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European Heart Journal Advance Access originally published online on December 22, 2007
European Heart Journal 2008 29(2):185-190; doi:10.1093/eurheartj/ehm586
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case control pilot study

Martin Hinterseer1,*, Morten B. Thomsen2, Britt-Maria Beckmann1, Arne Pfeufer3,4, Rainer Schimpf5, H.-Erich Wichmann3,6, Gerhard Steinbeck1, Marc A. Vos2 and Stefan Kaab1

1 Department of Medicine I, Klinikum Grosshadern, Ludwig Maximilians University Munich, Marchioninistrasse 15, D-81366 Munich, Germany
2 Department of Medical Physiology, Heart Lung Centre Utrecht, Utrecht, The Netherlands
3 Institute of Human Genetics and Epidemiology, GSF National Research Center for Environment and Health, Neuherberg, Germany
4 Institute of Human Genetics, Technical University Munich, Munich, Germany
5 1st Department of Medicine, Cardiology, University Hospital of Mannheim, Mannheim, Germany
6 Institute of Epidemiology, GSF, National Research Center, Neuherberg, Germany

Received 5 April 2007; revised 13 November 2007; accepted 22 November 2007; online publish-ahead-of-print 22 December 2007.

*Corresponding author. Tel: +49 89 7095 2251, Fax: +49 89 7095 5251, Email: martin.hinterseer{at}med.uni-muenchen.de


   Abstract
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 Abstract
Introduction
 Methods
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 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Aims: Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes.

Methods and results: Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched control individuals. An observer blinded to diagnosis manually measured lead-II, RR, and QT intervals from 30 consecutive beats. BVR was determined from Poincaré plots of QT intervals as short-term variability (STVQT = {Sigma}|QTn+1 – QTn|/[30 x {surd}2]). QRS interval and cycle length was comparable between study groups and controls. No difference was found in QTc between dLQTS and controls (428 ± 25 vs. 421 ± 34 ms, P = 0.26), whereas STVQT was significantly higher in dLQTS when compared with controls (8.1 ± 3.7 vs. 3.6 ± 1.3 ms, P = 0.001). Proarrhythmic predictive power of STVQT was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI: 0.79–0.99 vs. 0.39–0.75).

Conclusion: In the absence of QTc prolongation, baseline STVQT characterized patients with documented drug-induced proarrhythmia. STVQT could prove to be a useful non-invasive, easily obtainable parameter aiding the identification of the patient at risk for potentially life threatening arrhythmia in the context of drugs with QT prolonging potential.

Key Words: Torsades de Pointes • Drug induced Long QT Syndrome • Beat-to-beat Variability of repolarization • Proarrhythmia


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Torsades de Pointes arrhythmias (TdP) are potentially fatal ventricular arrhythmias that by definition occur in the setting of a prolonged QT interval. Multiple factors can modulate QT interval, including intrinsic (age, gender, heri channelopathies) and extrinsic factors (hypokalemia, drugs, fever, metabolic disorders, acquired cardiac pathologies, etc.).1–3 The congenital long-QT syndromes (cLQTS) are mainly caused by mutations in cardiac ion channels (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) that produce either a decrease in repolarizing potassium current (IKr, IKs) or an increase in a depolarizing current (INa).4,5 The drug-induced long-QT syndrome (dLQTS) can be induced in susceptible patients by a large heterogeneous group of cardiac and non-cardiac drugs.6,7

The concept of repolarization reserve has been used to describe the proarrhythmic risk of an individual by the ability of the heart to withstand a challenge on repolarization.1,8 Although QT prolongation is a hallmark of such a repolarization disorder, there are several clinical and experimental studies showing that the QT interval, especially in dLQTS at baseline, is a poor surrogate marker to forecast proarrhythmic events.9–14 Thus, alternative parameters that would quantify individual repolarization reserve and risk for proarrhythmia at baseline are needed.

