Drug-induced QT prolongation and proarrhythmia: an inevitable link?
St Michael’s Hospital, University of Toronto, 30 Bond Street, 6-050Q, Toronto, Ontario M5B 1W8, Canada
* Corresponding author. E-mail address: dorianp{at}smh.toronto.on.ca
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Abstract |
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 Top Abstract IntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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One of the most feared potential adverse effects of many drugs is life threatening or fatal arrhythmia — particularly torsade de pointes (TdP) ventricular tachycardia in conjunction with QT prolongation. To fully understand the implications of QT prolongation, it is essential to have an understanding of the ion currents that comprise repolarization and their relation to electrophysiological abnormalities associated with TdP. Also, the QT interval is subject to patient-specific and sometimes idiosyncratic variability. The following questions are addressed: How close is the relationship between QT prolongation and proarrhythmia? How accurately do QT-interval measurements reflect cardiac repolarization? How representative is a single QT measurement with respect to the QT response to a drug? The presumed relationship between the QT interval and myocardial repolarization will be deconstructed, demonstrating that most of the important aspects of repolarization, and subsequent arrhythmogenesis, cannot be understood only through the simple numerical measurement of the QT interval. Repolarization reserve is also discussed. Suggestions for refining the understanding of drug-induced QT prolongation, TdP, and shortcomings of some current definitions are outlined. We speculate on possible future developments in understanding this relationship.
Key Words: QT measurement, Torsade de pointes, Repolarization reserve
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Introduction |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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The road to regulatory approval and clinical acceptance and use of a drug is fraught with pitfalls and perils. One of the most feared potential adverse effects of many drugs is life threatening or fatal arrhythmia — particularly torsade de pointes (TdP) ventricular tachycardia (VT). Given the consequences (death and disability), clinicians, basic scientists, and developers of drugs are strongly compelled to forestall these problems. Prolongation of the QT interval has been assumed to be reflective of the risk of proarrhythmia associated with administration of a given drug. It can make or break a drug — either at the level of the physician prescribing for a specific patient, or a regulator faced with a decision regarding approval or rejection of a drug. Regulators have published detailed guidelines for drug developers on the assessment of QT intervals for new drugs in development (thorough QT study).1
In the clinical setting, the effect on QT interval and the perceived risk will sometimes supersede the potential benefit of a drug in making a decision regarding ongoing therapy. In this paper, we will discuss the relationship between QT prolongation and TdP. We will address the following questions: How close is the relationship between QT prolongation and proarrhythmia? How accurately do QT-interval measurements reflect cardiac repolarization? How representative is a single QT measurement with respect to the QT response to a drug?
The presumed relationship between the QT interval and myocardial repolarization will be deconstructed, demonstrating that most of the important aspects of repolarization, and subsequent arrhythmogenesis, cannot be understood only through the simple numerical measurement of the QT interval. Furthermore, the degree of myocardial substrate abnormalities and the frequency of TdP triggers (early afterdepolarizations: EADs) are not directly related to the degree of QT prolongation. The effects of drugs on ion channels are compared and contrasted with effects on the QT interval.
We discuss the concept of repolarization reserve — a kind of backup system to compensate for perturbations of myocardial repolarization. If it is impaired, QT prolongation and TdP may never occur in a baseline state, but may only be brought out during times of repolarization stress.
Finally, we outline suggestions for refining the understanding of drug-induced QT prolongation, TdP, and shortcomings of some current definitions. We speculate on possible future developments in understanding this relationship.
