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• W2019924979 abstract "EDITORIAL FOCUSThe complexity of genotype-phenotype relations associated with loss-of-function sodium channel mutations and the role of in silico studiesArthur A. M. Wilde, and Ruben CoronelArthur A. M. Wilde, and Ruben CoronelPublished Online:01 Jul 2008https://doi.org/10.1152/ajpheart.00494.2008This is the final version - click for previous versionMoreSectionsPDF (40 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat mutations in genes encoding the α-subunit of sodium channels are causal to a variety of diseases in several organ systems (12), including several primary arrhythmia syndromes, which are associated with mutations in SCN5a, the cardiac sodium channel gene (16). Whereas the association between, and the pathophysiological basis of, gain-of-fuction SCN5a mutations and the long QT syndrome is rather straightforward (6), the association and pathophysiological mechanisms of loss-of-function mutations are more complicated and less well understood. The associated diseases and syndromes include Brugada syndrome, familiar (progressive) conduction disease, atrial standstill, sick sinus syndrome, and various combinations thereof (12). Whereas, for some mutations, the pathophysiological mechanism is known (4, 6), including some referred to as “overlap syndromes” (7, 10, 17), it is not well understood why loss-of-function mutations in some patients lead to conduction disease, whereas in other patients it (also) leads to right precordial ST-elevation or atrial rhythm abnormalities. Other factors, among which are sex (13) and genetic factors, presumably play a role (11, 15).In this issue of the American Journal of Physiology: Heart and Circulatory Physiology, the Maastricht group, under the guidance of Paul Volders, deals with the electrophysiological characterization of a mutation in the cardiac sodium channel (Phe2004Leu or F2004L) in a relatively small Dutch kindred with Brugada syndrome/conduction disease (5). The study comprises two sections. The first part is the description of the clinical phenotype and the cellular biophysical characterization of the mutant sodium channel, expressed in a Chinese hamster ovary (CHO) cell expression system. The second part is a computer modeling study, where changes relevant for the mutant channel have been incorporated into a strand based on Luo-Rudy elements. A mechanism is proposed for the genesis of the ST-T-wave changes observed in the index patient.The authors of this paper are to be lauded for their attempt to bridge the gap between clinical observations, genetic identification of the mutation, biophysical characteristics of the mutant channel, and the electrophysiological mechanism of ST-segment changes in Brugada syndrome. Genotype-phenotype relations are very difficult to study in patients, especially when the mutation is related to a phenotype involving sudden cardiac death (14). Cardiac myocytes are not readily donated by the living and cannot be obtained from the dead individual. We, therefore, have to rely on extrapolation of data obtained from expression systems with the help of intricate computer simulations, except for the rare occasion when a patient undergoes cardiac transplantation (9). The extrapolation procedure of which we see an example in the paper by Bebarova et al. (5) relies, by necessity, on a cascade of assumptions. Although many of these assumptions are appropriately discussed by the authors, critical comments can be made on almost every level of the extrapolation cascade. Some of the assumptions and their related criticism are as follows.1) The signs of the patient are typical of the syndrome. The phenotype of the patient is not that easy to interpret. Although conduction disease is apparent, also and explicitly in the F2004L patient of Dr. Schulze-Bahr (see discussion section of Ref. 5), the authors emphasize the right precordial ST-elevation, suggesting Brugada syndrome. Their basic electrophysiological data are, in fact, used in an in silico model to explain the right precordial ST-elevation (see further). The question is whether the F2004L mutation is indeed a Brugada syndrome mutation. In the small family, the penetrance of ST-elevation is very low (0% at baseline, only 2 persons have been tested with class I drugs, one of them being positive), and there is also ST-elevation in the left lateral leads (patient III-3). The tachycardia in patient II-8 is a relatively slow monomorphic right bundle-branch block ventricular tachycardia, with a very long coupling interval (not shown in the paper). All of these features do not exclude Brugada syndrome, but are not very typical either.2) The mutation is causal to the disease. Whereas the authors are the first to associate the mutation with Brugada syndrome, F2004L has