Heart, Lung and Circulation (2014) 23, 1097–1099 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2014.09.018

Sudden Cardiac Death in the Young: What We Know, What We Don’t Know and What We Need To Do Jitendra Vohra, MD, FRACP Departments of Cardiology and Genetics, The Royal Melbourne Hospital and the University of Melbourne Received 2 September 2014; received in revised form 23 September 2014; accepted 23 September 2014; online published-ahead-of-print 5 October 2014

Sudden cardiac death in the young, generally defined as between the ages of one to 40 years, is frequently unpredictable and is a great tragedy for the family and society. Although we need to discover much more about the causes of sudden cardiac death, enough is known to indicate that all efforts should be made to facilitate early resuscitation and identification of asymptomatic individuals by screening the family of young sudden deaths and patients with inherited arrhythmic diseases. What is sudden death? Sudden death (SD) is defined as witnessed sudden death or death occurring within one hour of symptoms or unexplained death occurring in a person who was well the previous 24 hours. The term sudden unexplained death (SUD) is used when there is no obvious explanation and sudden arrhythmic death (SAD) is recommended when no cause for death is found at autopsy and the death is presumed to be due to an arrhythmia. Sudden infant death syndrome (SIDS) is a term used for death occurring from birth up to the age of one year and SIDS is not included in this discussion about SUD. Sudden cardiac death (SCD) is a term used to encompass all sudden deaths due to cardiac causes. How common is sudden death? In the age group one to 40 years the incidence of SD is reported to be 1.3 to 8.5 per 100,000 person years [1–3]. The incidence of death and SD increases with age but the proportion of deaths that are sudden is larger in younger age group and is highest in the first five years of life. Risgaard et al recently reported a nationwide study in Denmark and looked at the burden of SCD in persons aged one to 49 years between 2007 and 2009[4]. In the three-year study period, there were 893 cases of SCD, of whom 659 were males and 234 were females. Between the ages of one to 35 years, the incidence in men was 3.2 and in women was 1.5 per 100,000 person years. There was a significant increase

in the incidence between 36-49 years of age, to 32.1 in men and 11.1 in women per 100,000 person years. What are the causes of sudden death in the young? Van Der Werf et al. performed a meta-analysis of clinicopathological studies published over a 20-year period (1990-2009) and analysed the causes of SCD in 2087 subjects between the ages of one to 40 [3]. Coronary artery disease, mostly in 35-40 year olds, accounted for over 30% of SCD. Myocarditis, LV hypertrophy and hypertrophic cardiomyopathy each accounted for about 8 to 10% of deaths and dilated cardiomyopathy, arrhythmogenic RV cardiomyopathy (ARVC) and anomalous origin of the coronary arteries each accounted for 5% or less. About 27% were classed as unknowns or SUDs [3]. A major drawback of many studies of SCD in the young is the low rate of autopsies in many countries. In many European countries and in the USA an autopsy in a young SD is not mandatory. Where the autopsy rate is high, some 20 to 30% of autopsies fail to show any obvious cause of death. Two independent Australian studies from New South Wales analysed SCD under the age of 35 years [5,6]. Doolan et al. and Puranik et al. found that autopsies were negative and the hearts were normal in 31% and 29% of 192 cases and 241 cases of SCD, respectively [5,6]. These SADs were presumably due to cardiac arrhythmia arising from channelopathic disorders. Winkel et al. also reported an identical 29% proportion from Denmark [7]. However, Mazzanti and Priori reported that other autopsy series of SCD in the young had found a normal heart at autopsy in anywhere from 6 to 41% of cases [8]. While some of this variation is due to the variable autopsy rates, there is also geographical variation. The Veneto region in Italy for instance, has a high occurrence of ARVC and the proportion of SADs from that region is only 6%. The age group and the population under consideration also make a difference. In American military recruits, who had undergone

© 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.


