Sudden cardiac arrest, whether or not ultimately fatal, is a devastating event for the family, friends, and the entire community. In individuals aged between 3 and 25 years, these events are most likely secondary to an inherited cardiovascular condition or an undiagnosed congenital anomaly.Reference Meyer, Stubbs and Fahrenbruch 1 This article focusses on the incidence and aetiology of cardiac arrest in children and young adults, the investigative and management approach to survivors of sudden cardiac arrest, and subsequent investigations in the wider family.
Incidence and aetiology of cardiac arrest
Numerous population studies have recorded the incidence of out-of-hospital cardiac arrest at between 8.1 and 9.1 cases/100,000 person-years, although only one-quarter to one-third (2.3–3.2 cases/100,000 person-years) are cardiac in aetiology.Reference Meyer, Stubbs and Fahrenbruch 1 – Reference Gerein, Osmond and Stiell 5 During infancy and early childhood – that is, under 3 years of age – CHD accounts for over 80% of cases, whereas above 25 years of age coronary artery disease becomes the dominant aetiology (43%). In those aged 3–25 years of age, although CHD, specifically valvar disease and coronary artery anomalies, remains an important contributor to the overall burden, inherited cardiovascular disorders including cardiomyopathies, arrhythmia syndromes, and mitral valve prolapse become increasingly prevalent, along with acquired conditions such as myocarditis.Reference Bardai, Berdowski and van der Werf 3
Overall survival rates from out-of-hospital cardiac arrest remain poor, although they have improved over the last three decades with the implementation of new guidelines and community awareness of cardiopulmonary resuscitation and automated external defibrillator use. 6 , Reference Rea, Helbock and Perry 7 In cases of cardiac arrest with a cardiovascular aetiology, the survival rate has increased from 13% between 1980 and 1989 to 40% between 2000 and 2009.Reference Meyer, Stubbs and Fahrenbruch 1 If ventricular tachycardia or fibrillation – that is, a rhythm amenable to direct current cardioversion using an automated external defibrillator – is the first recorded rhythm, then survival is significantly improved.Reference Meyer, Stubbs and Fahrenbruch 1 – Reference Kitamura, Iwami and Kawamura 4
Understanding the potential aetiologies of cardiac arrest is important in considering subsequent investigations in cardiac arrest survivors and family members. Cardiomyopathic causes of sudden death include hypertrophic, dilated, and arrhythmogenic causes, with the incidence of each varying with the age of those studied and with geographic location. In young competitive athletes, hypertrophic is the most common cause of death and is seen particularly in those of African American background,Reference Maron, Doerer and Haas 8 whereas in certain geographic regions such as Italy and NewfoundlandReference Corrado, Basso, Pavei, Michieli, Schiavon and Thiene 9 , Reference Hodgkinson, Connors and Merner 10 arrhythmogenic is far more common, resulting from genetic founder effects and a high prevalence of this condition within the local populations. Primary electrophysiological causes include long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia in younger patients. Although mitral valve prolapse has long been associated with sudden death, only recently have the mechanisms been better understood. A common and typically benign valvar anomaly in the vast majority, ventricular arrhythmias and cardiac arrest occur in a very small subset of patients and are associated with bileaflet prolapse, ventricular ectopy alternating from the left ventricular base and ventricular outflow tracts, and myocardial fibrosis.Reference Ackerman 11 , Reference Basso, Perazzolo and Rizzo 12 Recently the genetic basis of mitral valve prolapse has been linked to the gene DCHS1.Reference Durst, Sauls and Peal 13 Wolff–Parkinson–White syndrome may lead to sudden cardiac arrest in a very small minority of patients with the condition, facilitated by pre-excited atrial fibrillation via the accessory pathway(s) leading to ventricular fibrillation. This condition is very rarely heritable.