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Measuring the QT interval accurately: technical and conceptual difficulties |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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The QT interval is simple to measure on paper, but can be very difficult to measure accurately and reproducibly between observers, between patients, and in the same patient at different time points. The standard definition of the QT interval is the interval from the beginning of the QRS complex to the end of the T wave. On an electrocardiogram (ECG) lead with a normal QRS complex, and a distinct and uniphasic T wave, this is straightforward to measure. However, even this is difficult to reproducibly measure in practice.2
Alterations in the QRST complex introduce uncertainty into the measurement; in addition, QRS abnormalities such as bundle-branch block will lengthen the QT interval without necessarily altering repolarization. Investigators have attempted to establish QT/QRS duration relationships, and in some studies, QRS duration has accounted for up to 16% of the variation in the QT interval.3 The T wave may be bifid or even biphasic. Compensations such as measuring the extrapolated end of the T wave or the initial return to baseline of a bifid T wave are used,4 but definite values for normal extrapolated QT intervals in this setting are also not established. Late repolarization waves may be part of the T wave and included in the QT interval, or considered a separate U wave and excluded. Whether total repolarization time should include the entire Q–TU complex has been the subject of controversy.5
Measuring the QT interval in one lead can only result in underestimation. Considerable variation in the QT interval can occur from lead-to-lead on an ECG and in some instances such a spatial QT dispersion can be predictive of prognosis. For example, increased QT dispersion has been correlated with ventricular arrhythmias in the early post-myocardial infarction period.6 QT dispersion has been theorized to be a surrogate of repolarization anisotropy in the heart — an established risk factor for the initiation of ventricular arrhythmias. QT dispersion, however, may be due to factors other than anisotropy itself. The orientation of ECG leads with respect to the T-wave axis and proximity of different leads to the heart will cause QT variation. The importance of QT dispersion in the setting of drug evaluation for proarrhythmia is therefore not known (and is sometimes called into question), even though dispersion of repolarization is known to be arrhythmogenic.7
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More QT measurement difficulties: intra-patient QT variability |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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The QT interval lengthens with decreasing heart rate. It also prolongs with sleep and with position (supine — increase vs. standing — decrease).8
The QT prolongation observed in practice may therefore differ from that measured under laboratory conditions. The QT interval at the exact time of development of TdP arrhythmia is of particular importance. It is (by definition) prolonged, but often the QT of the penultimate beat on whose T wave the first beat of TdP falls is much longer than the QT interval before the pause, which initiates the TdP9. Numerous formulas (Bazett, Fridericia, etc.) exist to correct for rate-related changes in QT to reveal the ‘true’ underlying QT interval. The assumption that formulas can accurately correct for heart rate depends on properties of the QT/RR relationship, which turn out not to be present: first, that the QT/RR relationship is easily predictable across a wide variety of heart rates; and second, that the QT/RR relationship is the same from patient to patient. Furthermore, QT dynamics even for a single healthy human subject are complex and are affected by factors, such as (but not limited to) position, sleep, autonomic tone, exercise, and electrolyte and fluid status. Idiosyncratic and unexpected lengthening of the QT interval has also been documented, and in some cases, this heralds the development of TdP. These intra-patient variations in the QT interval (in contrast to inter-patient QT variability) cannot be captured on a single 12-lead ECG, which may be taken to evaluate the effect of a drug on the QT interval. Isolated measurements of the QT interval without reference to these complicated QT dynamics can lead to inaccurate estimations of the risk of TdP.
