Sudden Cardiac Death in the Young

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ORIGINAL ARTICLE

Heart, Lung and Circulation (2019) -, -–1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.11.007

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Sudden Cardiac Death in the Young Richard D. Bagnall, PhD a,b,*, Emma S. Singer, BSc a, Jacob Tfelt-Hansen, MD, DMSc c,d a

Agnes Ginges Centre for Molecular Cardiology Centenary Institute, The University of Sydney, Sydney, NSW, Australia Sydney Medical School Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia c The Department of Cardiology, The Heart Centre, Copenhagen University, Rigshospitalet, Copenhagen, Denmark d Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark b

Received 20 July 2019; received in revised form 4 November 2019; accepted 11 November 2019; online published-ahead-of-print xxx

Sudden cardiac death (SCD) of a young person is a devastating and tragic ultimate outcome of a collection of cardiac disorders. The death often occurs in people who were thought to be well, by definition is sudden, can occur without prior warning symptoms, and is often the first presentation of an underlying genetic heart disease. Many of the genetic heart diseases are caused by single genetic variants that have a one-intwo chance of being inherited by each first-degree relative. Therefore, the surviving family not only have to deal with the sudden loss of a young family member but are also left with the compounding uncertainty as to whether SCD could strike again in another family member. In recent years, our ability to identify the causes of SCD in the young has improved. Finding a precise genetic cause of death allows cascade genetic testing of family members to identify those who are at risk and facilitate early intervention to prevent another sudden death. Thus, investigations to define the precise cause of SCD of a young person not only bring a level of closure for the family but are also of vital clinical relevance. Keywords

Sudden cardiac death  Molecular autopsy  Arrhythmia  Postmortem genetic testing  Concealed cardiomyopathy

Epidemiology of Sudden Cardiac Death in the Young Estimates in studies of the incidence of sudden cardiac death (SCD) in the young vary widely owing to differences in the age range of the populations studied and the limitations of small sample size and ascertainment bias. Although rare overall, the incidence of SCD in the young increases with age and is higher in some subgroups, such as people with congenital heart disease [1], or those with neurological or psychiatric disorders [2–4]. The most reliable incidence estimates of SCD in the young come from studies of unselected, population-based cohorts. Two such studies, in Denmark [5] and in the combined Australia and New Zealand study [6], share a number of similarities in design and findings (Table 1). Both studies included all persons aged 1 to 35 years in which SCD occurred within 1 hour of onset of symptoms in an otherwise

healthy person, or within 24 hours of the person last being seen alive and well when unwitnessed. The Danish study retrospectively reviewed death certificates, autopsy reports and other available information from the Danish health registries from a 7-year period and reported an incidence rate of 1.9 per 100,000 person-years when considering cases that underwent postmortem examination. The incidence rose to 2.8 per 100,000 person-years when including additional nonautopsied cases of sudden unexpected death. The Australia and New Zealand study prospectively collected all cases of SCD over a 3-year period from all major forensic pathology centres, nationwide coronial databases and the registries of births, deaths and marriages. The reported incidence rate was 1.3 per 100,000 person-years. In both studies approximately 70% of cases were males and the incidence was age dependent, with those aged 31 to 35 years having an almost 10-fold increased risk of SCD compared to people aged 6 to 10 years.

*Corresponding author at: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia., Email: r.bagnall@ centenary.org.au Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

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Table 1 Comparison of two nationwide studies of sudden cardiac death in the young. Denmark [5]

Australia and New Zealand [6]

Age range

1 to 35 years

1 to 35 years

Source of cases

Departments of forensic medicine,

Forensic pathology centres,

Hospital pathology departments,

Coronial registry,

Death certificates 7 years (2000 – 2006)

Births, deaths and marriages registry 3 years (2010–2012)

314 autopsied SCD

490 SCD

Study design

Case collection period Demographics Number of cases

156 non-autopsied SUD Male sex

67%

72%

Mean age at death (years)