Investigation of cardiac arrest survivors
Clinical history and physical examination
Investigations should ideally begin immediately following transfer of the patient to the hospital, although in many cases a complete or near-complete neurological recovery is necessary to allow specific investigation such as exercise testing to be performed. These should include a detailed past medical history of the patient specifically focussing on pertinent cardiac features, any symptoms immediately prior to the event, and any associated triggers. Although the association with exercise is well recognised largely due to the public media coverage of such events, only a small minority of cardiac arrests actually occur with exertion.Reference Mellor, Raju and de Noronha 14 , Reference Tabib, Loire and Chalabreysse 15 Individuals who suffer cardiac arrest typically experience retrograde amnesia and hence have little if any memory of the event, meaning details should be sought from witnesses and medical responders in the field. Arrhythmic syncope may be time-dependent and may occur in clusters, and should be specifically sought, as should a prior history of palpitations, pre-syncope, and any recently prescribed medications or environmental factors such as fever that may exacerbate arrhythmic expression of long QT syndrome or Brugada syndrome.Reference Vincent, Schwartz and Denjoy 16 , Reference Probst, Denjoy and Meregalli 17 New-onset exertional dyspnoea and/or reduced exercise capacity is suggestive of an underlying cardiomyopathy with associated myocardial dysfunction, or – if of very recent onset and associated with viral and/or gastrointestinal symptoms – may be consistent with viral myocarditis. Cerebral anoxia during ventricular fibrillation may precipitate posturing or seizure-like activity, such that many arrhythmic syncopal events are frequently mistaken for epilepsy. In long QT syndrome, this dates back to the very earliest description of the condition and remains an important misdiagnosis.Reference McCormick, McAlister and Crawford 18 Important clues to misdiagnosis are an “epileptic” with normal investigations and no response to escalating anti-epileptic medications. However, in a small minority of long QT syndrome patients, typically those with KCNH2 mutations, there is an overlap phenomenon between long QT syndrome and epilepsy. Importantly, sudden death in epilepsy is a major contributor to mortality in this population.Reference Johnson, Hofman, Haglund, Cascino, Wilde and Ackerman 19 , Reference Shorven and Tomson 20 Exercise as a trigger for cardiac arrest should heighten suspicions for long QT syndrome type 1 and catecholaminergic polymorphic ventricular tachycardia, both conditions where arrhythmias are exacerbated by adrenergic stimulation. In the case of catecholaminergic polymorphic ventricular tachycardia, the hallmark bidirectional ventricular tachycardia may be recorded on the automated external defibrillator traces, effectively securing the diagnosis, although Andersen–Tawil syndrome may also lead to bidirectional ventricular tachycardia but is associated with cardiac arrest far less frequently than is catecholaminergic polymorphic ventricular tachycardia.Reference Zhang, Benson and Tristani-Firouzi 21 Fundamental to the investigation is a detailed family history and pedigree construction, ideally performed by an experienced genetic counsellor, assessing any cardiac phenotype or factors within the wider family that may help explain or be highly relevant to the underlying aetiology.
Findings on physical examination are largely driven by anomalies within the cardiovascular system, such as features of left ventricular outflow tract obstruction, mitral valve regurgitation, and cardiomegaly in hypertrophic, or pulmonary oedema and hepatosplenomegaly secondary to systolic myocardial dysfunction in dilated. However, all clinical findings should be carefully re-evaluated on a daily basis to determine whether these are related to cause or effect. Importantly, many inherited cardiovascular disorders have associated non-cardiac findings. Subtle woolly hair and palmoplantar keratoderma may be seen in arrhythmogenic wherein life-threatening arrhythmia is associated with varying degrees of left ventricular dysfunction;Reference Beausejour-Ladouceur, Joyce and Stevenson 22 subtle features of skeletal myopathy are seen in lamin A/C and desmin cardiomyopathies;Reference Fatkin, MacRae, Sasaki and Wolff 23 , Reference Dalakas, Park and Semino-Mora 24 and Andersen–Tawil syndrome is associated with skeletal and neurological findings.Reference Zhang, Benson and Tristani-Firouzi 21
Laboratory investigations
The 12-lead electrocardiogram is fundamental to the investigation, although manifest abnormalities of cardiac conduction, ventricular depolarisation, and repolarisation may result from myocardial ischaemia during the cardiac arrest and should be interpreted with caution; the electrocardiogram should be repeated daily during recovery. Cardiac imaging – either echocardiography or cardiac magnetic resonance – identifies structural abnormalities such as left ventricular hypertrophy associated with hypertrophic or ventricular dilatation and wall motion abnormalities in arrhythmogenic. Specific attention should be paid to the course of the coronary arteries, which if abnormal and deemed sufficient to explain a cardiac arrest can be addressed surgically. Such patients often give a prior history of exertional chest pain or syncope. Although it would seem intuitive that patients who suffer a cardiac arrest secondary to a cardiomyopathy would have abnormal imaging, that may not always be the case, as arrhythmic events may precede the typical electrocardiographic, structural, and histological changes.Reference Delmar and McKenna 25 , Reference Sy, Gollob and Klein 26 A cardiac exercise stress test allows for assessment of ventricular repolarisation during both standing and in the recovery period from exerciseReference Adler, van der Werf and Postema 27 , Reference Sy, van der Werf and Chattha 28 for assessment of any changes in ventricular depolarisation suggestive of arrhythmogenic,Reference Perrin, Angaran and Laksman 29 and for arrhythmia initiation as is typical in catecholaminergic polymorphic ventricular tachycardia.