The intra-patient variability in the QT interval can be appreciated by examining Holter recordings of even a small group of healthy subjects. In a study of 53 individuals, serial 10 s ECGs were recorded over daytime hours and 200 ECGs from each subject were selected for analysis to model hypothetical QTc prolongation by a drug. The accuracy of several QT correction formulas was assessed. Individual patient-derived formulas for QTc were significantly more accurate than either whole study population-derived or Bazett and Fridericia correction formulas.10 In another study of healthy subjects, considerable intra-subject variation in the QT interval was found, which was not explicable by RR interval alone over a period of 24 h in the subjects studied. Although the authors did not report on subject-specific QT/RR relationships, there was more QT variability during the day than would be expected for RR variability. Linear models were not adequate to model the QT/RR relationship, but the application of non-linear models did not improve the prediction model significantly, emphasizing the complexity inherent in the relationship.11
In a study comparing long QT syndrome (LQTS) patients, differences in QT variation (day vs. night) were seen among LQT1, 2, and 3 genotypes. Overall, LQT2 patients exhibited significantly less day/night QT variability than the other groups (independent of heart rate). LQT1 patients had a small, but significant QT shortening during sleep, whereas LQT3 patients had a marked, significant prolongation of QT during sleep. Mechanistically, this is congruent with the observed increase in sudden cardiac death among LQT3 patients at night.12
Paroxysmal QT lengthening
Even the most accurate QT/RR modelling cannot account for what appear to be idiosyncratic and abrupt changes in the QT/RR relationship in specific patients immediately prior to documented TdP. In patients with acquired LQTS, mostly due to class I and class III antiarrhythmic drugs, and multiple episodes of TdP, the QT interval for the inciting beat was longer than would be predicted from prior or subsequent beats at the same RR interval. Thus, QT prolongation was not solely a function of the RR interval and the speed at which the QT adapted to changes in RR was variable, complex, and not adequately accounted for by short-term QT–RR patterning.13 In a group of congenital LQTS patients, 111 episodes of TdP were recorded. Most episodes (65%) started with the typical short-long-short pattern of initiation [short RR, pause, short-coupled premature ventricular contraction (PVC)], but 25% of episodes started with an increased sinus rate pattern — a gradual increase in sinus rate with a PVC then initiating TdP, and the remaining 10% of events were preceded by an alteration in depolarization, usually a PVC, followed by a longer coupled PVC initiating TdP.14 Other factors such as notching of the TU complex to a greater degree just before TdP compared with 6–24 h before onset have also been observed.15
These investigations demonstrate that the QT interval and the QTc are not a static quantity that can be measured at an index point (e.g. 12-lead ECG during drug evaluation) and then assumed to be the same at all time points. Each individual’s QT/RR relationship appears to be unique and not adequately modelled by simple correction formulas. In addition, idiosyncratic, sudden changes in the QT interval can occur, which are not accounted for by QT/RR predictors specific for an individual. Clearly, these unforeseen QT changes can immediately precede the development of TdP and may never be detected with conventional screening methods.
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QT interval vs. myocardial repolarization |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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Repolarization can refer to the time from depolarization of a myocyte to the return to baseline of the membrane potential (action potential duration: APD) or the time from the onset of depolarization of a whole heart to the return to resting potential of all myocytes. APD is due to the balance of ionic currents in each cell, whereas its supposed surrogate — the QT interval — is due to the ongoing presence of a repolarization gradient between cells [endocardium–epicardium, base–apex, left ventricle (LV)–right ventricle (RV)], resulting from differences in the moment of activation of cells and local APD. If the APD in all cells in the heart were exactly identical, a depolarization gradient would result in an identical repolarization gradient.
APD differs depending on anatomic location within the ventricle. Yan and Antzelevitch16 first described in detail the differing APDs in different transmural layers of the ventricular myocardium. Importantly, the end of the T wave on the surface ECG was suggested to correspond to the end of the mid-myocardial (M)-cell action potential (AP). Infusion of d-sotalol caused an increase in M-cell APD by 90 ms over control vs. an increase of only 50 ms in the epicardial cell layer. This transmural dispersion of repolarization (TDR; the time difference between the shortest and longest APs across a layer of myocardium) was later implicated in arrhythmogenesis in patients with LQTS, and also in arrhythmogenesis with d-sotalol and Na+ channel-activating agents. Testing of drugs by examining only the QT interval, or conversely by examining the effect on APD using only one myocardial cell type, can overlook the drug effect on TDR, which appears to be necessary for creating the substrate for TdP.
The Tpeak–Tend interval (the time from the peak of the T wave to its return to baseline) has been shown to correlate well with the TDR.16,17 Its prolongation is directly related to TDR in a canine LV wedge model and it is predictive of TdP during infusion of cisapride.18 It was also prolonged and predicted TdP in rabbits treated with dofetilide.19
In summary, a presumed feature of the QT interval linking it to TdP is that the duration of the QT interval is the same as the duration of repolarization throughout the whole heart. The examples above show that there are many components to cardiac repolarization beyond just its duration. The QT interval reflects heterogeneity in repolarization, as well as the latest area (relative to the onset of depolarization) to repolarize, whereas the TDR is one of the most important predictors of proarrhythmia.20 The QT interval also cannot be linked reliably to just one repolarizing current (IKr) arising from one ion channel (human ether-a-go-go-related gene: HERG).
