ORIGINAL ARTICLES

Diagnostic Performance of Various QTc IntervalFormulas in a Large Family with Long QT SyndromeType 3: Bazett’s Formula Not So Bad After All . . .

Jan Brouwer, M.D., M.Sc., Ph.D.,∗†‡ Maarten P. van den Berg, M.D., Ph.D.,∗Diederick E. Grobbee, M.D., Ph.D.,§ Jaap Haaksma, Ph.D.,∗and Arthur A.M. Wilde, M.D., Ph.D.¶From the ∗Department of Cardiology, Thorax Center, University Hospital Groningen, Groningen, †Department ofCardiology, Medisch Centrum Leeuwarden, Leeuwarden, ‡NIHES—Netherlands Institute for Health Sciences,§Julius Center of Patient-Oriented Research, University of Utrecht, ¶Experimental and Molecular CardiologyGroup, Academic Medical Center, Amsterdam, The Netherlands

Background: Recently, we identified a novel mutation of SCN5A (1795insD) in a large family withLQTS3. The aim of this study was to assess whether the various proposed corrections of the QTinterval to heart rate help to improve the identification of carriers of the mutant gene.

Methods: The study group consisted of 101 adult family members: 57 carriers and 44 noncarriers(mean age 44.6 ± 14.6 and 40.3 ± 12.8 years, respectively). In all individuals a 12-lead ECG, exerciseECG, and 24-hour Holter ECG were obtained.

Results: Correction for heart rate significantly improved the diagnostic performance of the QTinterval. Diagnostic performance of the Bazett formula was similar to that of the newer formulas(Fridericia, Hodges, Framingham, and a logarithmic formula). At a cut-off value of 440 ms, theBazett corrected QT interval was associated with a sensitivity and specificity of 90% and 91%,respectively. Using the 24-hour Holter ECG, a prolonged QTc at heart rates less than 60 beats/minwas almost pathognomonic for genetic mutation (sensitivity and specificity both 99%), whereas theQTc calculated at the lowest heart rate using Bazett’s formula provided full discrimination.

Conclusion: In the present family, the resting ECG gave a good indication about the presenceor absence of genetic mutation but a 24-hour Holter recording was mandatory to ascertain thediagnosis. In the diagnosis of this form of LQTS3, Bazett’s formula was at least as good as otherproposed corrections of the QT interval to heart rate. A.N.E. 2003;8(4):269–274

long-QT syndrome; QT interval; heart rate; Bazett’s formula

QT prolongation has been recognized as a marker ofincreased risk for cardiac arrhythmias and suddencardiac death. Already more than 35 years ago, thelong-QT syndrome (LQTS) was found to be a causefor sudden death in subjects with otherwise normalhearts.1,2 More recently, several genetic variants ofLQTS have been identified. We described a largefamily characterized by premature nocturnal sud-den death due to a mutation (1795insD) in the car-diac Na+-channel gene (SCN5A).3−6 Carriers of thisgenetic mutation exhibit features of both LQTS3and Brugada syndrome. An important feature is the

Address for reprints: M.P. van den Berg, M.D., Department of Cardiology, Thorax Center, University Hospital Groningen, P.O. Box 30.001,9700 RB, Groningen, The Netherlands. Fax: +31-50-3614391; E-mail: m.p.van.den.berg@thorax.azg.nl

presence of excessive bradycardia-dependent QTinterval prolongation in conjunction with mild si-nus bradycardia.

Although prolongation of the QT interval is ob-viously an essential characteristic of LQTS, identi-fication of affected individuals may sometimes bedifficult. In order to evaluate the QT interval underdifferent conditions at varying heart rates, Bazettproposed in 1920 a correction formula in whichthe observed QT interval is divided by the squareroot of the RR interval.7 However, Bazett’s formulais said to lead to some overcorrection at higher

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heart rates and undercorrection at lower heartrates. Therefore, several other formulas have beenpresented, all aiming to better describe the QT-heart rate (or RR interval) relationship.8−15 Never-theless, Bazett’s formula still is most often used forcorrection of the QT interval and, indeed, the ex-istence of an “optimal” formula and even the ne-cessity of any correction for heart rate have beenquestioned.16,17

The aim of this study was to assess whether thevarious proposed corrections of the QT interval toheart rate help to improve identification of carriersof the mutant gene in the above-mentioned family.

METHODS

The family came to our attention in 1958 whena 16-year-old boy was referred because of markedQT prolongation and biphasic T waves on an elec-trocardiogram (ECG). In view of a high familialincidence of unexpected nocturnal sudden death,clinical data were collected in subsequent years inas many family members as possible. Standard 12-lead resting ECGs, 24-hour ambulatory Holter ECGrecordings, and exercise ECGs were obtained aspart of routine investigations. At the time of the in-vestigation, none of the subjects was using any car-dioactive medication. Further details on the pedi-gree, clinical characteristics, electrophysiologic andgenetic studies, follow-up, and treatment have beengiven in earlier reports.3−6 In this study, analysiswas limited to adult individuals with definite ge-netic status, based either on DNA analysis4 or pedi-gree analysis (obligate carriers).

