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- John Triedman, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. John Triedman, 300 Longwood Avenue, Boston, Massachusetts 02115
In this issue of the Journal, Spazzolini et al. (1) report a study from several primary research centers in arrhythmogenic channelopathies of severe clinical manifestations of long QT syndrome in the infant. Before discussing their important and possibly controversial findings, it is worth commending the authors—several of whom are established experts in their own right in the field of cardiac channelopathy research—for a truly collaborative, international effort. They have succeeded in characterizing an exceedingly rare bird: the infant suffering from lethal, congenital arrhythmia.
This study draws on over 3,000 patients recorded in the International Long QT Registry, singling out those few who are symptomatic in the first year of their life. The mortality rate in this group is known to be high from anecdotes and small series, with sinus bradycardia and conduction defects often complicating the clinical presentation (2). The data presented here strongly confirm that clinical assessment, with most infant long QT patients presenting with death or aborted cardiac arrest and a high likelihood of recurrent arrest among the survivors. There are related questions that this article raises but does not completely answer. First, why is the lethality of long QT syndrome so much higher in infants than in older patients? And second, what are the implications for clinical management of these patients?
The impressive lethality of infantile long QT syndrome is likely due to a variety of pathophysiological and clinical factors. Of all long QT patients, only infants express the full range of mutations compatible with survival to delivery, because those most severely affected die young and never contribute to the mortality recorded in older groups. Although controversy has existed regarding the importance of channelopathic mutations in the pathogenesis of sudden infant death syndrome (SIDS), recent research suggests that approximately 10% of infants who die in this manner have a mutation that could be responsible for arrhythmic death (3). The distribution of long QT genotypes in infancy is not well-characterized, but reports on the genotype distribution among SIDS victims suggests that it might differ substantially from that observed in older populations, perhaps with a higher frequency of uncommon lethal genotypes or more lethal expression of common mutations (4,5). Continued accumulation of clinically well-characterized genotype databases will ultimately answer this question. It will be of particular interest to determine whether highly lethal mutations seen in young patients maintain their high-risk phenotype among patients surviving to older ages.
Further complicating management of the infant with long QT syndrome and plausibly contributing to its lethality is the developmental immaturity of the infant brainstem. Sympathovagal cardiovascular control evolves rapidly and asymmetrically during gestation and infancy (6). Cardiac autonomic input in infants might be further affected by immaturity of respiratory regulation and sleep state, which are tightly coupled to autonomic efferent activity. Autonomic traffic to the heart is a significant pathogenetic factor in long QT expression in older patients, and there is evidence from the SIDS published reports to suggest that it might have a similarly important role in infants, perhaps in the form of autonomic instability (7). It is fair to assume, in any event, that infants are very different from the adult patient with respect to their cardiac autonomic environment. As a result, one could speculate that infants might be more prone to fail in response to challenges to their repolarization reserve, given a certain genotype, or that they might respond less favorably to beta-blockade, a therapy whose value in infants is imputed from older patients and which was not noted to be protective in this limited study.
In addition to these important potential physiological differences, infants live in a somewhat isolated world with respect to presenting symptoms. In general, infants present “sicker” than adults, with major or even catastrophic events. They have had less time to be diagnosed and possess only a limited vocabulary to communicate “symptoms” such as syncope, which is notoriously vaguely defined in infancy. Additionally, life-threatening disease is generally rare in infancy, and so the clinical suspicion for diseases such as long QT syndrome is low. Thus, there will be fewer patients identified at this age with “mildly” symptomatic and asymptomatic disease. This is especially important for this specific study group—the International Long QT Registry—which represents an integration of clinical experience dating back to a time (not long ago) when patients were more frequently identified by symptomatic presentation (8). The evolution of QT case-finding to include phenotypic and genotypic analysis of asymptomatic individuals in affected kindreds and the recent increase in electrocardiographic (ECG) screening among groups conceived to be “at risk” due to channelopathy (e.g., those receiving potentially arrhythmogenic drugs for other indications) has diluted somewhat the phenotypic severity of the disease. As ECG screening is performed on a wider population base—including perhaps healthy, asymptomatic infants—this trend will continue, and the population known as “long QT patients” will increasingly represent the full spectrum of genotypic variation in the disease.
Even taking these potential epidemiological confounders into consideration, the severity of long QT syndrome in infancy seems striking. The data presented in this study has important and worrisome implications for therapy. First, the authors bring into question the value of standard and most widely accepted prophylactic therapy in older patients, finding that administration of beta-blockade was not clearly associated with survival benefit in the sickest patients. Although evidence for beta-blocker efficacy in this study is not encouraging, many will continue to use these agents in infants as we do for most first presentations of long QT syndrome, because they are generally well-tolerated, the negative evidence against their use in this study is not statistically strong, and as individual patients grow, eventually they will inhabit a population segment for which beta-blockers have been shown to be useful.
Lacking compelling evidence for beta-blockers in these patients, the authors suggest consideration of cardiac sympathetic denervation, also of proven value in older populations. Most clinicians are inclined to avoid destructive surgical intervention for patients of this age when possible. Given the relative autonomic immaturity of these patients and the very limited experience to date with sympathectomy in infants and toddlers, it would seem prudent to exercise caution in recommending it as a preferred therapy and note that the differences in pathophysiology affecting response of these patients to beta-blockade might not only be to some extent maturational but could also limit the utility of denervative therapy by similar mechanisms. Unfortunately, we lack proven device therapy for mitigation of sudden death risk in this age group—although ad hoc efforts have been made in difficult cases, implantable cardioverter-defibrillators truly suitable for use in high-risk small children have yet to be introduced. Because few patients need such therapy, access to such highly specialized technology will be determined only by affirmative health policy decisions promoting the availability of orphan devices.
Other important health policy issues are raised by the occurrence of lethal long QT syndrome in our young populations. It is legitimate to ask whether all infants should be electrocardiographically screened early in life to identify this malignant syndrome. This is a matter of urgent debate, because significant resource allocation issues are implied by such a decision. Such programs will undoubtedly identify patients with long QT syndrome, but many of these will be phenotypically borderline, asymptomatic patients—some with a mutation, others without—who are likely to have good outcomes regardless of early identification. Additionally, at least according to the data presented here, standard prophylactic medical therapies might be less efficacious in this population as compared with older groups. Both of these issues will decrease the cost-effectiveness of population-based ECG screening. Thus, it is important to consider this question in terms of public health policy, as well as in the context of individual patient care (9).
Dr. Triedman has received an honorarium from Boston Scientific.
↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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