concealed cardiomyopathy”, increasing the diagnosis rate for clinically-idiopathic SCA survivors.

Abstract

Background

Genetic heart disease is a common cause of sudden cardiac arrest (SCA) in the young and those without an ischaemic precipitant. Identifying a cause of SCA in these patients allows for targeted care and family screening. Current guidelines recommend limited, phenotype-guided genetic testing in SCA survivors where a specific genetic condition is suspected and genetic testing is not recommended in clinically-idiopathic SCA survivors.

Objective

To investigate the diagnostic utility of broad, multi-phenotype genetic testing in clinically-idiopathic SCA survivors.

Methods

Clinically-idiopathic SCA survivors underwent analysis of genes known to be associated with either cardiomyopathy or primary arrhythmia syndromes, following referral to a specialised genetic heart disease clinic in Sydney, Australia between 1997 and 2019. Comprehensive review of clinical records, investigations and re-appraisal of genetic data according to current variant classification criteria was performed.

Results

In total, 22% (n = 8/36) of clinically-idiopathic SCA survivors (mean age 36.9 ± 16.9 years, 61% male) had a disease-causing variant identified on broad genetic testing. Of these, 7 (88%) variants resided in cardiomyopathy-associated genes (ACTN2, DES, DSP, MYBPC3, MYH7, PKP2) despite structurally normal hearts or sub-diagnostic structural changes at the time of arrest, so-called “concealed cardiomyopathy”. Only one SCA survivor had a variant identified in a channelopathy associated gene (SCN5A).

Conclusion

Extended molecular analysis with multi-phenotype genetic testing can identify a “concealed cardiomyopathy”, and increase the diagnosis rate for clinically-idiopathic SCA survivors.

Introduction

Sudden cardiac arrest (SCA) in those aged over 35 years is most commonly due to coronary artery disease however genetic heart diseases represent an important cause in young patients and those where coronary ischaemia has been excluded [1,2]. Elucidating the aetiology of a SCA is paramount, facilitating disease-specific management for patients and focused screening for their families. Survival allows for a comprehensive clinical evaluation not possible in the postmortem setting which increases diagnosis rates in SCA survivors compared to sudden cardiac death (SCD) victims [3,4]. The CASPER registry [5] has demonstrated the benefit of a systematic approach to clinical investigation in apparently unexplained SCA. Nevertheless, the cause of non-ischaemic SCA remains elusive in up to 40% and this diagnosis rate has remained unchanged over the last decade despite growing clinical knowledge and technological advances in cardiac imaging [3,4,6].

Non-ischaemic SCA survivors are a heterogenous population and the yield of genetic testing varies according to cohort characteristics and the specific genes analysed. A yield of over 80% has been reported in patients with a clinical diagnosis of a genetic heart disease following SCA, compared to 2 to 21% in idiopathic SCA survivors depending on the extent of testing [6,7].

Current guidelines, published in 2011 and 2013, recommend targeted genetic testing only be performed in SCA survivors when a specific genetic condition is suspected [8,9]. The role of genetic testing in the management of clinically-idiopathic SCA survivors requires reappraisal given the advances in genetic testing technology, increasing accessibility of broad genetic analysis and standardisation of variant classification criteria. We sought to investigate the yield of broad genetic testing in clinically-idiopathic SCA survivors and assess the potential diagnostic utility of such multi-phenotype testing in this cohort.

Section snippets

Study population

This was 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 following SCA. Consecutive cases were identified from an existing database. Eligible patients had suffered an out of hospital cardiac arrest defined by circulatory collapse requiring cardio-pulmonary resuscitation

Clinical characteristics

Baseline characteristics of the cohort are detailed in Table 1. Of the 36 idiopathic SCA survivors, 61% (n = 22) were male. Twenty-one (58%) SCA survivors were aged ≤35 years at the time of their arrest and the average age across the cohort was 36.9 ± 16.9 years (Fig. 1A). Arrests most commonly occurred in the home (37%, n = 13) and nearly two-thirds of events during rest or sleep (65%, n = 22, Fig. 1B). Nine (25%) patients reported a history of syncope and 63% (n = 5) of these experienced

Discussion

This study identifies a diagnostic role for broad, multi-phenotype genetic testing in idiopathic SCA survivors who are not routinely considered for genetic testing based on current guidelines. The majority of disease-causing variants were identified in cardiomyopathy associated genes despite the absence of overt structural heart disease at the time of the arrest. These findings highlight the entity of “concealed cardiomyopathy”, whereby an arrhythmic phase of disease occurs prior to the

Conclusions

Genetic testing can identify a cause of arrest in 22% of SCA survivors where clinical investigations failed to reveal a diagnosis. The majority of causative variants were found in cardiomyopathy genes in the absence of structural disease. Concealed cardiomyopathy is an under-recognised cause of clinically-idiopathic SCA and can be detected with broad, multi-phenotype genetic analysis. More comprehensive cascade testing and longer follow-up of probands as well as genotype-positive relatives will

Acknowledgements

JCI is the recipient of a Cardiac Society of Australia and New Zealand Research Scholarship. LY is the recipient of a co-funded National Heart Foundation of Australia and National Health and Medical Research Council (NHMRC) PhD Scholarship (#102568 and #191351). BG is the recipient of a National Health and Medical Research Council (NHMRC) Early Career Fellowship (#1122330). JI is the recipient of a NHMRC Career Development Fellowship (#1162929). CS is the recipient of an NHMRC Practitioner

