Beat-to-beat variability of QT intervals is increasedinpatientswithdrug-inducedlong-qt syndrome: a case control pilot study

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1 European Heart Journal (2008) 29, doi: /eurheartj/ehm586 CLINICAL RESEARCH Arrhythmia/electrophysiology Beat-to-beat variability of QT intervals is increasedinpatientswithdrug-inducedlong-qt syndrome: a case control pilot study Martin Hinterseer 1 *, Morten B. Thomsen 2, Britt-Maria Beckmann 1, Arne Pfeufer 3,4, Rainer Schimpf 5, H.-Erich Wichmann 3,6, Gerhard Steinbeck 1, Marc A. Vos 2, and Stefan Kaab 1 1 Department of Medicine I, Klinikum Grosshadern, Ludwig Maximilians University Munich, Marchioninistrasse 15, D 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 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 Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched and results 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 (STV QT ¼ SjQT nþ1 2 QT n j/[30 p 2]). QRS interval and cycle length was comparable between study groups and controls. No difference was found in QTc between dlqts and controls ( vs ms, P ¼ 0.26), whereas STV QT was significantly higher in dlqts when compared with controls ( vs ms, P ¼ 0.001). Proarrhythmic predictive power of STV QT was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI: vs ).... Conclusion In the absence of QTc prolongation, baseline STV QT characterized patients with documented drug-induced proarrhythmia. STV QT 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 Keywords Torsades de Pointes Drug induced Long QT Syndrome Beat-to-beat Variability of repolarization Proarrhythmia Introduction 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, heritable 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 (I Kr, I Ks ) or an increase in a depolarizing current (I Na ). 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 * Corresponding author. Tel: þ , Fax: þ , martin.hinterseer@med.uni-muenchen.de Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 186 M. Hinterseer et al 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 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 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 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 ¼ 20) was recruited from an ongoing population-based cohort study from which 880 probands were available for matching 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 (STV D ¼ SjD nþ1 2 D n j/[30 p 2], where D n 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 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. 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 STV QT 0 we found higher values of STV QT in dlqts patients than in their

3 Beat-to-beat variability of the QT interval 187 Table 1 Characteristics of dlqts patients and age- and sex-matched controls CAD/MI FS < 30% PAF Hypertension Drug a... Patient þ þ Sotalol Rizatriptan 3 þ þ þ 2 Sotalol þ þ Sotalol 5 þ þ þ 2 Sotalol þ þ Sotalol þ 2 Sotalol Imipramine þ Citalopram þ þ Sotalol Amiodarone 12 2 þ 2 2 Sotalol þ Ciprofloxacin þ þ Moxifloxacin 15 þ Ciprofloxacin Clofazimine Amiodarone Haloperidol þ 2 Sotalol 20 þ þ þ þ Amiodarone Total Control 21 þ þ þ þ þ þ þ þ þ þ þ 31 2 þ þ þ þ 2 40 þ 2 þ þ Total CAD/MI indicates coronary artery disease or history of myocardial infarction; FS, fractional shortening; PAF, paroxysmal atrial fibrillation; hypertension, history of arterial hypertension (systolic.140 mmhg and diastolic.90 mmhg). a The medication most likely to have triggered the proarrhythmic event. respective controls ( ms vs ms, P ¼ 0.001), whereas STV RR was comparable between both groups (Table 2). STV QT for individual patients and controls are depicted in Figure 2. Within dlqts patients and their controls, the proarrhythmic-predictive power of STV QT was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI vs ). Discussion We find increased STV QT 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 STV LV MAP by a non-invasive parameter derived from ECG recordings. In order to evaluate the potential use of this new clinical parameter, we analysed STV QT 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 STV QT 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 STV LV MAP, 16 we analysed the new non-invasive parameter STV QT 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

4 188 M. Hinterseer et al 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 ¼ y) is for illustration purposes conclusions of other studies, where standard QTc analysis fails to identify reduced repolarization reserve under drug-free circumstances. 6 In contrast, STV QT 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 STV QT analysis immediately prior to onset of sotalol-induced TdP in 2 patients are available (patients 5 and 11 of Table 1). Mean STV QT before the start of the ventricular arrhythmia was ms, a clear increase from the baseline value of ms, concurrent with a QTc of and ms, respectively. Thus, prior to the proarrhythmic event, both QTc and STV QT increase momentarily, whereas STV QT is already elevated before drug-administration in these patients, identifying the diminished repolarization reserve. Thus, STV QT is likely to be the more sensitive of the two in detecting baseline latent repolarization disorder. Notably, the association between proarrhythmia and increased STV QT 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 STV QT with other parameters. Besides STV QT analysis under baseline conditions, STV QT analysis during initiation of treatment with QT prolonging drugs could potentially provide important information for patient safety. Thus, STV QT 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 drugs 6 is likely to be more complete by the addition of STV QT analysis, whereas the addition of a pre-treatment sotalol challenge can then be avoided. 14,30 Influence of heart rate and STV RR on STV QT 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 STV RR, was comparable between the two groups in the present study (Table 2). A positive, significant correlation between the STV QT and STV RR among control subjects was found (r s ¼ 0.664, P ¼ 0.01; n ¼ 20), which was not seen within the LQTS patient group (r s ¼ 0.2, P ¼ 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 STV LV 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 STV QT, 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 STV QT was not analysed by

5 Beat-to-beat variability of the QT interval 189 Table 2 Electrocardiographical characteristics of dlqts patients and age- and sex-matched controls dlqts Controls P-value... Group size Age, years RR, ms QRS, ms QT, ms QTc, ms STV QT, ms STV RR,ms Figure 2 Individual STV QT in patients with a history of druginduced TdP (dlqts, n ¼ 20) and their respective age- and sexmatched controls. *, Squares: mean + SD; P, 0.05 (Wilcoxon matched-pairs test) 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 These are the first results from humans showing that STV QT 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, STV QT 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, STV QT could prove to be a useful noninvasive, easily obtainable parameter aiding the identification of the proarrhythmic patient by unmasking a latent repolarization disorders in the drug-free situation. Acknowledgements 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. Funding 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 ). References 1. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350: Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, Towbin JA, Priori SG, Napolitano C, Robinson JL, Andrews M, Timothy K, Hall WJ. Age- and sex-related differences in clinical manifestations in patients with congenital long-qt syndrome: findings from the International LQTS Registry. Circulation 1998;97: Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. JInternMed2006;259: Sanguinetti MC, Tristani-Firouzi M. HERG potassium channels and cardiac arrhythmia. Nature 2006;440: Marban E. Cardiac channelopathies. Nature 2002;415: Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications Report on a Policy Conference of the European Society of Cardiology. Cardiovasc Res 2000;47: Thomsen MB, Matz J, Volders PGA, Vos MA. Assessing the proarrhythmic potential of drugs: Current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacol Ther 2006;112: Roden DM. Taking the idio out of idiosyncratic : predicting torsades de pointes. Pacing Clin Electrophysiol 1998;21: Nguyen PT, Scheinman MM, Seger J. Polymorphous ventricular tachycardia: clinical characterization, therapy, and the QT interval. Circulation 1986;74: Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med 1994;121: Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation 2001;103: Thomsen MB, Verduyn SC, Stengl M, Beekman JD, de Pater G, Van Opstal JM, Volders PG, Vos MA. Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs. Circulation 2004;110: Gbadebo TD, Trimble RW, Khoo MS, Temple J, Roden DM, Anderson ME. Calmodulin inhibitor W-7 unmasks a novel electrocardiographic parameter that predicts initiation of torsade de pointes. Circulation 2002;105:

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