Drug challenges may also provide helpful diagnostic information. Electrocardiographic changes in Brugada syndrome are highly dynamic, and may change from diagnostic to normal within a short period of time, especially if initially exacerbated by a dynamic environmental trigger such as fever. Drug provocation testing using a class 1 anti-arrhythmic agent such as ajmaline, flecainide, or procainamide can unmask the latent electrocardiogram changes.Reference Antzelevitch, Brugada and Borggrefe 30 Importantly, the Brugada syndrome-type electrocardiogram changes are non-specific and can be seen immediately after cardioversion from ventricular fibrillation.Reference Wilde, Antzelevitch and Borggrefe 31 In another report, about 25% of patients undergoing an electrophysiology study for atrioventricular nodal re-entry tachycardia were found to have similar Brugada syndrome electrocardiogram findings with drug provocation.Reference Hasdemir, Payzin and Kocabas 32 Catecholamine infusions performed in the electrophysiology lab can also be helpful in unmasking a catecholaminergic polymorphic ventricular tachycardiaReference Herman, Cheung and Gerull 33 or arrhythmogenicReference Denis, Sacher and Derval 34 phenotype in patients in whom other investigations may be normal.
Clinical management
In a small minority of patients a treatable cause may be identified, for whom an interventional or surgical approach can prevent further recurrence. Examples include anomalous course of the left coronary artery, which can be surgically corrected, and ventricular pre-excitation, which can be mapped and ablated during an electrophysiology study. It is important that the electrophysiological properties – specifically, the effective refractory period and shortest pre-excited R-R interval during atrial fibrillation – of the accessory pathway that are identified during an invasive study are sufficient to explain this as the aetiology of cardiac arrest. Conversely, very occasionally pre-excited atrial fibrillation may occur in the absence of pre-excitation during sinus rhythm, because atrial fibrillation may arise from the left-sided pulmonary veins and preferentially engage a left free wall accessory pathway. Given the fundamental difference in management and long-term prognosis of atrial fibrillation in the absence versus presence of pre-excitation, an electrophysiology study to exclude this phenomenon should be performed where appropriate post cardiac arrest.
Implantation of a cardioverter–defibrillator is a class 1 indication following cardiac arrest, and the vast majority of such patients will receive implantation of a cardioverter–defibrillators. However, the long-term complications of implantation of a cardioverter–defibrillators, including mortality, in younger patients with inherited cardiovascular disorders are well recognised.Reference Olde Nordkamp, Postema and Knops 35 In specific circumstances other strategies may be employed. Vincent reported 26 patients who suffered a cardiac arrest secondary to long QT syndrome type 1 who were successfully managed with β-blockers and avoidance of QT-prolonging medications rather than an implantation of a cardioverter–defibrillator.Reference Vincent, Schwartz and Denjoy 16 The complications of implantation of a cardioverter–defibrillators in catecholaminergic polymorphic ventricular tachycardia are being increasingly recognised. In particular, the sudden catecholaminergic surges that accompany shocks may trigger further arrhythmias and a potentially fatal, vicious cycle of continued shocks and arrhythmia. Pharmacological management with the β-blocker nadololReference Hayashi, Denjoy and Extramiana 36 and flecainideReference Watanabe, Chopra and Laver 37 coupled with surgical left cardiac sympathetic denervationReference De Ferrari, Dusi and Spazzolini 38 may therefore be a preferred strategy to implantation of a cardioverter–defibrillator implantation in carefully investigated, managed, and counselled patients.