29

24

Incidence rate

1.9 per 100,000 persons/year*

1.3 per 100,000 persons/year

2.8 per 100,000 persons/year Circumstances at death At rest

50%

Sleep

34%

43% 38%

Physical activity

11%

15%

Unexplained SCD

43%*

40%

Explained SCD

57%*

60%

Ischaemic heart disease Inherited cardiomyopathy

13%* 7%*

24% 16%

Myocarditis

7%*

7%

Aortic dissection

7%*

4%

Postmortem findings

Abbreviatiosn: SCD, sudden cardiac death; SUD, sudden unexpected death; *Autopsied SCD cases only

The majority of cases of SCD in the young are attributed to structural cardiovascular disorders that can be identified at postmortem investigation [5,6]. Such disorders include hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, coronary artery disease, aortopathies, and viral myocarditis. Structural cardiovascular disorders display characteristic morphology and histological hallmarks that guide the diagnosis. However, the single most common finding at postmortem investigation of young SCD, accounting for up to 40% of cases, is a structurally normal heart with no cause of death identified, including comprehensive toxicology analysis [5,6]. These cases, termed ‘unexplained SCD’, are presumed to be caused by cardiac arrhythmias. A range of potentially fatal arrhythmia syndromes, including the long QT syndrome (LQTS), Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), are caused by dysfunction of cardiac ion-channel proteins that regulate the cardiac conduction system. The cardiac ion-channel proteins are not visible on histological analysis and these disorders are not typically associated with the development of structural cardiac pathology that can be identified at postmortem investigation. When considering the circumstances immediately preceding SCD in the young, approximately half of cases occur

while at rest or during sleep [3,5,6]. The mechanisms associated with death during sleep are largely unclear, but may involve a disturbance in vagal autonomic regulation of cardiorespiratory activity. Death during exercise or physical activity is relatively uncommon, but is often witnessed [7]. There are important distinctions between the causes and circumstances of death between different age subgroups. The most common finding in those aged 1 to 5 years is an unexplained death during sleep, whereas premature coronary artery disease predominates in those aged 31 to 35 years [5,6]. Therefore, strategies to prevent SCD in the young should focus on understanding the mechanisms associated with death during sleep and measures to reduce premature coronary artery disease. A number of non-cardiac disorders are associated with a heightened risk of sudden unexpected death, including epilepsy and psychiatric disease. The most common epilepsy related cause of death is sudden unexpected death in epilepsy, or SUDEP, which has many similarities in circumstances to unexplained SCD. In both unexplained SCD and SUDEP, the death is sudden, the heart is structurally normal at postmortem investigation and no cause of death is identified. Risk factors for SUDEP include early onset epilepsy, severe intractable epilepsy, frequent drug changes and frequent seizures. Genetic analysis of SUDEP has revealed a

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clinically relevant variant in a major LQTS gene in 7% of cases [8]. This suggests there may be a likely shared arrhythmogenic cause of death in SUDEP and unexplained SCD in some cases.

Box 1. Key points for postmortem investigation of sudden cardiac death in the young [9,10] Collect information relevant to the postmortem

