Unexplained sudden cardiac death—often referred to as idiopathic ventricular fibrillation (IVF)—has been estimated to account for as much as 8–10% of all cases of cardiac arrest1 and has been a primary concern of arrhythmia specialists. IVF still remains a challenge in the current 'genetic' era. Krahn et al.2 have now investigated the causes of unexplained sudden cardiac death occurring in young individuals with structurally normal hearts and without known risk factors for cardiac arrest.
A key question faced by researchers in this field is whether genetic testing should be performed as the primary line of investigation if an autopsy in an individual who dies unexpectedly of cardiac arrest fails to identify the underlying cause. According to Ackerman et al.,3 up to 30% of sudden deaths occurring in young people remain unexplained after autopsy. Data from the Mayo Clinic,4 Rochester, MN, USA, initially raised the hope that genetic screening would identify mutations that might account for a large proportion of unexplained sudden cardiac deaths. This 'molecular autopsy' might, therefore, represent a breakthrough in terms of establishing a clinical diagnosis in these individuals, and might also be useful in familial screening to prevent such deaths in relatives.5 Although subsequent investigations6, 7 confirmed that up to 40% of unexplained deaths in young people are associated with inherited conditions, they also highlighted the pivotal role of clinical evaluations of family members in identifying a genetic basis for IVF. These findings are at variance with the initial optimism that genetic testing alone would provide sufficient diagnostic information on those who have experienced IVF.
Data from the population described by Krahn et al.2 confirm that approximately 50% of unexplained cardiac arrests in juvenile patients have an identifiable cause and that 40% of all patients resuscitated after IVF have an inherited arrhythmogenic disorder. The study also supports the view that clinical investigations are more effective than genetic screening in directing the clinician towards the correct diagnosis. Thus, clinical assessment identified a possible cause of cardiac arrest in 35 of the 63 individuals enrolled in the study, whereas genetic testing was performed in only 19 individuals. Several of the mutations identified were newly reported and, therefore, could not with sufficient certainty be considered causative of the arrhythmic events. Indeed, few of the genotyped patients carried mutations that might predispose to acquired arrhythmias, such as the single nucleotide polymorphisms KCNE1 G38S and KCNH2 K897T. This point highlights the fact that interpreting the results of genotyping remains a major challenge, particularly when clinical data are scanty and the functional consequence of mutations uncertain.
Consistent with previous studies that support clinical evaluation of family members of individuals who have died from IVF, the report by Krahn et al.2 shows that IVF survivors should undergo extensive clinical evaluation before genetic testing is attempted. In this setting, therefore, genetic testing would only be justified if, on the basis of clinical data, a diagnosis is either established or suspected in IVF survivors or their relatives. Rong et al. have shown that this approach is not only practical, but also cost-effective.8 The cost per positive genotyping result in IVF families is 5–10 times higher than the cost per positive genotyping result in families with a clinical diagnosis of an inherited arrhythmogenic syndrome.8 The logical conclusion, therefore, is that genotyping survivors of IVF, at current market costs, is not suitable as the first line of investigation (Figure 1).
Figure 1 | Yield of genetic testing (left y axis, red bar) and costs ($US) per positive genotyping result (right y axis, blue bar) in survivors of IVF-FSCD and their families.
![Figure 1 : Yield of genetic testing (left y axis, red bar) and costs (|[dollar]|US) per positive genotyping result (right y axis, blue bar) in survivors of IVF-FSCD and their families. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com](/nrcardio/journal/v6/n11/thumbs/nrcardio.2009.174-f1.jpg)
The actual number of positive and negative results of genetic testing is also reported in the bars. Overall, a conclusive genetic diagnosis is possible in only 9% of cases.7 Abbreviations: FSCD, familial sudden cardiac death; IVF, idiopathic ventricular fibrillation. Permission obtained from the American Heart Association © Rong, B. et al. Circ. Arrhythmia Electrophysiol. 2, 6–15 (2009).
In addition to supporting the value of clinical investigation in determining the basis of IVF, the study by Krahn et al.2 offers some interesting considerations about the selection of clinical tests that should be used. These researchers combined the use of standard investigations, such as signal-averaged electrocardiography exercise stress testing and MRI, with clinical tests that are still considered to be research tools. For example, the provocative test that uses epinephrine to trigger arrhythmias has not yet been validated as a diagnostic evaluation for long QT syndrome suitable for clinical use. The epinephrine test has been advocated as a useful tool for identifying mutations in individuals with a normal QT interval who are relatives of patients with long QT syndrome. However, the positive and negative predictive value of this test in the general population has not been defined. In the study by Krahn et al.,2 genotyping could not confirm the diagnosis of long QT syndrome made on the basis of epinephrine challenge. Furthermore, even a patient subsequently identified as carrying a mutation associated with right ventricular cardiomyopathy showed a prolonged QT interval after epinephrine infusion, which highlights the possibility that QT prolongation is a nonspecific response to this drug rather than a reliable marker that pinpoints a diagnosis of long QT syndrome. Overall, the data reported highlight that the accuracy of the epinephrine test should be properly evaluated before we can include it among the investigations mandated for relatives of individuals who die from sudden unexplained cardiac arrest. In addition, the study by Krahn et al.2 indicates that the use of epinephrine to trigger arrhythmias originating from the right ventricle (as a diagnostic indicator of right ventricular cardiomyopathy) is an even less robust diagnostic test for right ventricular disease than it is for long QT syndrome. In this study, exercise stress testing (to unmask the reduced repolarization reserve in patients with long QT syndrome, and thus facilitate the diagnosis of catecholamine-induced ventricular tachycardia), stands out as a much more robust provocative test than epinephrine challenge.
Another interesting finding from the study by Krahn et al.2 is the identification of 'early repolarization' in five patients. Unfortunately little information is available on the clinical profile and severity of repolarization abbreviation in these patients, and the researchers were unable to provide conclusive evidence of a causal link between this parameter and ventricular fibrillation. However, an important consideration is that shortened repolarization time is emerging as a heterogeneous group of conditions that might impair electrical stability. Systematic classification of early repolarization patterns is required to facilitate appropriate definition of arrhythmic risk.
Overall, Krahn et al.2 have refocused attention on the clinical evaluation of IVF survivors and of the family members of those who die from sudden cardiac arrest. Given the supporting evidence from other studies,6, 7, 8 this approach should become standard management for such individuals and should encourage clinicians to request genetic testing only after a thorough clinical investigation has identified a robust indication that the arrhythmic event was probably elicited by the presence of an inherited arrhythmogenic condition.