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Torsade de pointes: a syndrome rather than an arrhythmia |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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The link between QT prolongation and TdP is strongly engrained. There is not a clear, linear incremental relationship between QT prolongation and the risk of TdP, although the TdP risk tends to be clearly higher at the extremes of QT prolongation. To examine why the QT prolongation/TdP relationship is not monotonic, it is necessary to examine the pathogenesis of TdP itself.
TdP is traditionally described as an arrhythmia with the following features: QT prolongation of the beat prior to the initiating beat, a long- and short-coupling interval preceding the pre-initiating and the initiating beat, respectively, and the subsequent development of a polymorphic VT, with an axis undulating above and below the baseline. Not all instances of long–short coupled beats with a long QT produce TdP. Also, polymorphic VT can sometimes arise without obvious QT prolongation. What is unique about TdP? The reasons lie beneath the features seen on the surface ECG.
Arguably, TdP is better thought of as a syndrome, rather than just an arrhythmia.21 The features of the syndrome include ECG, clinical, and pathological components: QT prolongation, a pause-dependent increase in the abnormality of the QT interval and T-wave morphology, and VT (which does not always have to be polymorphic). Pathologically, conditions for triggered activity and re-entry must exist — this usually entails enough functional Na+ and Ca2+ channels to produce afterdepolarizations, in addition to dispersion of repolarization (usually transmural dispersion, but apex–base and RV–LV are also contributors). The specific patient must also have sufficient variability in their QT interval to allow for critical prolongation to occur and cause polymorphic VT (with a properly timed EAD).
The arrhythmia is difficult to reproduce in the electrophysiology laboratory in a controlled fashion, so knowledge of it comes from retrospective analysis of patients presenting with it (study of ECG and clinical factors) and from animal models. Consistent features of the substrate, the trigger, and the mechanism of perpetuation of the arrhythmia are notable. With respect to substrate, repolarization delay and inhomogeneity contribute both to the triggering event (the EAD) and the perpetuation of polymorphic VT. Clinically, the main manifestation of the abnormal electrical substrate has been the prolonged QT interval associated with the syndrome.22,23 Animal models confirmed the necessity of long QT, but more importantly the dispersion of repolarization. Studies in canine LV wedge preparations confirmed transmural dispersion and linked its presence and degree to the likelihood of TdP. In addition, these studies demonstrated that QT prolongation can occur in the presence of drugs such as amiodarone, but the dispersion of repolarization is not present to the same degree, and TdP is much less common.24,25
Initiating PVCs are also noted in early clinical reports of the arrhythmia and are a component of the long–short initiation sequences. Their pathophysiology gains greater significance when put in the context of the TdP syndrome. Repolarization delay is necessary to allow for late-plateau depolarizing currents (e.g. Ca2+ and Na+ currents) to initiate APs. Indeed, in animal models, a prerequisite for the formation of EADs is repolarization delay, which allows for these currents.26 The presence of an outward Ca2+ current is also necessary, as the initiating inward Na+ current is thought to be produced by the Na+/Ca2+ exchanger.27 The anatomic origin can also be traced to late-repolarizing Purkinje or M fibres.28 Removing the late-plateau depolarizing currents from the clinical or laboratory picture (e.g. by compounds that block the late INa) stops the EADs and also prevents TdP.29
Finally, the substrate functions to maintain TdP once it starts. In an intact canine heart model, TdP was studied using the sea anemone toxins ATX-II or anthopleurin-A, which slow the inactivation of the late Na+ current, to simulate LQT3. Results confirmed the presence of TDR, and EADs initiated undulating re-entry circuits — possible only with the anisotropic substrate. Bifurcation of the original circuit into separate right and left ventricular circuits was responsible for the morphology of the arrhythmia on the surface ECG.30
Conceptualizing TdP as a syndrome has relevance to drug development. Even if TdP is not observed in the laboratory or clinic, if a compound gives rise to the elements of the syndrome, without the actual arrhythmia, a high index of suspicion should be raised about the possible proarrhythmic potential. The opposite inference may not be as easy — i.e. if a drug prolongs QT, but is never associated with EADs, pauses, or marked TDR, TdP may be rare.