Postmortem Evaluation of Sudden Cardiac Death in the Young A major goal of the investigation of sudden death is to determine whether the death was caused by a cardiovascular disorder or a non-cardiac cause, as this has important implications for clinical evaluation of the surviving family. The postmortem investigation is a critical early step in identifying the precise cause and manner of death. In order to unify the examination and investigation of sudden cardiac death victims and their families, a best-practice guideline for the postmortem investigation of SCD in the young was created by the Trans-Tasman Response Against Sudden Death in the Young (TRAGADY) initiative [9]. This group comprises health professionals, scientists and patient advocates in Australia and New Zealand who share the aim of reducing SCD in the young. The guideline, formally approved by the Royal College of Pathologists of Australasia, mandates a full postmortem examination in these deaths to identify genetic causes and allow potentially life-saving interventions in the victim’s relatives. Guidelines for investigation of SCD were recently updated to reflect our increased understanding of possible genetic causes, the availability of new diagnostic methods and the experience gained by specialist cardiac examination of the heart [10]. The key points of the guidelines for postmortem investigation in SCD in the young are summarised in Box 1. The postmortem investigation should include relevant premorbid information collected from family members, medical records, witnesses to the death and police reports to the coroner. Valuable information includes age, sex, past medical history of significant illness, past symptoms of cardiac disease or in the minutes leading up to the death, and any family history of cardiac disease or sudden death. The circumstances of a witnessed death, including whether at rest or during activity or episodes of emotional stress, and the place and time of death can be helpful in determining whether the death was sudden or involved a non-cardiac cause. External examination of the body can exclude obvious non-cardiac causes of death and identify dysmorphic features that are characteristic of syndromes that have cardiac involvement. Body weight and height should be recorded to index with heart measurements. A special focus should be given to gross examination of the heart anatomy for signs of lesions, thrombosis or structural heart disease. Measures of heart weight and chamber size, and thickness of ventricle walls and interventricular septum may indicate an underlying cardiomyopathy. Histopathological examination of the myocardium, valves, conduction system and coronary arteries can identify some of the hallmarks of structural

investigation Age, gender, lifestyle Circumstances of death Past medical history Family history of cardiac disease External examination of the body Body weight and height Check for dysmorphic features Exclusion of non-cardiac causes Gross examination of the heart Check the anatomy of the heart Assess heart weight and wall thickness Check for ischaemic heart disease Histological examination of the heart Check myocardium Check coronary arteries Toxicology Check for prescribed and illicit drugs Microbiology Check for myocarditis Genetic testing Retain a frozen blood sample for DNA extraction Clinical evaluation of first-degree relatives Check for inherited cardiac disorders

cardiovascular disorders, such as myocyte disarray, fibrosis, fat deposits, inflammation, and amyloid or lysosomal storage deposits. Interpretation of postmortem findings is a complex task that requires a specialised cardiac pathologist to interpret the spectrum of normal macroscopic and microscopic variation of the heart so as to avoid misdiagnosis of disease. Since unexplained SCD is a diagnosis of exclusion of all other causes, there may be a tendency towards misinterpreting minimal histological changes as structural cardiovascular disease rather than an innocuous variant of an otherwise morphologically normal heart [11]. Importantly, clinical screening of family members after SCD with postmortem findings of uncertain significance identifies arrhythmia syndromes in a similar proportion to clinical screening of family members of unexplained SCD [12]. It is therefore important to consider that deaths with findings of

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uncertain significance may be caused by an underlying primary arrhythmogenic syndrome, and thus prompt appropriate clinical investigation of surviving family members. Misuse of illicit drugs should be investigated with toxicological analysis. Medications are often detected below therapeutic levels; however, some anti-epileptic and antipsychotic medications can prolong the QT interval. In a Danish cohort of SCD in the young, the prescription of medications increased with age and a positive toxicology was associated with an increased risk of unexplained death compared to explained death [13]. As previously mentioned, some SCD is caused by an inherited heart disease, therefore it is important to retain tissue suitable for DNA extraction to facilitate postmortem genetic testing. In some countries, including Australia and New Zealand, it is mandated to collect and freeze peripheral venous blood for future DNA extraction in young sudden deaths [9] and this practice has become a cornerstone of the guidelines for genetic testing and the management of arrhythmia syndromes [14]. Despite the relevant information that an invasive postmortem examination can provide, autopsy rates have declined worldwide [15]. This may be due to factors such as improved premorbid clinical diagnosis, funding constraints and the reluctance of families to provide consent. In some contexts of religious or cultural beliefs, an alternative to the invasive postmortem investigation would be preferred. Recent pilot studies have indicated that alternatives to the invasive postmortem examination, such as magnetic resonance imaging and computer tomography scanning, may be useful in identifying some structural cardiovascular disorders in young sudden deaths [16].