Experimental animal models of acquired QT prolongation and increased susceptibility to TdP have elucidated many aspects of the mechanisms behind repolarization reserve and proarrhythmia.7 Recently, beat-to-beat variability of repolarization duration has been developed as a proarrhythmic marker in such a model: the dog with chronic AV-block. Drug administration causing TdP in this model produced a temporary elevation of repolarization variability prior to the proarrhythmic event, whereas interventions decreasing repolarization variability were antiarrhythmic.12,15 Secondly, TdP-prone dogs showed larger beat-to-beat variability of repolarization already at baseline compared to dogs resistant to drug-induced proarrhythmia.16 Finally, a subset of dogs prone to sudden death under drug-free circumstances showed persistent high repolarization variability at baseline.17

The aim of this study was to determine if baseline repolarization variability quantified as short-term variability (STV) of QT is a clinically applicable marker of proarrhythmia in a group with a well defined risk for repolarization-dependent arrhythmias: patients with a history of drug-induced TdP, evaluated under baseline conditions in the absence of QT prolonging circumstances.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Drug-induced long-QT patients
From our LQTS patient database, at the time of this study 30 patients with dLQTS were identified. With a focus on LQTS, the database was started in 1998 including at present all patients of our cardiogenetics clinic and dLQTS patients from the arrhythmia clinic of the University Clinic of Mannheim. Drug-induced LQTS was defined as patients having experienced documented episodes of TdP under drugs with QT-prolonging potential, in combination with the absence of a mutation in any of the major LQTS genes (KCNQ1, KCNH2, SCN5A, KCNE1, or KCNE2). All patients provided written informed consent for the study, which was approved by the human-ethics committee of the Ludwig Maximilians University, Munich. Inclusion criteria for both groups were resting ECG recordings in sinus rhythm that allowed analysis of 30 consecutive beats without premature supraventricular or ventricular complexes. This reduced the actual study group sizes to 20 dLQTS patients (mean age 59 ± 17 years; 11 females), respectively. None of the study population was on beta-blocker therapy.

Control population
The LQTS patients were matched 1:1 with controls according to age (±5 years) and sex. The control population (n = 20) was recruited from an ongoing population-based cohort study from which 880 probands were available for matching.18–20 In cases where more than one matching partner was available, controls were selected based on comparable concomitant pathologies (e.g. histories of hypertension or atrial fibrillation). All controls were off beta-blocker therapy. Genetic testing for the major LQTS genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) in the controls was negative. All patients and controls were of Caucasian origin.

Electrocardiographic analysis
12-lead ECG over 5 min had been obtained from all subjects in supine position after 10 min at rest in the absence of QT-prolonging drugs using the Mortara Portrait XL-ECG recorder (Mortara Instruments, Milwaukee, USA). At the moment of the measurement, these patients did not show arrhythmias or ectopic beats. A single observer blinded to patient data manually measured RR, QRS, and QT intervals of 30 consecutive beats. QT intervals were determined in lead II from the onset of the QRS complex to the end of the T wave employing the method of Lepeschkin and Surawicz.21 QT intervals were corrected for heart rate (QTc).22

Poincaré plots were drawn by plotting either RR or QT intervals against the previous interval for 30 consecutive beats, as previously described.11 STV, defined as the mean dispersion of the points perpendicular to the line-of-identity in the Poincaré plot, was calculated (STVD = {Sigma}|Dn+1 – Dn|/[30 x {surd}2], where Dn represents the RR or QT interval of beat n). This analysis acknowledges large beat-to-beat differences in repolarization duration to a higher degree than previously clinically applied algorithms of QT variability, which are based on variance.23,24

Genotyping
Genomic DNA was prepared from lymphocytes. Amplification of KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A using polymerase chain reactions were performed, followed by direct sequencing of the known major LQTS-disease genes.25

Statistical analysis
Variables are reported as mean ± SD, respectively, as median and range as indicated. Wilcoxon test for matched pairs was used for the comparison of study and control group. Bivariate correlations were determined by Spearman's correlation coefficient with associated significance. Tests were two-sided. P < 0.05 was considered to be significant. Areas under the curves (AUC) of the receiver–operator characteristics were calculated to assess predictive power of variables.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Patient characteristics
In the dLQTS group, TdP had occurred during sinus rhythm. Median time on medication likely to have induced TdP was 2 (range 1–5) days, whereas the time between the proarrhythmic event and ECG recording for this analysis was 25 (4–39) days. Patient characteristics are shown in Table 1.


