Sudden death in the young is a relatively common problem which is recently receiving increasing recognition [Chugh 2004; Albert 2000]. In the U.S., estimates vary but probably ~300,000 deaths a year occur as a result of sudden cardiac death, the vast majority of which can be attributed to coronary heart disease in older individuals. The frequency of sudden death as a fraction of all cases has remained similar at ~50% over the last 3 decades, implying that the reduction in younger-age CHD deaths has not influenced the relative rate of sudden death as a mode of presentation.
The overall number of cases of sudden death is unknown in those at younger ages (e.g. < 40 years), since there is no unifying diagnoses that allows the incidence to be tracked. Worldwide, such unexplained deaths are often certified by general practitioners as myocardial infarction, epilepsy or by the mechanism of death which might have been drowning, road traffic accident or other apparently accidental cause of death. Cases fortunate enough to receive forensic autopsy are categorised as death by ‘natural causes’, or possible lethal cardiac arrhythmia if a post mortem diagnosis cannot be elucidated. Additionally, these individuals tend to fall into 3 age groups (0-1, 1-16 and 16-40 years), with overlapping major causes of sudden death some of which may be identified autopsy. Three recent studies in the latter group [Eckart 2005; Chugh 2004] have shown 35-59% frequency of structural causes, including coronary heart disease (CHD) with dilated- and hypertrophic, cardiomyopathy, and the major non-CHD structural causes which are not always readily apparent at autopsy.
Recent data from the USA suggests an incidence of sudden death in children higher than leukaemia, leading to a bill currently before the senate to raise funds to tackle this issue (the “Teague Ryan” bill). In New South Wales, recent post mortem studies suggest an annual estimated incidence of approximately 20 per million in children and young adults (Doolan 2004) (all references highlighted like this in blue link to the original article- just double click on it). In the UK, in response to a campaign led by surviving relatives of young sudden death victims (500 ‘unsolved’ cases per annum in UK) and sudden cardiac death charities, there was parliamentary legislation (Dari’s bill) to add sudden death syndromes to the Cardiac National Service Frameworks with appropriate funding. The incidence in New Zealand is also not known, but if the data from the USA, UK and NSW is similar in New Zealand, then we may expect about 80 such deaths per year between 0 and 39 years of age.
Cardiac inherited disease associated with sudden cardiac death
Forensic autopsy may reveal structural causes, which often have a hereditary basis, such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and Marfan’s syndrome. Alternatively, no structural cause may be identified at conventional forensic autopsy as is the case with cardiac channelopathy disorders such as Long QT syndrome (LQTS) or Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), or Brugada syndrome. HCM and DCM are major causes of familial genotype-positive sudden deaths, with >60% and 25% respectively having a heritable/genetic cause identified when appropriate investigations are undertaken. HCM is the most frequently identified cardiac inherited disease with a frequency of ~1/500 in the general population [Maron 2002]. However, at forensic post-mortem neither HCM nor DCM is invariably identified. The myofibril disarray which is the characteristic histological feature of HCM only occurs in 80-90% of cases, but this feature also can occur infrequently in non-hereditary disorders. In addition, other ‘structural’ causes of sudden death such as familial DCM and Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) may be missed at autopsy because a fatal arrhythmic event may have occurred at a relatively early stage in the evolution of these disorders; when the left ventricular dilatation and fatty infiltration, respectively, were subtle and not appreciated. Alternately, deaths from the long QT syndrome (LQTS) in individuals aged in their 20s and 30s may not be appreciated or considered when some autopsy evidence of coronary artery disease is found, a finding which is almost ubiquitous in this age group [Nissen 2005]. Finally victims with myocardial infarction may have survived their event had it not been for a familial arrhythmic syndrome. Thus in this study, though patients will be initially classified according the presence or absence of post-mortem findings of structural heart disease (with the exclusion of congenital abnormalities), genetic causes will be considered and investigated in both groups.
Careful clinical evaluation of relatives of sudden death victims (<40 years of age) has revealed 22-40% have familial arrhythmic syndromes [Behr 2003; Tan 2005]. In the latter study sudden death victims aged < 40 years were revealed as having primary electrical diseases more commonly (12/43, 28%) than heart muscle disorders (cardiomyopathies; 4/43, 9%), though, since this report emanated from a tertiary/quaternary referral centre there may have been referral biases, as the authors acknowledged. When these cellular receptor channels for potassium, sodium or calcium are dysnfunctional, they can lead to a vulnerability to develop either ventricular tachycardia or ventricular fibrillation [Ackerman 2004]. The commonest channelopathy in the study of Tan et al was cathecholaminergic polymorphic ventricular tachycardia (CPVT, 5 subjects) followed by LQTS (4 subjects), Brugada syndrome (2 subjects), and a LQTS/Brugada hybrid (1 subject). For each sudden death victim, an average of 9 presymptomatic gene carriers, also at risk of suddden death, were identified in each family. The NSW studies indicate that approximately a third of sudden unexpected death in children and young adults has a negative post-mortem, signalling a likely arrhythmic cause of death [Doolan 2004].
In the cases of sudden death in infancy (less than one year of age), molecular studies reveal that between 4 and 11% are associated with pathological mutations with genes linked to LQTS [Ackerman 2001, Arnestad 2005, and Skinner 2005]. We have recently identified that Brugada syndrome can also cause sudden infant death [Skinner 2005]. CPVT has also implicated rarely in SIDS, and a single molecular autopsy studies have suggested this may be an important cause of sudden death in children and young adults.
Further research is needed to discover the true incidence of both young sudden death, and the role of inherited heart diseases as a cause. For now though it is abundantly clear that when a sudden unexpected death occurs in a fit young person, such diseases need to be considered. An autopsy, with preservation of material suitable for genetic study, and family investigation are imperative if further such deaths are to be prevented through identification and treatment of inherited heart disease in the deceaseds family.
Has your family experienced a young sudden death?
If you would like to meet someone from CIDG please contact the coordinator of this group, Jackie Crawford (jackiec@adhb.govt.nz) and she will find you a professional from CIDG nearest to you or members of your family to help. CIDG works with pathologists across NZ when no cause is found at autopsy, by organising genetic testing and family heart screening. Referrals from GPs, other physicians and family members are welcome. Help and advice with regards to grief management and counselling is available from a number of sources- skylight is a very good start. Other families who have had similar experiences can be contacted via ASK Y (see family support groups).
Want to read more?
The National Heart Lung and Blood Institute in the USA has a useful website- click here.