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Drug-induced QT prolongation and drug effects on ionic currents |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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Because it is complicated and expensive to measure QT prolongation in intact whole hearts for every compound in pre-clinical development, several laboratory measures are used, which are assumed to predict changes in QT interval. The delayed rectifier current (IKr) is a major contributor to APD and is carried by HERG potassium channels. HERG blockade (assessed by IC50 assays) is assumed to translate into increased APD. The HERG block–APD prolongation relationship is complex. In a canine Purkinje fibre model, Martin et al.31
demonstrated the lack of a reliable correlation between drug concentration, HERG block, and prolongation of APD. Haloperidol was assessed for HERG block and for APD prolongation. HERG block increased in a concentration-dependent manner; APD prolongation occurred at lower concentrations (0.026 and 0.26 µM), but at high concentrations (2.66 µM), the APD actually shortened and its configuration changed (triangulation, lower plateau). Individual features of the AP configuration changes were re-created with nifedipine (Ca2+ channel block), lidocaine (late Na+ channel block), and dofetilide (IKr block). Another experiment tested 10 different drugs for HERG block. Progressive HERG block was exhibited in 9 of the 10 drugs, with increasing supratherapeutic concentrations, but only 4 of 10 demonstrated convincing monotonic concentration-dependent APD prolongation with increasing HERG block. This lack of a strong correlation probably occurred due to multi-channel block at higher drug concentrations. The potency of HERG block may overestimate the effect on APD if other depolarizing currents are inhibited (e.g. L-type calcium channels) and may underestimate the effect if other repolarizing currents are also inhibited [e.g. slowly activating delayed rectifier current (IKs) and transient outward current (Ito)].
Comparing ion current effects: bepridil vs. ranolazine
Bepridil and ranolazine are Ca2+ channel blockers that both prolong the QT interval but have very different torsadogenic properties. Bepridil is an anti-anginal agent whose primary mode of action is through Ca2+ channel blockade. It also blocks multiple ion channels, resulting in APD and QT prolongation. It has little effect on QRS duration and His-ventricular interval — effects that would be expected for a class I agent (even though it blocks Na+ channels). An average of 30 ms QTc-interval prolongation is observed; 80% of patients taking the drug can expect to have some QTc prolongation, with 5% experiencing prolongation >25% above baseline. As reports of proarrhythmia (including TdP) increased, recommendations for careful patient selection were made, but the drug was eventually withdrawn from the market due to the proarrhythmic risk.32,33
Bepridil increases TDR (from 100 ± 40 to 160 ± 50),34 possibly by block of both INa and IKs.35,36 In a dog model, bepridil decreased the amplitude of Purkinje EADs at short rather than long-cycle lengths.37 Conversely, if the amplitude is increased at long-cycle lengths, then this provides a trigger for TdP in the setting of an altered substrate — this inference is speculative but would be consistent with the reverse-use dependence, which is common in QT prolonging drugs that result in TdP.
