In the last 10 years, the management of cardiac arrhythmias has evolved to an impressive pace, thanks to the development of highly sophisticated technologies for diagnosis and treatment. Mapping of the site of origin of arrhythmias, ablation, and implant of defibrillators have reduced the importance of the traditional approaches based on electrocardiographic reading and prescription of drugs. In this context, inherited arrhythmogenic diseases such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and Brugada syndrome represent the exception in which the ECG has remained the pivotal diagnostic tool. When approaching the diagnosis of one of these diseases, the cardiologist has to leave fancy computer screens and go back to the ‘ruler and caliper’ to measure the duration of an ‘interval’ or the elevation of an electrocardiographic ‘segment’. This apparently simple diagnosis, however, is far from being easy and even ‘experts’ in the field may face substantial diagnostic dilemma

Priori SG

Rossenbacker T

PRIORI, SILVIA GIULIANA

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

EditorialClinical diagnosis of long QT syndrome: back to thecaliperTom Rossenbacker1 and Silvia G. Priori2*1Molecular Cardiology, IRCCS Fondazione Maugeri, University of Pavia, Via Maugeri 10/10A, 27100 Pavia, Italy and2Department of Cardiology, University of Pavia, Pavia, ItalyOnline publish-ahead-of-print 20 February 2007This editorial refers to ‘Diagnostic criteria for congenitallong QT syndrome in the era of molecular genetics: dowe need a scoring system?’† by Hofman et al., on page 575In the last 10 years, the management of cardiac arrhythmiashas evolved to an impressive pace, thanks to the develop-ment of highly sophisticated technologies for diagnosis andtreatment. Mapping of the site of origin of arrhythmias,ablation, and implant of defibrillators have reduced theimportance of the traditional approaches based on electro-cardiographic reading and prescription of drugs. In thiscontext, inherited arrhythmogenic diseases such as longQT syndrome (LQTS), catecholaminergic polymorphic ventri-cular tachycardia, short QT syndrome, and Brugada syn-drome represent the exception in which the ECG hasremained the pivotal diagnostic tool. When approachingthe diagnosis of one of these diseases, the cardiologist hasto leave fancy computer screens and go back to the ‘rulerand caliper’ to measure the duration of an ‘interval’ orthe elevation of an electrocardiographic ‘segment’. Thisapparently simple diagnosis, however, is far from beingeasy and even ‘experts’ in the field may face substantialdiagnostic dilemma.The diagnosis of the LQTS, for example, ‘simply’ requiresthe measurement of QT interval duration on a standard ECGrecording and the correction of the duration for ‘heart rate’using the Bazett’s formula. In real-life, however, the diagno-sis is far from being straightforward and it is often moreelusive than anticipated for a variety of reasons that encom-pass the difficulty to define the ‘end’ of the T-wave, the lackof linear behaviour of the Bazett’s formula at slower andfaster heart rates, and the arbitrary definition of thegender-based diagnostic cut off values that define an abnor-mally prolonged QTc (QTc .440 for males and QTc .460 forfemales).1 A large body of literature has been dedicated tothe discussion of limitations of manual and automatic QTinterval measurement2,3 thus promoting the interest in thedevelopment of new diagnostic criteria for LQTS. Twopoint score systems have been developed in an effort toenhance the diagnostic reliability of clinical parametersand have become quite popular even if their accuracy hasnot been systematically investigated. The Keating criteriaare a binary combination of QTc values with LQTS-relatedsymptoms.4 The Schwartz score incorporates, besides QTc,other electrocardiographic features of the LQTS in additionto the patient’s clinical and familial characteristics.5 At theend, scoring systems allow for an estimation of a certainprobability of the LQTS. The specificity of these scoringsystems is rather good but the low sensitivity has been amatter of dispute.The advent of molecular diagnosis has provided theunique opportunity to address this debate allowing tocompare the accuracy of the different diagnostic strategiesin patients in whom genetic analysis has confirmed or dis-missed the presence of the disease. This is the exercisethat Hofman et al.6 have performed in the attempt tocompare the diagnostic accuracy of QT interval measure-ment vs. the use of the 1993 Schwartz5 criteria or theKeating4 criteria in the diagnosis of LQTS.Hofman et al.6 studied 513 relatives of 77 LQTS probandswith a known disease-causing mutation. All family memberswere more than 10 years of age and both scores wereobtained blinded to the result of genetic testing. TheSchwartz5 criteria identified ‘high probability of LQTS’(score 4) in 41 of 208 mutation carriers, yielding 19% sen-sitivity and 99% specificity. The Keating4 criteria detectedmore mutation carriers, yielding 36% sensitivity and 99%specificity. The authors conclude that, despite high speci-ficity, the sensitivity of both criteria is probably too low tobe adopted in clinical practice. In a second part of thestudy, the authors sought to determine the diagnostic accu-racy of different values of QT duration based on the manualmeasurement of QTc obtained using Bazett’s formula. Inter-estingly, a QTc430 ms was identified as the optimal value todistinguish carriers (430 ms) from non-carriers (,430 ms),yielding 72% sensitivity and 86% specificity.Before we comment on the practical implications of theseresults, few considerations on the limitations of the studyare needed. First of all, the study has been performed infamily members of positively genotyped patients thusexcluding probands. As a practical consequence, theresults of the study cannot be applied to the clinical evalu-ation of an individual without family history of the disease. AThe opinions expressed in this article are not necessarily those of theEditors of the European Heart Journal or of the European Society ofCardiology.