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  		Table 1 Characteristics of dLQTS patients and age- and sex-matched controls

 
Electrocardiographical characteristics
Representative examples of ECG recordings from dLQTS and control individuals are shown in Figure 1, together with corresponding QT- and RR-Poincaré plots. Patients with dLQTS did not show longer QRS intervals or cycle lengths than their matched controls (Table 2). Furthermore, the patients did not show longer QT or QTc intervals. When analysing STVQT' we found higher values of STVQT in dLQTS patients than in their respective controls (8.1 ± 3.7 ms vs. 3.6 ± 1.3 ms, P = 0.001), whereas STVRR was comparable between both groups (Table 2). STVQT for individual patients and controls are depicted in Figure 2.


Figure 1
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  		Figure 1 Representative ECG tracings and associated Poincaré plots of the QT and RR intervals. (A) Patient with a history of drug-induced QT prolongation and TdP arrhythmias. (B) A representative control. RR and QT intervals are indicated above and below lead II in the ECG, respectively. ECG calibrated to 50 mm/s and 10 mm/mV. Poincaré plots of 30 consecutive QT or RR intervals measured in the same two patients, showing increased dimensions of the QT-Poincaré plot in dLQTS. Inserts, short-term variability. Poincaré plots of the RR intervals indicate comparable temporal variability of the ventricular cycle length. In all plots, the diagonal line (x = y) is for illustration purposes

 

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  		Table 2 Electrocardiographical characteristics of dLQTS patients and age- and sex-matched controls

 

Figure 2
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  		Figure 2 Individual STVQT in patients with a history of drug-induced TdP (dLQTS, n = 20) and their respective age- and sex-matched controls. *, Squares: mean ± SD; P < 0.05 (Wilcoxon matched-pairs test)

 
Within dLQTS patients and their controls, the proarrhythmic-predictive power of STVQT was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI 0.79–0.99 vs. 0.39–0.75).


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
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 Acknowledgements
 References
 
We find increased STVQT in patients with a history of torsades de pointes in the context of QT prolonging drugs compared with population-based control groups.

From non-clinical to clinical repolarization variability
In the past, several methods for the quantification of repolarization lability have been proposed.11,23,24,26 Whereas micro T-wave alternans is a phenomenon seen only at exercise-induced fast heart rates, repolarization lability is coined to normal-to-slow heart rates. Common for many lability algorithms including standard deviation is that the order in time of beats is disregarded. We hypothesized that beat-to-beat consecutiveness was critical in the analysis and suggested STV as the superior algorithm to predict TdP.12 Experiments have identified repolarization variability as an intrinsic property of cardiac myocytes, and STV have successfully predicted torsadogenic properties of drugs in in vitro models of proarrhythmia.12,27,28 In the proarrhythmic dog with chronic AV-block, a transiently increased STV of left ventricular monophasic action potential (LV MAP) was successfully antagonized by antiarrhythmic prevention strategies that stabilized or even decreased STV.12,29 In this clinical study, we replaced the invasive marker STVLV MAP by a non-invasive parameter derived from ECG recordings. In order to evaluate the potential use of this new clinical parameter, we analysed STVQT in patients with enhanced risk for proarrhythmic death due to history drug-induced proarrhythmia in the setting of dLQTS.

Susceptibility to drug-induced TdP is identified by STVQT
We have previously shown that patients with documented drug-induced TdP had an enhanced prolongation of the QT interval upon sotalol challenge compared with the response of control patients, but we were not able to identify patients at risk for proarrhythmia at baseline.14 On the basis of the results from the proarrhythmic dog with chronic AV-block, where proarrhythmic remodeling was associated with increased STVLV MAP,16 we analysed the new non-invasive parameter STVQT in dLQTS patients with documented enhanced risk for proarrhythmia. With focus on drug-induced LQTS individuals, we excluded individuals with mutations in any of the major cLQTS genes. Looking at the global repolarization parameter QT and QTc we found a normal QTc interval at baseline (Table 2), indicating that impaired repolarization strength is not uniquely identified by an excessively prolonged global repolarization. These findings confirm the conclusions of other studies, where standard QTc analysis fails to identify reduced repolarization reserve under drug-free circumstances.6 In contrast, STVQT was clearly increased in dLQTS patients compared with age- and sex-matched controls at baseline, although there is some overlap (Figure 2).

