Unexplained sudden cardiac death: an opportunity to identify hereditary cardiac arrhythmias

This editorial refers to ‘Nationwide study of sudden cardiac death in persons aged 1–35 years’†, by B.G. Winkel et al., on page 983 Death is inevitable, and what better way to die than suddenly. This statement is applicable to the elderly, but sudden death in a young person not only is a tragedy for the victim but also has a devastating effect on parents, spouses, and the victim's children. But why study the causes of sudden death, particularly sudden death, in the young since there is little that can be done to bring them back to life? The answer is that these untimely deaths can reveal clinical and genetic defects that trigger arrhythmias and this information may prevent inherited sudden cardiac death in family members. However, first, we need to examine the magnitude of the problem. In the meticulously performed study by Winkel et al.,1 all deaths in persons age 1–35 years in Denmark, from 2000 to 2006, were carefully evaluated. In retrospective studies of the causes of sudden cardiac death, a major concern is the lack of a medical history of the patients and absence of uniformity in the quality of the autopsy findings due to lack of cardiac expertise of the pathologist. However, in this study, the investigators had access to the National Patient Registry containing information on all in- and outpatient activity in Danish Hospitals and emergency rooms. Death certificates were evaluated independently by two physicians to identify the causes of sudden unexpected deaths. The cause of death was reportedly revised based on autopsy findings. There was an exceptionally high autopsy rate of 75%. Autopsies were performed at three centralized departments of forensic pathology. The investigators found that, in a population of 2.38 million people aged 1–35 years, the incidence of sudden cardiac death was 2.8 per 100 000 person years (total n = 625). There were 469 autopsy cases of sudden unexpected death of which 314 (or 67%) were attributed to sudden cardiac death. Most importantly 43% (n = 136) of all autopsies in individuals in which sudden unexpected death occurred were attributed to unexplained cardiac causes, consistent with smaller autopsy series (Figure 1).2–5 These findings confirm the preponderance of sudden unexplained cardiac deaths identified in younger age groups compared with rates of 4–5% in the overall population.6,7 Although there has been recent emphasis on preventing sudden cardiac deaths during athletic activities it is of note that only 10% of sudden deaths in the young occurred during moderate or intense physical activities. These findings are consistent with a recent analysis in the general population that reported that only 5% of sudden deaths were associated with significant physical exertion,8 and put into perspective the need to prevent all sudden cardiac deaths in the young and not only sports-related sudden death. It is controversial whether screening young athletes including a family history of sudden cardiac death, history of syncope, obtaining ECGs, and possible further imaging studies, such as echocardiograms, is cost-effective, particularly when most sudden cardiac deaths do not occur during athletic activities. Causes of sudden cardiac death in 314 autopsied cases (adapted from Winkel et al., Fig. 3).1 The miscellaneous category includes valvular heart disease (n = 8), dilated cardiomyopathy (n = 4), hypertrophic cardiomyopathy (n = 2), and other congenital heart diseases (n = 31). The question arises of whether these sudden unexplained cardiac deaths may be caused by hereditary cardiac arrhythmias. If so, then clinical evaluation and genetic testing of family members may be able to prevent sudden cardiac death in family members by identification of the disease followed by appropriate risk stratification and treatment. In 2003, Behr et al.9 performed a detailed cardiovascular evaluation of relatives of 32 cases of sudden unexplained death and documented that 22% of these families had evidence of inherited cardiac disease, primarily features suggestive of the long QT syndrome. In 2005, Tan et al.10 found that 28% of families had an identifiable cardiac channelopathy following a clinical assessment of first-degree relatives of young sudden unexplained death victims. Thus, identifiable and potentially treatable cardiac channelopathies account for nearly one-third of all sudden unexplained deaths in young people. These include the long QT syndrome, catecholaminergic ventricular tachycardia, Brugada syndrome, and the early stages of arrhythmogenic right and left ventricular cardiomyopathy. Using focused genetic testing to determine inherited arrhythmogenic cause of death, Tester and Ackerman11 found that over one-third of the 29 cases of sudden unexplained deaths in the young harboured a putative cardiac channel mutation primarily associated with the long QT syndrome. A confirmatory approach to detect the aetiology of unexplained cardiac arrest was provided by Krahn et al.12 who evaluated 63 patients resuscitated from cardiac arrest who had no evident cardiac disease. The patients were evaluated clinically in nine centres. They found a diagnosis in 35 patients (56%) consisting of the long QT syndrome in eight, catecholaminergic polymorphic ventricular tachycardia in eight, arrhythmogenic right ventricular cardiomyopathy in six, early repolarization in five, coronary spasm in four, Brugada syndrome in three, and myocarditis in one. It is thus well established that there is a substantial diagnostic yield of the cause of sudden unexplained cardiac death in the victims and/or relatives by both clinical and genetic evaluation. Ideally, investigation of sudden unexplained cardiac death in the young requires evaluation of the victim and family members. Evaluation of families requires a multidisciplinary approach by cardiologists, clinical geneticists, genetic counsellors, and forensic pathologists.13 It should be emphasized that the absence of a genetic abnormality in the victim should not be interpreted to indicate that the victim did not have a genetically determined cause of death. Negative genetic findings do not exclude the above diseases because only a minority of patients with hereditary arrhythmogenic cardiomyopathies have an identifiable gene. With the recent completion of the first two genome-wide association studies of sudden cardiac death, the list of candidate genes for fatal arrhythmogenesis is likely to expand rapidly.14,15 Nonetheless, clinical evaluation for the hereditary diseases should be done in first-degree family members regardless of the presence or absence of a genetic abnormality in the victim to determine whether they are at risk of sudden cardiac death, particularly since the genotype–phenotype relationship can be quite variable. Recent and ongoing technological advances in genetic sequencing will increasingly facilitate the ability to screen for more genes, decreasing both the time and cost of genetic screening. In summary, this important, carefully performed study1 of unexplained cardiac death in the young, although an uncommon event, can lead to identification of others who may be at risk, and steps can be taken to reduce that risk. Among the unfortunate probands who succumb to sudden unexplained death, a molecular autopsy needs to become an inherent part of the post-mortem examination. This will enhance the ability to screen family members of victims of unexpected sudden death who do have an identifiable genetic cause. These ongoing advances in the ability to identify the causes of sudden unexplained death in the young suggest the need to establish regional cardiac pathology centres where the hearts of victims of sudden cardiac death can be sent for expert pathological evaluation as well as for genetic testing. It is important that such centres should also include the provision of genetic counselling for surviving family members. Conflict of interest: none declared.