Methods have been detailed previously.4,6

Briefly, the standard 12-lead resting ECG wasrecorded at a paper speed of 25 mm/s. The QTinterval was measured from the beginning of theQRS complex to the end of the T wave whereits terminal limb joined the baseline, taking thelongest QT interval in any lead. From 1978 un-til 1988, 24-hour ambulatory Holter ECG record-ings were obtained using Avionics two-channel 445recorders and an Avionics 680 analyzer. Thereafter,Marquette three-channel series 8500 recorders anda Marquette series 8000 XP analyzer were used.Recordings were made using modified leads V1, V5and aVF. Measurements of the QT interval weremade at the lowest heart rate and at fixed heartrates of 40, 50, 60, 70, 80, 90, and 100 beats/min,again taking the longest QT interval in any lead.Symptom-limited exercise tests were performed us-ing a bicycle ergometer. The protocol consisted of

an initial work load of 50 Watts, and thereafter astepwise 10-Watt increase every 30 seconds. The12-lead ECG was continuously monitored using aMarquette Case 12 electrograph. A hard copy ECGwas produced at regular intervals. Measurementsof the QT interval were made at fixed heart ratesof 110, 120, 130, 140, 150, and 160 beats/min andat the highest heart rate.

Corrections of the QT interval for heart rate weremade in accordance with earlier reports.7−11,13−15

Using Bazett’s formula,7 the corrected QT interval(QTc) is calculated as QT/(RR) 1/2. QTc according tothe Fridericia formula8 is calculated as QT/(RR)1/3,and QTc according to Hodges formula9 is calculatedas QT + 0.00175 × ((60/RR) − 60). Linear regres-sion analysis using data of the Framingham HeartStudy10 yielded a linear adjustment QTc = QT +0,154 × (1 − RR). Furthermore, we used an earlierdescribed empirical formula,11 for which the pa-rameters were optimized using the observations inthe nongene carriers in our study. This resulted inthe following formula: QTc = 0.402/(0.402 + (0.134× Ln (RR))), which is further referred to as the “log-arithmic” formula. In all the given formulas, valuesfor the QT and RR interval are entered in seconds.

Data are presented as mean ± standard devia-tion, unless indicated otherwise. Differences be-tween gene carriers and nongene carriers wereassessed by the Student t-test for unpaired sam-ples. Fisher’s Exact test was used for comparisonof binary variables. Multivariate regression anal-ysis was used to evaluate potential influences ofgender and age. To evaluate the diagnostic perfor-mance of each formula in establishing the pres-ence or absence of the genetic mutation in indi-vidual family members, Receiver-Operator Curves(ROCurves) were constructed, in which sensitivitywas plotted against 1-specificity at varying cut-offlevels. For comparison of diagnostic performance,the Area Under the Curve (AUC) of each ROCurvewas calculated—a larger area indicating a better di-agnostic performance. All statistical analyses werecarried out using SPSS for Windows, version 9.0.

RESULTS

The study group described in the current reportcomprised 101 individuals, 57 gene carriers (meanage 44.6 ± 14.6 years, 48% male) and 44 non-gene carriers of the mutant gene (mean age 40.3± 12.8 year, 50% male). As expected, the QT andQTc intervals on the resting ECG were significantlylonger for carriers as compared to noncarriers

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Table 1. Patient Characteristics

Carriers Noncarriers(n = 57) (n = 44) P-value

Age (years) 44.6 ± 14.6 40.3 ± 12.8 0.128Male (%) 48 50 0.848Resting ECG

Heart rate (bpm) 68 ± 15 72 ± 13 0.120Uncorrected QT interval (seconds) 0.466 ± 0.095 0.377 ± 0.031 <0.001QTc-Bazett (seconds) 0.481 ± 0.044 0.409 ± 0.023 <0.001QTc-Fridericia (seconds) 0.475 ± 0.057 0.398 ± 0.019 <0.001QTc-Hodges (seconds) 0.479 ± 0.074 0.398 ± 0.019 <0.001QTc-Framingham (seconds) 0.474 ± 0.060 0.398 ± 0.019 <0.001QTc-Logarithmic (seconds) 0.477 ± 0.058 0.399 ± 0.019 <0.001

Holter ECGMean heart rate (bpm) 70 ± 8 77 ± 9 <0.001Lowest heart rate (bpm) 41 ± 8 47 ± 8 <0.001Highest heart rate (bmp) 124 ± 24 141 ± 16 <0.001

Values are mean ± SD.