also been identified in sudden infant death syndrome (3, 18) and in adult sudden cardiac death victims (2). As these clinical disease entities have been associated with Brugada syndrome, these data are compatible with an association between F2004L and Brugada syndrome. However, the mutation is also described in control patients: 2 of 295 Caucasian and 1 of 103 Hispanic (1). The study itself does not provide strong evidence for causality either. Obviously, the family is too small for linkage analysis, and penetrance is very low. Furthermore, it is unclear how many control alleles were tested for the mutation. Based on these data, it is difficult to decide whether this variant is a rare single nucleotide polymorphism or a disease-associated variant.3) The expression system reflects the changes in the cardiac myocyte, and a heterozygous mutation is faithfully represented by expression of only the mutant gene in CHO cells. Wang et al. (18) have observed that the F2004L exhibits increased persistent sodium current typical of long QT syndrome-associated mutations (6). In the Maastricht study, a loss of function is described with technically sound pathophysical data, showing decreased peak and persistent Na+ current based on increased closed-state inactivation, accelerated slow inactivation, and delayed recovery from inactivation (5). The authors indicate that different cellular models (CHO cells vs. tsA201 cells) might explain the differences, but, at the same time, these differences should also shed some doubt on the value of these heterologous cell systems in explaining the pathophysiological mechanisms of these diseases. Clearly, more sophisticated cell systems (like human stem cell-derived cell lines) are needed to resolve these issues.4) The computer model represents the heart. The Markov model is characterized by a multitude of states that do not necessarily correspond to physical states of the ion channel. This makes the model less transparent and more difficult to understand in terms of cellular electrophysiology. In general, simpler models allow conveyance of understanding easier than more complex models (8). Another aspect is that the Luo-Rudy model consists of longitudinally coupled myocytes, a condition that does not exist in reality. Has oversimplification been coupled to overcomplication in this case?One could say that the model tests a hypothesis that may be of general applicability for Brugada syndrome and should work for every loss-of-function sodium channel mutation. This has, however, not been tested. In addition, the most relevant patient in this family also shows left lateral ST-elevation, and this seems not to be accounted for by the model data.5) The simulated rate-dependent ECG changes are clinically reproducible. The rate dependence of the ST-elevation, which indeed is typical for most Brugada syndrome patients, but not for all (17), has not been tested clinically. A simple exercise test would have done the job and would have further validated the modeling exercise.Finally, the nomenclature introduced by the authors (phase 0 block) is as confusing as the term phase 2 reentry (which is not a form of reentry but a mechanism for impulse initiation) and is nothing more than classical conduction block, consistent with one of the existing hypotheses on Brugada syndrome. We prefer the traditional terminology in this case, but agree that “delayed phase 2 propagation” or “phase 2 block” may add to insight and possibly to clinical implications, as suggested by the authors. It is to be noted that the right precordial high ST-segment take-off is virtually always associated with a terminal negative T wave, which, as stated by the authors (5) and suggested previously (14), is potentially explained by significant conduction delay.The present study (once again) launches an interesting concept for the mechanism of the right precordial ST-elevation in Brugada syndrome. Whatever criticism can be generated on these valorous attempts to understand genotype-phenotype relations in life-threatening conditions, the authors of the paper have shown us a way to obtain the much needed insights that will eventually provide us with the tools to prevent the arrhythmias and treat the patient.REFERENCES1 Ackerman MJ, Splawski I, Makielsky JC, Tester DJ, Will ML, Timothy KW, Keating MT, Jones G, Chadha M, Buroow CR, Stephens JC, Judson R, Curran ME. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 1: 600–607, 2004.Crossref | PubMed | ISI | Google Scholar2 Albert CM, Nam EG, Rimm EB, Jin HW, Hajjar RJ, Hunter DJ, MacRae CA, Ellinor PT. Cardiac sodium channel variants and sudden death in women. Circulation 117: 16–23, 2008.Crossref | PubMed | ISI | Google Scholar3 Arnestad M, Crotti L, Rognum T, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George AL, Schwartz PJ. Prevalence of long QT syndrome gene variants in sudden infant death syndrome. Circulation 15: 361–367, 2007.Google Scholar4 Baroudi G, Pouliot V, Denjoy I, Guicheney P, Shrier A, Chahine M. Novel mechanism for Brugada syndrome: defective surface localization of an SCN5A mutant (R1432G). Circ Res 88: E78–E83, 2001.Crossref | PubMed | ISI | Google Scholar5 Bebarova M, O'Hara T, Geelen JLMC, Jongbloed RJ, Timmermans C, Arens YH, Rodriquez LM, Rudy Y, Volders PGA. Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation. Am J Physiol Heart Circ Physiol (May 2, 2008). doi:10.1152/ajpheart.91495.2007.Link | ISI | Google Scholar6 Bennett PB, Yazawa K, Makita N. Molecular mechanism for an inherited cardiac arrhythmia. Nature 376: 683–685, 1995.Crossref | PubMed | ISI | Google Scholar7 Bezzina CR, Veldkamp MW, van den Berg MP, Postma AV, Rook MB, Viersma JW, van Langen IM, Tan-Sindhunata MB, Bink-Boelkens MTE, van der Hout AH, Mannens MMAM, Wilde AAM. A single sodium channel mutation causing both long QT- and Brugada syndrome. Circ Res 85: 1206–1213, 1999.Crossref | PubMed | ISI | Google Scholar8 Coronel R. Myths metaphors and mathematical models. Heart Rhythm 4: 1046–1047, 2007.Crossref | PubMed | ISI | Google Scholar9 Coronel R, Casini S, Koopmann TT, Wilms-Schopman FJG, Verkerk AO, de Groot JR, Bhuiyan Z, Bezzina CR, Veldkamp MW, Linnenbank AC, van der Wal AC, Tan HL, Brugada P, Wilde AAM, de Bakker JMT. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic and computational study. Circulation 112: 2769–2777, 2005.Crossref | PubMed | ISI | Google Scholar10 Grant AO, Carboni MP, Neplioueva V, Starner CF, Memmi M, Napolitano C, Priori SG. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest 110: 1201–1209, 2002.Crossref | PubMed | ISI | Google Scholar11 Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, van Langen IM, Sandkuyl L, Smits JPP, Hulsbeek M, Jongsma HJ, Wilde AAM. A cardiac SCN5A mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res 92: 14–22, 2003.Crossref | PubMed | ISI | Google Scholar12 Koopmann TT, Bezzina CR, Wilde AAM. Voltage-gated sodium channels: action players with many faces. Ann Med 38: 472–482, 2006.Crossref | PubMed | ISI | Google Scholar13 Kyndt F, Probst V, Potet F, Demolombe S, Chevalier JC, Baro I, Moisan JP, Schott JJ, Escande D, le Marec H. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation 118: 3081–3086, 2001.Google Scholar14 Meregalli PG, Wilde AAM, Tan HL. Pathophysiology of Brugada syndrome: repolarization, depolarization disorder or more. Cardiovasc Res 67: 367–378, 2005.Crossref | PubMed | ISI | Google Scholar15 Scicluna B, Wilde AAM, Bezzina CR. The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand why? J Cardiovasc Electrophysiol 19: 445–452, 2008.Crossref | PubMed | ISI | Google Scholar16 Tan HL, Bezzina CR, Smits JPP, Verkerk AO, Wilde AAM. Genetic control of sodium channel function. Cardiovasc Res 57: 961–973, 2003.Crossref | PubMed | ISI | Google Scholar17 Veldkamp MW, Viswanathan P, Bezzina C, Baartscheer A, Wilde AAM, Balser JR. Two distinct congenital arrhythmias evoked by a multi-dysfunctional sodium channel. Circ Res 86: e91–e97, 2000.Crossref | PubMed | ISI | Google Scholar18 Wang DW, Desai RR, Crotti L, Arnestad M, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Rognum T, Schwartz PJ, George AL. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation 115: 368–376, 2007.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: A. A. M. Wilde, Heart Failure Research Centre, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByArrhythmic substrate, slowed propagation and increased dispersion in conduction direction in the right ventricular outflow tract of murine Scn5a+/ − hearts9 July 2014 | Acta Physiologica, Vol. 211, No. 4Inherited arrhythmia syndromes leading to sudden cardiac death in the young: A global update and an Indian perspectiveIndian Heart Journal, Vol. 66Reduced Na + and higher K + channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice1 June 2012 | Open Biology, Vol. 2, No. 6Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/− mouse modelClaire A. Martin, Laila Guzadhur, Andrew A. Grace, Ming Lei, and Christopher L.-H. Huang1 May 2011 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 300, No. 5Spatial and temporal heterogeneities are localized to the right ventricular outflow tract in a heterozygotic Scn5a mouse modelClaire A. Martin, Andrew A. Grace, and Christopher L.-H. Huang1 February 2011 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 300, No. 2 More from this issue > Volume 295Issue 1July 2008Pages H8-H9 Copyright & PermissionsCopyright © 2008 by the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00494.2008PubMed18502906History Published online 1 July 2008 Published in print 1 July 2008 Metrics" @default.
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