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Cited by (35)

Concealed Cardiomyopathy in Autopsy-Inconclusive Cases of Sudden Cardiac Death and Implications for Families
2022, Journal of the American College of Cardiology
Citation Excerpt :
All cases were reviewed by 2 expert pathologists, and findings were then confirmed by an expert cardiac pathologist. It should be noted that CCM has also been described in clinically idiopathic sudden cardiac arrest cohorts.13,16,25 Although CM-associated variants are seen across the spectrum of autopsy-inconclusive SCD, we show for the first time in a combined cohort that CCM appears to be more common in SCD victims with subdiagnostic structural changes at autopsy than in those with a normal heart.
Genetic testing following sudden cardiac death (SCD) is currently guided by autopsy findings, despite the inherent challenges of autopsy examination and mounting evidence that malignant arrhythmia may occur before structural changes in inherited cardiomyopathy, so-called “concealed cardiomyopathy” (CCM).
The authors sought to identify the spectrum of genes implicated in autopsy-inconclusive SCD and describe the impact of identifying CCM on the ongoing care of SCD families.
Using a standardized framework for adjudication, autopsy-inconclusive SCD cases were identified as having a structurally normal heart or subdiagnostic findings of uncertain significance on autopsy. Genetic variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Family follow-up was performed where possible.
Twenty disease-causing variants were identified among 91 autopsy-inconclusive SCD cases (mean age 25.4 ± 10.7 years) with a similar rate regardless of the presence or absence of subdiagnostic findings (25.5% vs 18.2%; P = 0.398). Cardiomyopathy-associated genes harbored 70% of clinically actionable variants and were overrepresented in cases with subdiagnostic structural changes at autopsy (79% vs 21%; P = 0.038). Nine of the 20 disease-causing variants identified were in genes implicated in arrhythmogenic cardiomyopathy. Nearly two-thirds of genotype-positive relatives had an observable phenotype either at initial assessment or subsequent follow-up, and 27 genotype-negative first-degree relatives were released from ongoing screening.
Phenotype-directed genetic testing following SCD risks under recognition of CCM. Comprehensive evaluation of the decedent should include assessment of genes implicated in cardiomyopathy in addition to primary arrhythmias to improve diagnosis of CCM and optimize care for families.
European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases
2022, Heart Rhythm
Citation Excerpt :
These variants were immediately useful in guiding family evaluation and they increased the diagnostic yield by 50% when undertaken in families who were also undergoing clinical testing. Furthermore, a proportion of these variants were present in cardiomyopathy genes, indicating a concealed structural cause of SCD.417,418 If focus is placed on younger cases, exertional circumstances of death and the use of exome sequencing in parent and child trios, then yields can increase substantially.419,420
Latent Causes of Sudden Cardiac Arrest
2022, JACC: Clinical Electrophysiology
Citation Excerpt :
Additional testing depending on initial workup results can be arranged after patient discharge, and should include provocation testing (exercise testing and sodium channel blocker challenge), Holter monitoring (if implantable cardioverter-defibrillator [ICD] is not inserted) and possibly signal-averaged ECG. In conjunction with a genetics expert, targeted or broad cardiac panel genetic testing may be considered in the workup of patients with resuscitated cardiac arrest.17,18 Further discretionary testing may be sought in certain instances, such as epinephrine test in patients who are unable to exercise, provocation testing for coronary artery spasm, and electrophysiology study for identification of electroanatomical triggers and substrate abnormalities.
Inherited arrhythmia syndromes are a common cause of apparently unexplained cardiac arrest or sudden cardiac death. These include long QT syndrome and Brugada syndrome, with a well-recognized phenotype in most patients with sufficiently severe disease to lead to cardiac arrest. Less common and typically less apparent conditions that may not be readily evident include catecholaminergic polymorphic ventricular tachycardia, short QT syndrome and early repolarization syndrome. In cardiac arrest patients whose extensive testing does not reveal an underlying etiology, a diagnosis of idiopathic ventricular fibrillation or short-coupled ventricular fibrillation is assigned. This review summarizes our current understanding of the less common inherited arrhythmia syndromes and provides clinicians with a practical approach to diagnosis and management.
Idiopathic ventricular fibrillation: is it a case for genetic testing?
2024, Herzschrittmachertherapie und Elektrophysiologie
The genetic basis of apparently idiopathic ventricular fibrillation: A retrospective overview
2023, Europace
Identification of concealed cardiomyopathy using next-generation sequencing-based genetic testing in Korean patients initially diagnosed with idiopathic ventricular fibrillation
2023, Europace

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¹: This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

View full text

“Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest

Highlights

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Clinical characteristics

Discussion

Conclusions

Acknowledgements

Heart Rhythm.

Heart Rhythm.

Int. J. Cardiol.

Heart Rhythm.

J. Am. Coll. Cardiol.

Genet Med.

Genet Med.

Int. J. Cardiol.

J. Am. Coll. Cardiol.

Heart Rhythm.

J Arrhythm.

HeartRhythm Case Rep.

Sudden cardiac death

Circulation.