Ranolazine is an anti-anginal agent, which also has complex electrophysiological properties. It has been observed clinically to modestly prolong the QT interval from 277 to 307 ms in canine cardiac wedge preparations.38 In contrast to bepridil, however, EADs were decreased with increasing ranolazine concentrations, and TdP could not be induced with extra stimulation at any concentration of ranolazine, despite a dose-dependent increase in QT interval. In the presence of ranolazine (100 mM), TDR actually decreased from 33 (control) to 28 ms. Although IKs and IKr were significantly inhibited in most cardiac fibres, overall the APD was not prolonged and was actually abbreviated in mid-myocardial cells, thus averting an increased TDR. In addition, the late sodium current was preferentially inhibited by ranolazine (the late INa current density is higher in mid-myocardial cells), as well as the INa–Ca exchange current — important in the genesis of EADs. Overall, a fortuitous combination of multi-channel block resulted in a more stable substrate (reduced TDR) and fewer triggers — decreased EADs. Hence TdP was not inducible in ranolazine-treated wedge preparations in spite of a longer QT. In human clinical trials, modest QT prolongation has been observed, but there were no reports of TdP arrhythmia, or of ranolazine discontinuation due to QT prolongation.39
Comparing ion current effects: amiodarone vs. sotalol
Amiodarone and sotalol provide an illustrative contrast between two class III drugs that prolong the QT interval but have very different arrhythmogenic effects. Sotalol is well known to cause ventricular arrhythmias and the incidence of TdP ranges from 1 to 5%.40 Risk factors for TdP include bradycardia, hypokalaemia, hypomagnesaemia, ventricular hypertrophy, female gender, and prolongation of repolarization mainly through a higher frequency of EADs. Other risk factors include renal failure and pre-existing QT prolongation. In a rabbit model in vitro, both amiodarone and sotalol increased the QT interval. However, TDR was increased by sotalol, but not by amiodarone, and reverse-use dependence, the property of more marked QT prolongation with slower rate, was seen with sotalol but not with amiodarone. Furthermore, triangulation of the AP, via preferential prolongation of phase 3 over phase 2, was observed with sotalol, but not with amiodarone.41 Clinically, QT prolongation and TdP with sotalol are well documented, whereas amiodarone is infrequently associated with TdP.42
From these examples, it is clear that QT prolongation does not translate directly into easily predictable effects on ionic currents, cellular repolarization and tissue repolarization changes, and proarrhythmia. Instead, assessment of specific ion currents and their integrated effects on the AP provides a better insight into why certain drugs may promote or protect against TdP.
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Repolarization reserve |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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It is clear that cardiac repolarization (as represented by the QT interval) is not the same for each heartbeat. Repolarization stressors may be intrinsic or extrinsic to the myocardium. Their effect may be to delay the entire process of repolarization (e.g. a potent multi-channel blocking drug) or only a component current of it at a specific location within the heart (e.g. an IKr blocker that preferentially works in mid-myocardial cells). The capacity for the maintenance of myocardial repolarization in the face of some degree of inhibition of repolarization has been termed repolarization reserve.43
Repolarization reserve is increasingly relevant to understanding the differences between patients in their response to a QT-prolonging drug and the incidence of TdP.
The speed, strength, and duration of ionic currents involved in cardiac depolarization and repolarization can be explained teleologically. The depolarizing current needs to be rapid, synchronous, and co-ordinated over the myocardium, and the phase 0 Na+ current fulfils this role. The subsequent phases must then allow for an adequate duration of excitation–contraction coupling (phase 2), and then a co-ordinated re-setting of the cell membrane voltage so that the process can be repeated (phase 3). It is mainly during phase 3 that the synchrony, duration, and strength of repolarizing currents can be disrupted, creating the substrate for TdP (e.g. TDR) and/or the triggers for it (EADs). During repolarization, stressors on the balance of inward (Ca2+, Na+) and outward (K+) currents can come from many sources. They include, but are not limited to, genetic abnormalities, e.g. inadequate outward potassium current (KVLQT1, HERG ion channel defects) or excessive, prolonged inward sodium current (SCN5A ion channel defect); defective ion channel deployment and trafficking to the cell membrane; lag in upregulation of outward current after increases in heart rate (including patient-specific differences in QT adaptation to heart rate — QT hysteresis)44; pharmacological or toxin-mediated block of repolarizing currents; electrolyte abnormalities (hypokalaemia or hypomagnesaemia); disruptions of autonomic nervous system output that can occur with central nervous system lesions. Understandably, reserve currents have evolved that are capable of being recruited in order to compensate for these disruptions.45