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Genetic Analysis of Unexplained Sudden Cardiac Death The Molecular Autopsy Genetic testing of the decedent (a person who has died) is a valuable addition to the investigation of SCD in the young. It can provide confirmation of a suspected structural cardiovascular disorder, but is especially useful in establishing whether a cardiac arrhythmia syndrome is responsible for unexplained deaths. For this reason, the addition of genetic testing to the postmortem investigation can identify additional causes of death over postmortem investigation alone [6]. The process of postmortem genetic testing, often termed ‘molecular autopsy’, involves DNA sequencing analysis of selected genes that are established to cause the main primary arrhythmogenic diseases (Figure 1). Current American Expert Guidelines for the prevention of SCD recommend a four-gene molecular autopsy if circumstantial evidence points towards a clinical diagnosis of LQTS or CPVT [14]. The four-gene molecular autopsy involves analysis of the three major genes causing LQTS (KCNQ1, KCNH2, SCN5A) and the main gene causing CPVT (RYR2). Early studies evaluating the role of the molecular autopsy were limited in scope by the use of Sanger DNA sequencing, which investigates one DNA segment at a time. Additionally, the reported diagnostic yield of up to 30% for molecular autopsy of unexplained SCD was an overestimate as study cohorts suffered from referral bias and the criteria to define pathogenic variants were overly lenient. Newer sequencing technologies are now able to analyse multiple genes in parallel, including simultaneous sequencing of all 22,000 protein coding genes using so-called ‘exome sequencing’. Thus, the

Figure 1 The molecular autopsy. A postmortem blood sample is collected during autopsy investigation and stored frozen. DNA is extracted, ideally from frozen blood or spleen, or as a last resort from formalin fixed and paraffin embedded tissue. Postmortem genetic testing of cardiac genes relevant to the cause of death is performed and variants are classified for pathogenicity. Variants deemed to be the cause of death can be used for cascade genetic testing of family members in conjunction with clinical screening. Relatives who do not carry the causal variant (2/2) can be released from on-going clinical evaluation, whereas those who have inherited the variant (1/2) are at risk of developing disease.

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scope of the molecular autopsy has expanded to include additional cardiac arrhythmia and cardiomyopathy genes. An important but complex step in the molecular autopsy is determining whether a variant is the underlying cause of death. Previously, the absence of a variant in a few hundred population control samples was considered sufficiently rare to be a candidate pathogenic variant. However, collating variants from over 100,000 population controls has revealed that very rare protein altering variants are more common overall than once thought. Many established cardiac disease genes have a surprising level of rare variants in the general population and classification of variants for pathogenicity must take this benign genetic ‘background noise’ into consideration. The widespread adoption of stringent guidelines for determining the pathogenicity of variants and analysis of nationwide unselected cohorts has revised the diagnostic yield of the four-gene molecular autopsy for unexplained SCD to 10–15% [6,17,18]. Although postmortem blood is a preferred source of DNA, for some SCD cases this is not available. As a last resort, formalin-fixed and paraffin-embedded tissue, which is usually prepared for histological analyses, can provide an alternative source of DNA with the limitation that it is severely degraded. Nevertheless, exome sequencing-based molecular autopsy using DNA extracted from archival fixed postmortem tissue up to 15 years old identified a genetic cause of sudden death in two out of five cases [19].

