© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
What we can learn from individual resuscitated patients
aAcademic Medical Center, Experimental and Molecular Cardiology Group, Amsterdam University, Amsterdam, The Netherlands
bInteruniversity Cardiology Institute The Netherlands (ICIN), Amsterdam, The Netherlands
* Corresponding author. Tel.: +31-20-566-3265; fax: +31-20-697-5458 a.a.wilde{at}amc.uva.nl
Received 31 January 2000; accepted 3 February 2000
See article by Deschênes et al. [3] (pages 55–65) in this issue.
Successfully resuscitated patients without structural cardiac abnormalities (despite extensive investigations) are diagnosed as suffering from "primary electrical disease". Within this group of patients the Long QT syndrome (LQTS) and Brugada syndrome are electrocardiographically discernible, although the abnormalities may be difficult to appreciate. Both syndromes share an autosomal dominant transmission based on mutations in ion channel genes and a high incidence of sudden cardiac death [1]. The number of disease-related mutations in various genes is growing rapidly, challenging the scientific community to get insight into channel (dys-)function and its relation to these diseases. In HERG for example, different mutations, ultimately leading to functionally less repolarizing currents, appear to affect channel function in different ways [2]. Such data are important because they relate to human disease and may shed light on the pathophysiology of the relevant arrhythmia syndromes. In addition, this information will also undoubtedly advance the study of the pathophysiological basis of lethal arrhythmias in more common acquired heart disease.
The manuscript of Deschênes et al. in this issue [3] describes human ion channel gene mutations, identified in individual patients with LQTS or Brugada syndrome, and their impact on channel function. Before going into the details of the study one should address the question whether the mutations identified are indeed disease-related. For a correct genetic diagnosis linkage data are pivotal. A LOD-score >3, leaving a change of <1 out of 1000 that a false-positive result is obtained, is generally accepted as sufficient evidence that a particular gene or chromosomal region links to a particular disease. Such data are available for all genes identified in LQTS patients, including SCN5A, the gene encoding the fast cardiac sodium channel, which underlies LQTS3 [4]. SCN5A has also been implied in Brugada syndrome [5], but significant linkage lack data. An exception forms a recently described large family with features of both LQTS3 and Brugada syndrome, indeed tightly linked to SCN5A [6]. By definition, linkage data lack in individual patients and only circumstantial evidence can be obtained that the mutation identified is causally related to the disease. An aminoacid substitution in a well conserved region of the gene and its absence in 100 control alleles (i.e. 50 individuals) are accepted criteria for causal involvement. Both mutations described by Dechênes identified in patients with clinical characteristics compatible with Brugada syndrome (R1432G and R1512W) meet these criteria [3]. For the third mutant, identified in a patient with LQTS, no data on control alleles are reported. Further evidence linking the identified genetic aberrations to the diseases comes from the literature. The E1784K and the R1512W have been identified before in (probably) unrelated patients elsewhere in the world [7,8]. Clearly, this significantly strengthens the case of causality for these two mutants. A final argument may be that the mutant significantly alters channel function, preferably in such a way that the phenotype is explained. This is the subject of the study by Deschênes et al. in this issue [3].
Characteristics of the LQTS3 mutant are largely comparable to those published before [8]. Similarly and most importantly, a small persistent inward current was present during long depolarizations, resulting from a defect in fast inactivation. Besides, a negative shift of the voltage dependence of inactivation was observed, as well as a faster recovery from inactivation for the E1784K mutant channel [3]. Coexpression with the β subunit, on the other hand, aggravated the negative shift of the inactivation curve in the study of Wei et al. [8], whereas it did not affect the kinetics of the E1784K mutant channel in this study of Deschênes et al. [3] So far, the role of the β subunit on cardiac Na+ channel function is far from clear. A broad range of results have been reported, diverging from opposite effects to no effect at all.
The alterations in channel kinetics due to the mutation will affect the contribution of the Na+ current to the cardiac action potential. The defect in fast inactivation may give rise to a small persistent inward current during the plateau of the action potential, thereby delaying repolarization. The negative shift in voltage dependence is likely to reduce Na+ channel availability, whereas the faster recovery from inactivation may increase Na+ channel availability. A change in Na+ channel availability would affect the upstroke and early repolarization of the action potential. The fact that the LQTS3 patient did not suffer from conduction delays, may suggest that Na+ channel availability is not significantly disturbed.
The characteristics of the R1512W mutant, associated with the Brugada syndrome, compare to those previously reported [7] in that they show a reduction in the rate of recovery from inactivation. The functional consequence would be a reduced Na+ channel availability at the shorter diastolic intervals. The negative shift in both the voltage dependence of activation and inactivation, as shown in the study of Rook et al. [7], was not observed by Deschênes et al. [3]. The use of different expression systems, oocytes versus mammalian cell line, may underlie this discrepancy. The R1432G mutant completely failed to express current in the mammalian cell line [3], similarly to one of the mutants described by Chen et al. [5], in contrast to the missense mutation R1432G resulting in a truncated protein. The impaired channel expression, as well as the reduction in rate of recovery from inactivation, have in common that they will result in a reduction of Na+ channel function. Although the underlying mechanisms may differ, they share this property with two other reported Brugada mutations, T1620M and 1795insD [6,9].
It is generally assumed that LQTS3 mutants express a gain of sodium channel function, whereas SCN5A mutations related to Brugada syndrome result in loss of function. The present findings seem to confirm this notion. The E1784K mutant, identified in a patient with LQTS, displays a persistent inward current (‘gain of function’), which easily explains prolongation of the action potential. The R1432G mutant, identified in a patient with Brugada syndrome, does not express current in the ts201 cell line (‘loss of function’). It is not clear whether the channel is expressed at all or whether the channel protein itself is not functioning.
Electrocardiographically, the initial description of Brugada syndrome focussed on the right precordial ST-segment elevation. A review of the literature revealed that the majority of patients also had (discrete) conduction abnormalities [10]. It is of interest that SCN5A mutations also underlie progressive cardiac conduction disease, i.e. (progressive) conduction disease without repolarization abnormalities [11]. Both patients described by Deschênes et al. [3] had prolonged PR-intervals, and in the one patient in whom HV-interval had been measured, it was at the upper limit of normal. QRS-width is not reported, but, judged from the ECG, appears to be slightly prolonged as well. In the Dutch R1512W patient, QRS width was equally prolonged (120 ms), but PR-interval was normal [7]. The origin of late potentials, reflecting local conduction delay as seen in the R1512W patient [3] and many other patients [10], is not clear. Similar to LQTS, Brugada syndrome is a heterogeneous disease. Although genotype-phenotype studies in Brugada syndrome are as yet not available, one may speculate that conduction delay refers to SCN5A involvement.
There is little doubt that the identification of disease-related mutations in ion channel genes has greatly advanced our knowledge of ion channel structure-function relationship. Studies like this one [3] and others [5–9] have significantly increased insight into the pathophysiological basis of relevant arrhythmia syndromes. For these rare patients more specific therapy may ensue. More importantly however, understanding of ion channel function in physiological and pathophysiological conditions is undoubtedly of benefit to a great number of patients with more common cardiac disorders suffering from life-threatening arrhythmias.
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Acknowledgements |
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The Dutch Heart Foundation (NHS 95-014) is acknowledged.
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References |
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