Efflux of potassium is recognized as the major current contributing to repolarization. In most cases (including those described earlier), it is a block of the potassium current that leads to an AP and QT prolongation on the surface ECG. The potassium efflux would be particularly vulnerable if it were mediated by one current/channel, however, the discovery that the delayed rectifier potassium current (IK) is composed of two currents/channels (IKr/IKs and HERG/KVLQT1 with associated proteins) allows for the possibility that evolution has provided for some redundancy in the potassium efflux that can be activated during times of repolarization stress.46
Some representative investigations serve to illustrate the role of IKs as the reserve repolarization current. In computer modelling of the IKs current and the KCNQ1 ion channel in virtual myocytes, IKs was activated (recruited) more quickly at faster-pacing rates, held in an activated (but not open) state during times of increased IKr activation, and increased gradually by 
50% in the setting of IKr block. The KCNE subunit of the channel appeared to be responsible for mediating this reserve behaviour.47 In human myocytes, IKs blockers on their own did not cause marked APD lengthening, but when given with IKr blockers or sympathetic stimulation, significant APD lengthening occurred.48 These findings support the ability of IKs to be recruited during times of IKr block or inadequacy. One of the mechanisms for IKs recruitment may be activation triggered by Ca2+, mediated by an interaction with calmodulin. A specific LQT1 mutation impairs the binding of KCNQ1 with calmodulin — rendering it Ca2+ insensitive and allowing for excessive QT prolongation due to inadequate K+ efflux.49
In the presence of impairment of IKs, IKr block is more likely to cause TdP. In rabbits with atrioventricular block, slow pacing (60–90 bpm) caused IKs and IKr downregulation, but fast pacing (350–370 bpm) caused only IKs downregulation. Continuous monitoring revealed spontaneous TdP in 75% of rabbits with slow pacing, but only isolated ventricular ectopy in rabbits with fast pacing. Administration of dofetilide (0.02 mg/kg) to mimic IKr downregulation produced ultimately lethal TdP in all fast-paced rabbits.50
In another rabbit model, dofetilide (IKr blocker) prolonged APD90 in a concentration-dependent manner with reverse-rate dependence (increased prolongation at slower rates). In contrast, HMR 1556 (IKs blocker) alone did not prolong APD90. However, in the presence of dofetilide, HMR 1556 further prolonged the APD and increased the extent of reverse-rate dependence, demonstrating that in the presence of IKr block, IKs current becomes increasingly important for repolarization.51 The ultimate consequences of IKr block are modulated by IKs current density. This reserve is determined by both genotype and drug effects.
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Conclusions |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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The relationship between a drug (or class of drugs), the QT interval, and the development of TdP is complicated, and in some cases, it may be unpredictable. This causes formidable challenges in drug development and in the reassessment of existing drugs for their propensity towards proarrhythmia. However, the need for newer and more effective anti-arrhythmic drugs is ongoing, as is the need for new agents in all areas of medicine.
Because of its relative ease of measurement compared with other indices, the QT interval will, for the foreseeable future, remain as a clinical surrogate for proarrhythmia liability — imperfect as it is. Its measurement could be improved by sampling a larger number of QT intervals (particularly during new drug testing), and refining methods for accurate, precise, and reproducible measurement of the QT interval.
Better surrogates are needed for pre-clinical screening of the proarrhythmic liability of new compounds.52 Hondeghem53 proposes a system for evaluating propensity to proarrhythmia, using four characteristics, measured in an in vitro rabbit heart preparation: (i) triangulation of the AP (increasing time from APD30 to APD90) can be present with lengthened, shortened, or unchanged total QT interval54; (ii) instability of the AP (beat-to-beat variation in its duration) is a marker of myocardium prone to TdP; this can be assessed using the QT/RR slope (a steeper slope implies a higher risk for arrhythmia); (iii) reverse-rate dependence, manifested by a shortened QT interval at fast rates and a longer QT interval at slow rates while a drug is administered, is correlated with arrhythmia; (iv) dispersion (i.e. TDR) is a clear predictor of arrhythmia as it facilitates EADs and re-entry in TdP.53
A comprehensive method to assess the potential for TdP could include:
- in vitro indicators — AP triangulation, APD instability, reverse-rate dependence;
- drugs or interventions that diminish repolarization reserve — testing of the new drug in the presence of IKs block;
- non-invasive assessment of TDR in humans — measurement of the Tpeak–Tend interval (the difference between QT interval and QT wave–peak interval) and the late T-wave area (the area under the T wave from its peak to its end).