* Corresponding author. fax: þ39 0382 592059.E-mail address: spriori@fsm.it†doi:10.1093/eurheartj/ehl355& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.orgEuropean Heart Journal (2007) 28, 527–528doi:10.1093/eurheartj/ehl552 at FOND. MAUGERI on May 10, 2010eurheartj.oxfordjournals.orgDownloaded from second limitation derives from the fact that the authorshave excluded children,10 years of age because of the age-dependency of the QTc. This choice is rather arbitrary andprofoundly limits the applicability of results because veryoften the diagnosis of LQTS has to be made in the paediatricpopulation that therefore cannot benefit of the data pro-vided by this study.Bearing these limitations in mind, the study by Hoffmanet al.6 raises the important point that the use of the morecomplex scoring systems is unlikely to improve diagnosticaccuracy when compared with the simple measurement ofthe QT interval. On the contrary, the score systems increasethe number of the ‘missed’ diagnosis (false negatives) thatof course represents a major drawback to the use of thescoring systems.In support to the data presented by Hofman et al.6 are theresults of a similar study that we performed in our cohort ofgenotyped LQTS patients in 20037 in a group of 1209 individ-uals including 254 probands, 443 genetically affected, and512 genetically non-affected family members. Our objectivewas to define sensitivity and specificity of QTc measurement(using Bazett’s formula) and of the use of the 1993Schwartz’s criteria5 in identifying LQTS affected individuals.No limitations of age were used in our study and probandswere also included in the analysis. The study showed thatthe performance of QTc interval measurement was betterthan that of the Schwartz’s score and the best cut off tocall an individual as affected by the disease was a QTc.440 ms that had a 81% sensitivity and 90% specificity. Thebest performance of the score system was found for a cutoff 2 (76% sensitivity and 90% specificity). Interestingly,the same cut off was also the most accurate in the studyby Hofman et al.6 (Figure 1).Taking the data of Napolitano and Hofman together, wecome to the conclusion that (1) there is no benefit to intro-duce the use of the scores in the clinics and (2) geneticanalysis is the only method to identify the relatively highproportion of silent carriers of disease causing mutations.In practical terms, when molecular diagnosis is available ina family, there is no question that all members should bescreened to define if they carry the disease causing mutationor not.In this respect, we do not agree with Hofman et al.6 whenthey propose that it may be worthwhile to use clinical cri-teria to select individuals suitable for molecular screening.When the mutation is known, DNA analysis to search for asingle mutation is rather cheap and provides results withinfew days and therefore it is perfectly reasonable to offerthis test to all family members irrespective of their clinicalphenotype. Our data8,9 have suggested that at 30% of gen-otyped individuals have a completely normal QT interval anda non-diagnostic score. Therefore, it is wrong to limit accessto genotyping based on phenotypical characteristics.Accordingly, we feel that every first-degree relativeshould be offered genetic screening when the causalmutation has been detected in the proband. This serviceshould even be strongly encouraged in the light of the pro-minent 10% risk of major cardiac events when silent genecarriers are left untreated.8 To accomplish a service of pro-viding a fast and reliable test result without substantialcosts for fully-informed and prepared individuals, the callof Hofman et al.6 for a centralization of the care of patientswith inherited cardiac arrhythmias in specialized cardio-genetic facilities should be fully endorsed. In centresspecialized in the care of patients with inherited arrhythmo-genic diseases, the expertise of trained staff in accurate andreproducible ECG reading is expected to be able to identifya high proportion of ‘probands’ suitable for genetic testing,thus optimizing the cost–benefit ratio of moleculardiagnosis.Conflict of interest: none declared.References1. Schwartz PJ, Priori SG. Long QT syndrome: genotype–phenotype corre-lations. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology From Cellto Bedside. Philadelphia: WB Saunders Co.; 2004. p. 651–659.2. Murray A, McLaughlin NB, Bourke JP, Doig JC, Furniss SS, Campbell RW.Errors in manual measurement of QT intervals. Br Heart J 1994;71:386–390.3. Murray A, McLaughlin NB, Campbell RW. Measuring QT dispersion: manversus machine. Heart 1997;77:539–542.4. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkageof a cardiac arrhythmia, the long QTsyndrome, and the Harvey ras-1 gene.Science 1991;252:704.5. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria forthe long QT syndrome. An update. Circulation 1993;88:782–784.6. Hofman N, Wilde AAM, Kääb S, van Langen IM, Tanck MWT, Mannens MMAM,Hinterseer M, Beckmann B, Tan HL. Diagnostic criteria for congenital longQT syndrome in the era of molecular genetics: do we need a scoringsystem? Eur Heart J 2007;28:575–580. First published on November 7,2006, doi:10.1093/eurheartj/ehl355.7. Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Grillo M,Veia A, Cappelletti D. Value and accuracy of clinical diagnosis criteriafor the Long QT syndrome in the era of molecular diagnosis. Circulation2003;108:IV-363.8. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vice-ntini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stra-tification in the Long QT syndrome. N Engl J Med 2003;348:1866–1874.9. Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J,Bottelli G, Cerrone M, Leonardi S. Genetic testing in the long QTsyndrome.JAMA 2005;294:2975–2980.Figure 1 Sensitivity and specificity of the different cut off values for QTc(Bazett’s formula) (Panel A) and for the 1993 Schwartz’s score (Panel B) cal-culated on the basis of the ability to correctly detect as ‘affected’ or ‘non-affected’ by long QT syndrome based on the results of genotyping. Datafrom Napolitano et al.7Editorial528 at FOND. MAUGERI on May 10, 2010eurheartj.oxfordjournals.orgDownloaded from 

Clinical diagnosis of Long QT Syndrome: back to the caliper.

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