Defining New Causes of Unexplained Sudden Cardiac Death Ongoing research to define new genetic causes of cardiac arrhythmia syndromes and sequencing of larger panels of cardiac genes has revealed some new genetic underpinnings of unexplained SCD. An increasingly recognised but rare form of severe LQTS with early occurrence of life-threatening arrhythmias is caused by variants in any one of three genes encoding calmodulin (CALM1, CALM2 and CALM3) [20]. Calmodulin is a ubiquitous calcium binding protein that can modulate the activity of cardiac ion channels. Isolated case reports of calmodulin variants causing cardiac arrhythmias present an incomplete clinical picture of this newly recognised genetic disorder. This has prompted the creation of the International Calmodulinopathy Registry to collect case reports and has revealed new clinical and genetic insights [20]. Variants within two short calcium binding domains of calmodulin are associated with arrhythmia phenotypes including LQTS, CPVT and unexplained SCD. Almost all disease-causing calmodulin variants found in affected individuals arise de novo; that is, they are absent in both parents. Over half of patients with calmodulin variants and a LQTS or CPVT phenotype had cardiac events despite therapy with beta blockers, sodium channel blockers or other antiarrhythmics, which suggests that these medications offer only modest benefits. Another recently described genetic cause of unexplained SCD is variants that truncate the plakophilin 2 protein,

encoded by the PKP2 gene. PKP2 variants have long been associated with arrhythmogenic cardiomyopathy, characterised by fibrofatty replacement of the ventricular myocardium. However, emerging reports suggests there may be an early phase of disease progression that mimics the phenotype of CPVT and Brugada syndrome, during which structural disease is not evident [21–23]. Truncating PKP2 variants have been found in exertion-related unexplained SCD, resuscitated sudden cardiac arrest, and patients clinically diagnosed with CPVT who did not have variants found following genetic testing of established CPVT genes. The notion of ‘concealed cardiomyopathy’, in which the heart appears morphologically normal, or shows minor structural changes that are insufficient for a diagnosis of a structural cardiac disorder, suggests that molecular autopsy of unexplained SCD should include genes associated with arrhythmia syndromes and cardiomyopathy.

The Multidisciplinary Team Approach The molecular autopsy is not without challenges. Selection of the optimal panel of genes for testing is increasingly complex and larger panels of genes are more likely to find the genetic ‘background noise’, instead of signal. There are often multiple variants for which the evidence of pathogenicity needs to be collected and evaluated. Distinguishing pathogenic variants from background variation can be time-intensive and especially complex in the absence of a clear clinical phenotype. The molecular autopsy should thus be performed with a multidisciplinary team-based approach that combines the expert input from medical examiners, cardiologists, genetic counsellors and geneticists to provide the highest level of confidence in the genetic interpretation.

Clinical Evaluation of Surviving Family Members The primary purpose of managing families affected by SCD of a young relative is to prevent sudden death from striking again. Clinical evaluation of families where SCD has occurred is a critical step given the significant possibility of an underlying genetic cause. Indeed, up to half of the families in which unexplained SCD has occurred have a genetic heart disease identified on clinical evaluation. Finding an inherited arrhythmogenic or structural cardiac disorder as the cause of death should thus prompt clinical screening of first-degree family members to identify affected individuals and facilitate early initiation of appropriate life-saving intervention strategies to prevent further deaths. The clinical investigation of the family, including firstdegree relatives, obligate carriers, and symptomatic relatives, is based largely on the recent expert consensus document [14]. Clinical screening should include taking a detailed family history with a focus on identifying cardiac disease or a family history of sudden death, and specific clinical evaluations should be tailored to the postmortem investigation findings. These may include