Familial investigations following sudden cardiac death
In cases of sudden cardiac death the first investigation of upmost importance is a comprehensive and detailed autopsy of the deceased. This is typically performed initially by the medical examiner or coroner, although a secondary review of either the whole heart or histological sections by a specialist cardiac pathologist familiar with the specific details of sudden cardiac death in the young should be considered if there is any uncertainty. Specialist secondary opinions by cardiac pathologists can identify subtle diagnostic features that are potentially critical to subsequent familial investigations,Reference Corrado, Basso and Thiene 39 – Reference Tan, Hofman and van Langen 42 and have become a class 1 recommendation as per the 2013 expert consensus statement on inherited arrhythmic syndromes.Reference Priori, Wilde and Horie 43 A detailed autopsy should include the following:Reference Wilms, Midgley, Morrow, Stables, Crawford and Skinner 44
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∙ A clinical history including a comprehensive review of prior personal medical and family history, including syncope and seizures, antecedent symptoms, witness reports, activity and location at the time of death, possible triggers, and the use of prescription medication, illicit drugs, or alcohol.
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∙ Gross pathological measurements including overall heart weight indexed for body surface area, maximal thickness of the interventricular septum, right and left free walls at different points, and appearance of the myocardium, valves, and proximal coronary arteries. Critical samples should be retained for future DNA analysis, urine and blood toxicology.
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∙ Histological analysis including sampling of the septal, right, and left ventricular myocardium, especially at sites that show hypertrophy or gross visual abnormalities, as well as analysis of the atrial myocardium and cardiac conducting system. Further detailed analysis of the coronary arteries and any luminal anomalies should also be performed. The use of other specific histological stains or viral polymerase chain reaction testing in cases of suspected myocarditis should also be recorded.
Despite a detailed postmortem examination, in ~30–40% of cases the autopsy will be negative – that is, no cause for sudden death will be identifiedReference Seminarian, Ingles and Wilde 45 – and in such cases stored DNA can be used for subsequent genetic testing – that is, for molecular autopsy (see below under genetic testing).
Following cases of sudden death or cardiac arrest in the young and given the highly variable and age-related penetrance exhibited by many inherited cardiac disorders, first-degree family members should be referred to a specialist inherited cardiovascular clinic, which has the capacity to see all family members irrespective of age. There, the full complement of specialists can address the significant associated medical and psychological issues. The exact make-up of such clinics varies, but should include an adult cardiologist, a paediatric cardiologist, a geneticist, and a genetic counsellor, all of whom have specific training and expertise in the clinical and genetic manifestations of inherited cardiac conditions; such clinics should also have other subspecialists such as a neurologist and a pathologist, a clinical psychologist familiar with the specific conditions and associated issues related to cardiac arrest and sudden cardiac death,Reference Hidayatallah, Silverstein and Stolerman 46 specialist nurse(s) to aid with clinical investigations, and a programme coordinator who can arrange the visit based on collation of prior information such as autopsies or medical records. This approach facilitates a targeted strategy, based on prior diagnoses, and perhaps most importantly ensures that the family does not have to be concerned with organising specific logistical issues during the grieving process.