detailed examination at enrolment, the proportion of SADs was reported to be 35% [9,10]. What causes sudden arrhythmic death? Important causes of SADs include channelopathic disorders like Long and Short QT syndromes, Brugada syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Early Repolarization syndrome [11]. These disorders are caused by genetic defects or mutations, which affect transport of ions like Na+ and K+ resulting in prolongation or shortening of cardiac action potential. CPVT results from increase in intracellular calcium concentration causing late diastolic potentials and triggered automaticity. Other causes include: Concealed structural abnormalities, such as ARVC, dilated cardiomyopathy and sarcoidosis, where the morphological changes in the heart may be subtle and not apparent; coronary artery spasm occurring in the presence of coronary arterial narrowing causing ventricular fibrillation without producing myocardial infarction can also cause SCD and the heart structurally appears normal. Another important cause is sudden death during epilepsy (SUDEP) where the heart is normal at post-mortem. Idiopathic ventricular fibrillation (IVF) is the term applied to SAD where no cause for death can be found. With advances in genetic techniques from candidate gene approach to the next generation sequencing and the whole genome analysis, this diagnosis is expected to become less common. Until recently, the incidence of IVF has been quoted as 50% [11]. How can we identify the cause of sudden death in the young? Through the efforts of TRAGADY (Transtasman Action Against Sudden Death in the Young), uniform autopsy recommendations have been drawn up by the Royal Australasian College of Pathologists. This includes preservation of post-mortem DNA and tissue samples [12]. In most major cities in Australia and New Zealand, multidisciplinary clinics operate along the lines of the Cardiac Society of Australia and New Zealand guidelines [13]. Accordingly, the referral of families of young sudden death to these clinics is recommended. These clinics undertake family screening, provide diagnosis and make recommendations regarding management. However, one major obstacle to arriving at a diagnosis of SCD in the young is the cost of genetic testing for which there are no government reimbursements. Cost effectiveness of genetic testing has been demonstrated [14]. It is hoped that with reduction in the cost of genetic testing this situation will improve in the future. How does age influence the cause of sudden cardiac death? The Cook County Washington Cardiac arrest database analysed 361 cardiac arrests with the means age of 25.1 10 years [15]. The overall survival rate was 26.9% and the data was from such sources as clinical records, autopsy reports and death certificates. This report provided useful information on the effect of age on the aetiology of cardiac arrests and SCD. Between the ages of 0 to two years, 84% of deaths were related to congenital heart disease and 8% were due to primary electrical arrhythmias (PEA). The incidence of PEA increased to 25% between the ages of three to 13 years

J. Vohra

and 14% of these were due to LQTS. Between the ages of 14 to 24, PEA incidence was 31% but between 25 to 35 years 43% of deaths were due to coronary artery disease and PEA accounted for 16% of death. This study also looked at the effect of exercise on the cause of SCD and divided those who had a history of exercise within one hour of death and those who died at rest. Contrary to expectation, most deaths occurred at rest and there was no difference in the cause whether the death occurred at rest or exercise. What do we know about SCD in children? Winkel et al. reported on 87 SCD in children between the ages of one to 18 years over a period of eight years [16]. They reported an incidence of 1.1/100,000 person years and found that 6% of all deaths in children were SCD and male deaths accounted for 2/3 of all SCD. Antecedent symptoms such as seizures, syncope, chest and arm pains were present in 45%. Twentynine percent had negative autopsies (SADs) and 9% had myocarditis. They recommended autopsies in all children who suffered SCD except for those with known congenital heart disease. What do we know about SCD in athletes? Although the incidence of SCD in athletes is not high these deaths are frequently recorded in the media and they receive wide publicity. The incidence of SCD in athletes has been variously reported as 1:9000 person years (US military recruits between the ages of 18 to 35 years) to 1:160,000 person years in US athletes between ages of 12-35. The commonest cause of SCD in 47 US College Athletes was hypertrophic cardiomyopathy followed by coronary artery anomalies and coronary artery disease [17]. In 17 other athletes the cause of sudden death was presumed (but not confirmed) to be cardiac. In European athletes, Corrado et al. found HCM, ARVC, coronary artery disease and anomalous origin of the left and occasionally right coronary artery as causes of death [18]. Basso et al. analysed 27 athletes who died suddenly and who had anomalous origin of coronary arteries arising from the wrong sinus [19]. Twenty-three had left coronary artery arising from the right sinus and four had right coronary artery arising from the left sinus. Only 10 out of 27 had prior symptoms of syncope or chest pain and 6/6 had normal ECG and 4/4 had normal exercise tests. Therefore, ante mortem diagnosis of anomalous coronary artery origin is not easy. Commotio Cordis as a cause of SCD in athletes is now widely recognised. In this situation cardiac arrest is caused by precordial impact with a hard projectile such as a cricket ball or baseball, fist or elbow. The contributing factors are a thinner, more compliant chest wall, greater hardness of the projectile causing a rapid increase in intracavity pressure and the blow timed within a 20 msec window at the upstroke of the T-wave causing ventricular fibrillation [20]. Resuscitation is frequently delayed because of lack of recognition but survival with prompt defibrillation with an automatic external defibrillator is reported [21]. What do we know about sudden death during epilepsy (SUDEP)? SUDEP is a recognised cause of SCD and has been