(Table 1). Similar results were found for QTc mea-surements on the exercise ECG (434 observations)and 24-hour Holter ECG (625 observations). (Re-sults not tabulated.) Again, the QT and QTc inter-vals were markedly longer in carriers, especiallyat lower heart rates. This difference gradually de-creased with increasing heart rate. At a heart ratehigher than 140 beats/min, the difference between

1 - Specificity

1,00,75,50,250,00

Sen

sitiv

ity

1,00

,75

,50

,25

0,00

Figure1. ROC curves for corrected QT interval—RestingECG dashed line: uncorrected QT interval; solid line: ref-erence line; : QTc-Bazett; : QTc-Fridericia; : QTc-Hodges; : QTc-Framingham; : QTc-Logarithmic.

carriers and noncarriers was no longer statisticallysignificant. Using multivariate regression analy-sis, the possible influence of gender and age wasevaluated. The calculated regression coefficientswere small and statistically not significant for allmeasurements.

The ROCurves are shown in Figure 1 (restingECG), Figure 2 (exercise ECG), and Figure 3 (Holter

1 - Specificity

1,00,75,50,250,00

Sen

sitiv

ity

1,00

,75

,50

,25

0,00

Figure2. ROC curves for corrected QT interval—Exercise ECG dashed line: uncorrected QT interval; solidline: reference line; : QTc-Bazett; : QTc-Fridericia; :QTc-Hodges; : QTc-Framingham; : QTc-Logarithmic.

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1 - Specificity

1,00,75,50,250,00

Sen

sitiv

ity

1,00

,75

,50

,25

0,00

Figure3. ROC curves for corrected QT interval—HolterECG dashed line: uncorrected QT interval; solid line: ref-erence line; : QTc-Bazett; : QTc-Fridericia; : QTc-Hodges; : QTc-Framingham; : QTc-Logarithmic.

ECG). The data on the accompanying AUC aregiven in Table 2. For the resting ECG, heart-rate-corrected QT intervals had a significantly largerAUC than the uncorrected QT interval (P < 0.001),indicating better diagnostic performance (Fig. 1,Table 2). However, the differences between theQTc intervals based on the five formulas weremarginal and not statistically significant. For theexercise ECG, the AUC was lower for each QT andQTc measurement as compared to the resting ECG(Fig. 2, Table 2). Correction of the QT interval forheart rate according to the formulas of Bazett, Frid-ericia, and Hodges and the logarithmic formularesulted in better diagnostic performance as com-pared to the uncorrected QT interval. The differ-

Table 2. Corrected QT Interval in Relation to Genetic Status-Area Under Curve of Receiver Operator Curve(95% CI)

Type of QT Correction Resting ECG Exercise ECG Holter ECG

Uncorrected QT 0.876 (0.808–0.944) 0.612 (0.559–0.665) 0.809 (0.776–0.842)QTc-Bazett 0.953 (0.915–0.991) 0.720 (0.673–0.768) 0.963 (0.950–0.976)QTc-Fridericia 0.957 (0.918–0.996) 0.678 (0.628–0.727) 0.958 (0.943–0.972)QTc-Hodges 0.951 (0.909–0.993) 0.693 (0.643–0.743) 0.949 (0.933–0.965)QTc-Framingham 0.960 (0.922–0.998) 0.661 (0.610–0.711) 0.958 (0.944–0.973)QTc-Logarithmic 0.958 (0.920–0.996) 0.702 (0.653–0.750) 0.960 (0.946–0.975)

ence in AUC between the uncorrected QT andQTc calculated according to the Framingham for-mula was not statistically significant. For the HolterECG, the results were similar to those for theresting ECG (Fig. 3, Table 2). Again, heart-rate-corrected QT measurements had a significantly bet-ter diagnostic performance than the uncorrectedQT interval (P < 0.001), whereas the differencesin diagnostic performance between the five QTcmeasurements were negligible and not statisticallysignificant.

In the resting ECG, using cut-off values of 400,420, and 440 ms resulted in a sensitivity and speci-ficity for establishing the presence or absence of thegenetic mutation as listed in Table 3. It appears thatthe optimal cut-off value, in which a high sensitiv-ity is combined with a high specificity, was higherfor the Bazett corrected QT interval than for theother QTc intervals. Using cut-off values of 440 msfor the Bazett corrected QT interval and 420 ms forthe other QTc intervals, a sensitivity and specificityof both approximately 90% could be achieved.

Given the characteristic feature in this family ofexcessive bradycardia-dependent prolongation ofthe QT interval, we additionally examined diag-nostic performance at low heart rates using mea-surements from the Holter ECG. Using only obser-vations at heart rates of less than 60 beats/min re-sulted in a sensitivity of 99% in combination with aspecificity of 99% for the Bazett corrected QT inter-vals (cut-off level 440 ms). Using the cut-off level of420 ms, comparable values for sensitivity and speci-ficity were observed for the other formulas. Usingthe QTc at the lowest heart rate during the Holterrecording led to a full discrimination between car-riers and noncarriers of the mutant gene using theBazett formula (i.e., AUC = 1, both sensitivity andspecificity 100%). By contrast, such full discrimina-tion could not be achieved using the other formulas(AUC ranging from 0.990 to 0.995).