In terms of a familial diagnosis following sudden death, the Dutch experience is worthy of note. Reported in 2005, a comprehensive clinical assessment of first-degree relatives following sudden cardiac death and a normal autopsy in a specialist cardiovascular genetics centre identified a clinical diagnosis in 17/43 (40%) families studied, primarily with inherited arrhythmic syndromes. A diagnosis was significantly more likely in families with more individuals assessed, and the electrocardiogram at rest, during exercise, or with drug provocation provided the highest diagnostic yield. Clinical findings were often supported by identification of concordant genetic variants in known disease-associated genes.Reference Tan, Hofman and van Langen 42 Subsequently, a larger-scale analysis was reported over the period 1996–2011, where sudden death cases were investigated using a combination of acquisition of all details regarding the victim, including autopsy reports, secondary review by a specialist cardiac pathologist, retrieval of frozen DNA for molecular autopsy, and comprehensive familial assessment. This yielded a clinical diagnosis in 93/372 (25%) families, supported by a molecular diagnosis in 52 families (56%).Reference Hofman, Tan and Alders 47
Genetic testing
Genetic testing in cardiac arrest and sudden death cases should be performed as part of the comprehensive familial evaluation. Ultimately, the power of genetic testing is best realised when causality can be attributed to any identified variant. This is best achieved by demonstrating segregation of the variant with the phenotype across the extended family such that the statistical chance that these two findings are coincidental is <1:1000, that is, logarithm of odds score ⩾3. In such situations the family itself becomes the tool used to validate the identified variant. However, given that sufficiently large families are not always available, other criteria to determine variant pathogenicity have been created.Reference Richards, Aziz and Bale 48
Genetic testing is best performed in a targeted manner based on identification of a phenotype within the wider family, although this is always challenging given the varied penetrance and pleiotropy associated with many inherited cardiac disorders. Family members who undergo genetic testing should be carefully counselled by an experienced cardiac genetic counsellor or clinician regarding potential outcomes, including a negative result or identification of a variant that, despite detailed familial assessment, remains one of uncertain significance. Individuals and families should also be counselled regarding future life insurance and potential employment issues, and they should be offered information regarding the Genetic Information Non-discrimination Act. Ultimately if a variant considered pathogenic can be identified within any given family, this can be used as part of more extensive cascade testing to detect other at-risk individuals within the community.Reference Earle, Crawford and Smith 49
Genetic testing in cardiac arrest survivors or unselected family members of sudden death cases where no phenotype can be demonstrated is associated with a low yield overall (9%),Reference Bai, Napolitano and Bloise 50 and using expansive panels in the hope of identifying a culprit variant is not recommended.Reference Priori, Wilde and Horie 43 In sudden death cases with a normal conventional autopsy, genetic testing – that is, molecular autopsy – has traditionally been performed in a targeted manner, sequencing genes most commonly associated with long QT syndrome and catecholaminergic polymorphic ventricular tachycardia – namely, KCNQ1, KCNH2, SCN5A, and RyR2. This has yielded encouraging results, especially if the phenotype is further refined – for example, in exertional sudden death – wherein 34% of 32 cases were found to carry variants in concordant genes, KCNQ1 (2/11) or RyR2 (9/11). The detection rate can be increased to 14/32 (44%) by using more comprehensive whole-exome analysis, although this comes with the caveat of identifying a significant number of variants of unknown significance.Reference Anderson, Tester, Will and Ackerman 51 Catecholaminergic polymorphic ventricular tachycardia is an attractive candidate for molecular autopsy given the malignant nature of the disease, especially in young boys, the high likelihood of a negative autopsy, and the high rate of de novo cases with a consistent disease expression where familial evaluation will be, by definition, negative.Reference Priori, Napolitano and Memmi 52
Conclusion
Although thankfully rare, sudden cardiac death and cardiac arrest have profound effects on the family and entire community. Services must be in place to support survivors and the wider family, ensuring clinical and genetic evaluation is performed in a specialist centre for inherited cardiovascular disorders by professionals familiar with the medical and psychological aspects of these conditions. Evaluation of the entire family as a single unit remains the cornerstone of clinical care, in order to better define the specific phenotype within that specific family but also to ensure every affected member at potential risk is identified and afforded adequate protection against further tragic cardiac events.
Acknowledgements
The Inherited Cardiac Arrhythmia Program at Boston Children’s Hospital is generously supported by the Mannion and Roberts families.
Financial support
This research or review received no specific grant from any funding agency or from commercial or not-for-profit sectors.
Conflicts of Interest
None.
Ethical Standards
The authors assert that all referenced work contributing to this review complies with the ethical standards of biomedical or medicolegal investigation.