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electrocardiography, echocardiography and additional adjunct tests such as a Holter monitor, exercise stress test or pharmacological provocation testing. A challenging aspect of clinical evaluations is that family members who have inherited the genetic causing of disease may not display symptoms or clinical evidence of disease due to incomplete penetrance and variable expressivity. Up to 40% of gene carriers of LQTS have a normal QT interval. Therefore, asymptomatic relatives are generally recommended to undergo on-going clinical evaluation to detect clinical evidence of disease that may present later in life. If a pathogenic or likely pathogenic variant has been found in the decedent then cascade genetic testing of first-degree family members is recommended. Resolving the genetic cause of SCD has major clinical and psychological benefits for the surviving family. It provides a level of closure. Genenegative family members are released from lifelong clinical surveillance and the psychological burden of an unknown SCD risk status. Gene-positive family members can be targeted for disease prevention strategies, including avoiding risk activity, preventive medication and, in some cases, implantation of a cardioverter defibrillator. The family can also be offered future reproductive choices, such as preimplantation genetic diagnosis. It is important to note that only variants deemed to be pathogenic or likely pathogenic have sufficient evidence of causality to be clinically relevant and used for cascade genetic testing. Another challenging aspect of managing families with SCD is the psychological toll of losing a young family member. In particular, mothers who witness the death of a child are understandably among those with the highest anxiety levels and may benefit from psychological support as they try to come to terms with the sudden loss of a young relative [24]. During the process of clinical and genetic evaluation of the family, specialist cardiac genetic counsellors are uniquely placed to explain complex genetic information and develop a supportive relationship with surviving relatives.

Conclusions and Future Directions Our understanding of the combined interplay between clinical and genetic factors that influence risk for SCD in the young has greatly improved in recent years (Figure 2). The availability of specialised forensic pathology services and guidelines for postmortem investigation have improved diagnosis of the cause of death. The addition of newer sequencing technologies has expanded the scope of genetic testing beyond the four-gene molecular autopsy to define additional genetic causes and facilitate cascade genetic testing of at-risk family members. Strategies to prevent sudden death from occurring in at-risk family members are now available. Encouraging reports of a decline in the incidence of SCD in the young have recently emerged [25]. It is enticing to consider whether this is the result of improved diagnosis of

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Figure 2 Multiple hit model for SCD risk prediction. Abbreviations: SCD, sudden cardiac death; ECG, electrocardiograph. genetic heart diseases and better management of families after SCD, including the use of life-saving cardioverter defibrillators. Increased public access to automatic external defibrillators provides a means to increase survival of witnessed out-of-hospital cardiac arrest. An important focus for further reducing SCD in our communities should include understanding the mechanisms of death during sleep and prevention of premature coronary artery disease in young adults. The intriguing disparity between the incidence of sudden cardiac death between males and females is not well understood, and although the incidence increases with age in both sexes, the annual rate in females is almost half that of males. This may arise from the possible protective effects of female endogenous oestrogen, including modulation of mitochondrial function and vasodilation, and protection against cardiac fibrosis [26,27]. A key area for future clinical research is the identification of new arrhythmogenic disorders that may cause sudden death. Very recently, a previously unrecognised arrhythmia syndrome with the electrocardiographic pattern of widespread ST-segment depression was reported in five families with an autosomal dominant inheritance pattern [28]. Affected family members display heterogeneous clinical presentations with variable penetrance, from no symptoms to syncope, atrial fibrillation, ventricular tachycardia, heart failure and unexplained SCD. No underlying genetic cause has yet been found despite comprehensive cardiac gene panel sequencing analysis. Further insights will likely require pooling of individual cases, as performed for the International Calmodulinopathy Registry. Further insights into the underlying genetic causes of SCD in the young will likely arise from genetic studies using genome sequencing, which is the most comprehensive genetic test [29]. While many genetic cardiovascular disorders

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show autosomal dominant inheritance, some may have alternative complex genetic underpinnings. Brugada syndrome is found in up to 15% of families on clinical evaluation after SCD of a young relative, but the genetic basis is largely unresolved. Recent expert re-evaluation of disease-gene associations in Brugada syndrome left only one gene, SCN5A, with a definitive association with disease, which accounts for approximately 20% of cases. Further insights may benefit from combining international cohorts of unexplained SCD that have sufficient power to perform statistical genetic analyses. The goal is to prevent SCD in the young by improving risk prediction, diagnosis and management strategies for SCD families. Risk prediction in the young general population is the ultimate goal.

[13]

[14]

[15] [16]

[17]

Disclosures Q3

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Please cite this article in press as: Bagnall RD, et al. Sudden Cardiac Death in the Young. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.007

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