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Table 3. Corrected QT Interval in Relation to Genetic Status—Sensitivity and Specificity of Resting ECG

400 ms 420 ms 440 msCut-off ValueType of QT Sensitivity Specificity Sensitivity Specificity Sensitivity Specificitycorrection (%) (%) (%) (%) (%) (%)

Uncorrected QT 89 70 67 89 58 93QTc-Bazett 100 36 95 68 90 91QTc-Fridericia 97 55 93 91 74 98QTc-Hodges 97 57 91 91 65 98QTc-Framingham 98 59 93 91 68 98QTc-Logarithmic 98 55 93 91 75 98

DISCUSSION

To the best of our knowledge, this is the firststudy in which various formulas for correction ofthe QT interval to heart rate were evaluated in in-dividuals with a genotypically established form ofLQTS. A certain genotype of all members of thislarge family with features of both LQTS3 and Bru-gada syndrome provided a unique opportunity toassess the diagnostic performance of each separateformula. The results indicate that correction of theQT interval for heart rate indeed greatly improvedthe ability to identify gene carriers in this fam-ily. In addition, the diagnostic performance of the“good old” Bazett formula was at least as good asthat of the newer formulas that were introduced toimprove heart rate correction of the QT interval.In fact, only using Bazett’s formula in correctingthe QT interval at the lowest heart rate during the24-hour Holter monitoring allowed full discrimina-tion between carriers and noncarriers of the mutantgene.

Already in the report of Bazett7 it was recog-nized that the QT interval at comparable heart ratesis usually of longer duration in females comparedto males. In contrast, we observed no differencesin QT interval measurements between males andfemales. The absence of such a difference in ourstudy is compatible with the finding of Lehmann etal.,18 who also observed no clear gender differencesin their subgroup with LQTS3.

In the present family, the QT interval on the rest-ing ECG gave a good indication of the presence orabsence of the genetic mutation but failed to as-certain the right diagnosis in all family members.Using only the resting ECG, roughly 10% of the car-riers were incorrectly labeled as noncarrier (false-negative) and also roughly 10% of the noncarrierswere incorrectly labeled as carrier (false-positive) of

the mutant gene, irrespective of the formula usedfor heart rate correction of the QT interval. It is tobe noted that patients in the present family werealso characterized by changes in T-wave morphol-ogy (like LQTS patients in general).4,6 However,analysis of this phenomenon was beyond the scopeof this study. Our data are in agreement with theprevious finding by Vincent et al.19 in other pa-tient groups with LQTS that the value of the QTinterval on the resting ECG is limited, in particu-lar, regarding the possibility of false-negatives. Bycontrast, analyses based on 24-hour Holter ECGproved very accurate in this family. At heart rates of60 beats/min or less, a prolonged QTc was thusalmost pathognomonic for the genetic mutation,whereas the QTc interval calculated at the lowestheart rate using Bazett’s formula actually providedfull discrimination between carriers and noncarri-ers. Although in the exercise ECG differences inQT and QTc intervals between carriers and non-carriers remained statistically significant up to 140beats/min, the diagnostic performance of the exer-cise ECG was limited in comparison with the rest-ing ECG and Holter ECG. Still, the diagnostic per-formance of the Bazett formula was again at leastas good as that of the other formulas.

The observation that the optimal cut-off value forQTc using Bazett’s formula is higher than for theother QTc formulas may be explained by earlierobservations that Bazett’s formula leads to someovercorrection at higher heart rates and undercor-rection at lower heart rates. Given the fact thatfor most observations in this study heart rate washigher than 60 bpm, on average some overcorrec-tion is to be expected. As discussed above, thissuboptimal correction of QT interval to heart rateapparently does not adversely influence diagnosticperformance. Although it is clear that some formof correction of the QT interval to heart rate is

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important, one should view the magnitude ofchange induced by the various formulas in compar-ison with other well-known sources of variation inthe QT interval such as autonomic nervous systemactivity, posture, diurnal variations etc.20−22

CONCLUSION

In this particular family, the QT interval on theresting ECG gave a good clue about the presence orabsence of genetic mutation, but a 24-hour Holterrecording provided almost full discrimination. Inaddition, Bazett’s formula was at least as good asother the formulas to correct the QT interval forheart rate. Whether these observations also apply toother forms of congenital LQTS (particularly thosewith relative QT prolongation at higher heart rates)or in acquired LQTS remains to be established. Forthe time being, Bazett’s formula does not seem sobad after all.

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