Syncope accounts for 3–5% Emergency Department visits and for 1–6% of urgent hospital admissions each year. 1 In the USA, between 1 and 2 million patients are evaluated annually for syncope. Despite the updated clinical guidelines and the development of diagnostic algorithms over recent years, the cost associated with hospitalization and clinical management of syncope is still overwhelming. One of the problems is that syncope is not a disease per se , but a symptom related to an extensive range of differential diagnoses, which could span from cardiac to neurological to psychiatric conditions. Furthermore, up to 47% of patients presenting with syncope may be discharged without the diagnosis 1 and, even if their outcome is generally benign, the 1-year mortality rate in syncope of cardiac origin could reach 18–33%. 2
Overall, these data point towards the importance of identifying which are the most useful clinical tools that physicians could use in their practice to correctly differentiate between syncopal events with benign vs. those with serious outcome.
When analysis of the substrate of transitory loss of consciousness is narrowed to a population of children or young adults, the importance in selecting which episodes are associated with a malignant prognosis becomes even more evident. As a matter of fact, most of these episodes may be situational or vasovagal syncope, therefore benign events. However, syncope is the main symptom also in inherited channelopathies, such as long QT syndrome (LQTS), Brugada syndrome, or catecholaminergic polymorphic ventricular tachycardia, disorders that, if left unrecognized and untreated, may lead to sudden cardiac death.
Colman et al.3 present an interesting analysis focused on the identification of signs that could direct physicians in suspecting LQTS when collecting the clinical history for an episode of loss of consciousness.
Among inherited channelopathies, LQTS is the one so far with the highest estimated prevalence, ranging from 1:2000 to 1:5000. It is caused by mutations in different genes encoding for cardiac ionic channels whose ultimate common effect is a prolongation of the repolarization phase of the action potential, manifesting on the surface electrocardiogram (ECG) as a prolonged QT interval. Recently, the creation of International Registries has allowed developing genotype–phenotype correlation and genotype-based risk stratification studies at least for the three most common genetic variants of the syndrome. These studies have highlighted that arrhythmic events tend to occur during exercise in LQT1 patient, during emotional stress or in the presence of abrupt loud noises in LQT2 and at rest or during sleep in LQT3. 4
In their study, Colman et al.3 compared a group of genotyped LQTS patients symptomatic for syncope with two different groups of ‘controls’: patients admitted for syncope in the Emergency Department and a group of subjects younger than 40 years old, with a history of vasovagal syncope. An important observation emphasized by the study is the limited use of ECG in the common practice while evaluating syncope, particularly in young individuals. In the control groups, almost half the patients did not have an ECG, even if it was part of the enrolment protocol, and they were significantly younger than patients who did. In the presence of the clinical history strongly suggestive of a vasovagal episode, the general tendency was to base the diagnosis on the clinical history without recording an ECG.
However, most of fainting episodes associated with LQTS are caused by the occurrence of torsade de pointes; hence, at variance with other arrhythmia-related syncope, complete loss of consciousness could often be preceded by prodromic symptoms like dizziness or lightheadedness, similarly to what happens during vasovagal episodes.
This is the main reason that prompted the authors to investigate which elements in the clinical history of a patient should press physicians to perform a cardiological evaluation. Their results corroborated and confirmed the previous knowledge that emotion and exercise are two main triggers of events in LQTS 4 and that syncope while in supine position or palpitations are more frequent than in other conditions. The analysis also underlined how family history could suggest a suspect LQTS.
The authors selected a small group of symptomatic LQTS patients with a known genotype. One can argue that this sample is not representative of the general population presenting at the Emergency Room for evaluation of a first syncopal episode; nor is it taking into account the group of LQTS patient without a known mutation, in whom genetic screening is not helpful in confirming the diagnosis. However, the selection of a group with classical characteristics of LQTS has the value of allowing a clearer definition of those symptoms that should be considered suspicious when evaluating the loss of consciousness.
The significance of a careful and detailed collection of medical history to direct clinical care towards the appropriate tests and exams is another important point presented in this work.
Additionally, the paper calls the attention to the limited use of the ECG in the assessment of loss of consciousness. Electrocardiogram is a relatively inexpensive test; however, most young people do not receive one even when admitted for a fainting episode. In ‘high-risk’ LQTS adolescents, 1-year life event-rate of life-threatening events could reach up to 1%; 5 patients 40–60 years old with recent syncope have two-fold increased relative risk of fatalities compared with non-affected subjects. 6 Beta-blocker therapy could significantly reduce the risk of sudden death in most individuals. 7
The QT interval duration >500 ms have been demonstrated to be associated with a higher arrhythmic risk, and LQTS patients 8 often have peculiar alterations in morphology of the T-wave: all these findings could be diagnosed simply by performing a surface ECG. However, the diagnosis of LQTS is not always straightforward, and in the majority of cases, only groups with long experience and high series of patients may be able to appropriately recognize or exclude diagnosis. Taggart et al.9 demonstrated that diagnostic discordance was present in at least one-third of cases seeking a second opinion at their centre and that it was mainly attributable to miscalculation of QTc interval values and misinterpretation of normal QTc distribution.
Recently, the availability of genetic testing through commercial companies has increased the generalized use of genetic screening as a tool to rule out inconclusive clinical diagnosis. However, cost-effectiveness analyses have shown that the cost per one positive genotyping is significantly higher in cases without a clear clinical diagnosis, whereas the yield of the test could reach up to 56% in definitive LQTS cases. 10 As Colman et al.3 suggest, in the presence of suspected LQTS-related syncope, it should be advisable to refer the patients to centres specialized in inherited arrhythmias. Borderline and inconclusive diagnosis could be improved by additional clinical testing and expert evaluation. Ultimately, better cost-effectiveness of genetic testing could favour the development of reimbursement policies, therefore rendering it accessible to a large population of patients. In the case of LQTS, where the identification of specific mutations could direct treatment strategies and implement gene-specific therapies, higher accessibility to genetic screening could translate into better clinical care of families.
Conflict of interest: none declared.