Sudden Cardiac Death in the Young

defined as sudden unexpected, nontraumatic and nondrowning death in an individual with epilepsy with or without evidence for a seizure, and excluding documented status epilepticus and a negative autopsy [22]. SUDEP is more common in drug resistant epilepsy and causes 50-100 deaths a year in Australia. It is the commonest epilepsy related cause of premature death in a young person. Causes of SUDEP are thought to be multifactorial and may be cardiac, respiratory, neurological or a combination of factors. What can be done to reduce SCD in the young? Primary Electrical Arrhythmias due to channelopathies, hypertrophic cardiomyopathy and a significant proportion of dilated cardiomyopathy are inherited. It is therefore essential, that once a diagnosis of any of these conditions is made in an individual, the whole family is examined to detect disease in other family members who may be asymptomatic. The same applies to families of sudden cardiac death victims and aborted cardiac arrest (ACA) victims who have normal coronary angiograms and echocardiograms, as the causes of ACA are similar to SADs. Baseline investigations like 12-lead ECGs, echocardiograms and exercise tests may provide an answer. Further discriminatory tests such as drug provocation with flecainide for Brugada syndrome, adrenaline for LQTs, Holter monitoring and signal averaged ECG for ARVC may be indicated [13]. The Cardiac Society of Australia and New Zealand Genetic Working Group has published guidelines for investigations of inherited heart diseases, which provide further details. Investigation is best performed in specialised multidisciplinary clinics, staffed by cardiologists, geneticists, genetic counsellors and specialist nurses, with access to a molecular laboratory able to perform genetic testing. In addition, cardiopulmonary resuscitation education in schools and availability of automatic external defibrillators in selected places where large number of people congregate, is also helpful.

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[3] Van der Werf C, Van Laugen IM, Wilde AA. Sudden death in the young. Circ Arrhythm Electrophysiol 2010;3:96–104. [4] Risgaard B, Winkel BG, Jabbari R, Behr ER, Inglemann-Hansen O, Thomsen JL, et al. Burden of sudden death in persons aged 1 to 49 years: nationwide study in Denmark. Circ Arrhyth Electrophysiol 2014;7: 205–11. [5] Doolan A, Langlois N, Semsarian C. Causes of sudden cardiac death in young Australians. Med J Aust 2004;180:110–2. [6] Puranik R, Chow CK, Duflou JA, Kilborn MJ, McGuire MA. Sudden death in the young. Heart Rhythm 2005;2:1277–82. [7] Winkel BG, Holst AG, Theilade J, Kristensen IB, Thomsen JL, Ottesen GL, et al. Nationwide study of sudden cardiac death in persons aged 1-35 years. Eur Heart J 2011;32:983–90. [8] Mazzanti A, Priori SG. Molecular autopsy for sudden unexplained death? Time to discuss pros and cons. J Cardiovasc Electrophysiol 2012;23:1099–102. [9] Tester DJ, Ackerman MJ. The molecular autopsy: should the evaluation continue after the funeral? Pediatr Cardiol 2012;33:461–70. [10] Eckart RE, Scoville SL, Campbell CL, Shry EA, Stajduhar KC, Potter RN, et al. Sudden death in young adults: a 25-year review of autopsies in military recruits. Ann Int Med 2004;141:829–34. [11] Modi S, Krahn AD. Sudden cardiac arrest without overt heart disease. Circulation 2011;123:2994–3008. [12] Skinner JR, Duflou JA, Semsarian C. Reducing sudden death in young people in Australia and New Zealand: the TRAGADY Initiative. Med J Aust 2008;189:539–40. [13] Vohra J, Skinner J, Semsarian C. Cardiac genetic investigations of young sudden unexplained death and resuscitated out of hospital cardiac arrest. Heart Lung Circ 2011;20:746–50. [14] Phillips KA, Ackerman MJ, Sakowski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases. Heart Rhythm 2005;2:1294–300. [15] Meyer L, Stubbs B, Fahrenbruch C, Maeda C, Harmon K, Eisenberg M, Drezner J. Incidence, causes, and survival trends from cardiovascularrelated sudden cardiac arrest in children and young adults 0 to 35 years of age: a 30-year review. Circulation 2012;126:1363–72. [16] Winkel BG, Risgaard B, Sadjadieh G, Bundgaard H, HaunsØ S, TfeltHansen J, et al. Sudden cardiac death in children (1-18 years) symptoms and causes of death in a nationwide setting. Eur Heart J 2014;35:868–75. [17] Maron BJ, Haas TS, Murphy CJ, Ahluwalia A, Rutten-Ramos S. Incidence and causes of sudden death in U.S. college athletes. J Am Coll Cardiol 2014;63:1636–43. [18] Corrado D, Schmied C, Basso C, Borjesson M, Schiavon M, Pelliccia A, et al. Risk of sports: do we need a pre-participation screening for competitive and leisure athletes? Eur Heart J 2011;32:934–44. [19] Basso C, Maron BJ, Corrado D, Thiene G. Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. J Am Coll Cardiol 2000;35:1493–501. [20] Maron BJ, Estes 3rd NA. Commotio Cordis. N Engl J Med 2010;362:917– 27. [21] Sharma S, Papdakis M. Improved survival rates from commotio cordis: a case for automatic external defibrillator provision during high-risk sports. Heart Rhythm 2013;10:224–5. [22] Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12:966–77.

Sudden cardiac death in the young: what we know, what we don't know and what we need to do.

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