In our previous study of dLQTS patients, the sotalol challenge was associated with excessive QT prolongation.14 ECG recordings suitable for STVQT analysis immediately prior to onset of sotalol-induced TdP in 2 patients are available (patients 5 and 11 of Table 1). Mean STVQT before the start of the ventricular arrhythmia was 12.2 ± 1.9 ms, a clear increase from the baseline value of 6.9 ± 1.3 ms, concurrent with a QTc of 504 ± 17 and 421 ± 12 ms, respectively.

Thus, prior to the proarrhythmic event, both QTc and STVQT increase momentarily, whereas STVQT is already elevated before drug-administration in these patients, identifying the diminished repolarization reserve. Thus, STVQT is likely to be the more sensitive of the two in detecting baseline latent repolarization disorder. Notably, the association between proarrhythmia and increased STVQT in the context of QT-prolonging drugs is demonstrated in the absence of excessive QT prolongation, unmasking a latent repolarization disorder.

Other lability parameters suggested from in vitro studies were not tested in this proof-of-concept study, because they mostly depend on dynamic drug-induced changes on repolarization. On this account, we realize that further mechanistic studies are warranted and larger, multi-centered prospective studies are necessary to compare STVQT with other parameters. Besides STVQT analysis under baseline conditions, STVQT analysis during initiation of treatment with QT prolonging drugs could potentially provide important information for patient safety.

Thus, STVQT is superior compared with QT duration in the identification of patients with a latent proarrhythmic risk and characterization of patients before treatment with potentially proarrhythmic drugs6 is likely to be more complete by the addition of STVQT analysis, whereas the addition of a pre-treatment sotalol challenge can then be avoided.14,30

Influence of heart rate and STVRR on STVQT
In all groups, we found a strong correlation between the length of the QT interval and heart rate (data not shown). Beat-to-beat heart-rate variability, quantified as STVRR, was comparable between the two groups in the present study (Table 2). A positive, significant correlation between the STVQT and STVRR among control subjects was found (rs = 0.664, P = 0.01; n = 20), which was not seen within the LQTS patient group (rs = 0.2, P = 0.4). Animal studies have shown that steady state ventricular pacing can reduce increased STV and terminate drug-induced TdP. In drug-free circumstances, this frequency dependency of STVLV MAP is however very small and only present at severe bradycardic cycle lengths.15 Resting heart rate in patients from the present study were not fast enough to induce marked T-wave alternans, which would be evident on the Poincaré plots. Additional studies are required to elucidate the precise causal link among STVQT, heart rate, and variability thereof.

Limitations
All measurements were performed manually on paper tracings of lead II to demonstrate easy application of the analysis. The temporal behavior and development of STVQT was not analysed by follow-up ECG recordings in any patient group. When compared with the matched controls, significantly more dLQTS patients had a history of paroxysmal atrial fibrillation (Table 1). However, all ECG recordings that were used for the measurements showed sinus rhythm.


   Conclusions
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 Acknowledgements
 References
 
These are the first results from humans showing that STVQT is increased in patients with an increased risk for arrhythmia in the context of a latent repolarization disorder as in drug-induced LQTS. While QT and QTc intervals failed to unmask this latent repolarization disorder, STVQT was able to distinguish between patients with a history of drug-induced proarrhythmia at baseline and age and sex-matched controls, in the absence of QT prolongation. Therefore, STVQT could prove to be a useful non-invasive, easily obtainable parameter aiding the identification of the proarrhythmic patient by unmasking a latent repolarization disorders in the drug-free situation.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
Acknowledgements
 References
 
The German Federal Ministry of Education and research (BMBF) funded this work in the context of the German National Genome Research Network (NGFN) by the grants (01GS0499, NHK-S19T19, PGE-S04T13, PGE-S15To4). The KORA platform is funded by the German Federal Ministry of Education and Research and the State of Bavaria. Dr Thomsen was funded by the grants of CONTICA (EUFP6-STREP-LSHM-CT-2005-018802).


   Acknowledgements
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
References
 
The KORA group (Cooperative research in the region of Augsburg) consists of H.-E.W. (speaker) and his co-workers who were responsible for the design and conduct of the KORA studies. This work contains parts of the doctoral thesis of B.-M.B.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 

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