Clinicians, scientists, and drug manufacturers have an enormous stake in the satisfactory evaluation of drugs in development for QT prolongation and potential TdP. Laboratory and clinical assessment of drugs so far has shown that such an evaluation is complex and multifaceted. To fully understand the implications of QT prolongation, it is essential to have an understanding of the ion currents that comprise it and lead to TdP-inducing substrate abnormalities; its potential for patient-specific and sometimes idiosyncratic variability; and the importance of reserve currents in maintaining adequate repolarization when the primary mechanisms are impaired. Emerging technologies may improve the predictive accuracy further.54 It is hoped that these new approaches will more accurately warn of a high risk of TdP earlier on in a drug’s development (particularly in the absence of a markedly prolonged QT interval) and, in selected cases, allow for the continued development of drugs with QT prolongation but other features which mitigate the risk of TdP.
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Acknowledgements |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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We are indebted to Marta Boszko, who provided invaluable assistance in the preparation of this manuscript.
Conflict of interest: P.D. has received grant support or consulting fees from Sanofi-Aventis, AstraZeneca, Proctor and Gamble, and Cardiome.
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References |
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TopAbstractIntroductionMeasuring the QT interval...More QT measurement...QT interval vs. myocardial...Torsade de pointes: a...Drug-induced QT prolongation and...Repolarization reserveConclusionsAcknowledgementsReferences |
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[1] Shah RR. Drugs, QTc interval prolongation and final ICH E14 guideline: an important milestone with challenges ahead. Drug Saf (2005) 28:1009–28.[CrossRef][Web of Science][Medline]
[2] Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm (2005) 2:569–74.[CrossRef][Web of Science][Medline]
[3] Zhou SH, Wong S, Rautaharju PM, Karnik N, Calhoun HP. Should the JT rather than the QT interval be used to detect prolongation of ventricular repolarization? An assessment in normal conduction and in ventricular conduction defects. J Electrocardiol (1992) 25(Suppl):131–6.[CrossRef][Web of Science][Medline]
[4] Lanjewar P, Pathak V, Lokhandwala Y. Issues in QT interval measurement. Indian Pacing Electrophysiol J (2004) 4:156–61.[Medline]
[5] Ritsema van Eck HJ, Kors JA, van Herpen G. The U wave in the electrocardiogram: a solution for a 100-year-old riddle. Cardiovasc Res (2005) 67:256–62.
[6] Zaputovic L, Mavric Z, Zaninovic-Jurjevic T, Matana A, Bradic N. Relationship between QT dispersion and the incidence of early ventricular arrhythmias in patients with acute myocardial infarction. Int J Cardiol (1997) 62:211–6.[CrossRef][Web of Science][Medline]
[7] Sahu P, Lim PO, Rana BS, Struthers AD. QT dispersion in medicine: electrophysiological holy grail or fool’s gold? QJM (2000) 93:425–31.
[8] Williams GC, Dunnington KM, Hu MY, Zimmerman TR Jr, Wang Z, Hafner KB, et al. The impact of posture on cardiac repolarization: more than heart rate? J Cardiovasc Electrophysiol (2006) 17:352–8.[CrossRef][Web of Science][Medline]
[9] Nikhilanandhan J, Wulffhart Z, Barr A, Newman D, Dorian P. QT interval and QTU morphology effectively predict torsades de pointes polymorphic ventricular tachycardia. (Abstract). Pacing Clin Electrophysiol (1999) 22:715.
[10] Malik M, Hnatkova K, Batchvarov V. Differences between study-specific and subject-specific heart rate corrections of the QT interval in investigations of drug induced QTc prolongation. Pacing Clin Electrophysiol (2004) 27:791–800.[CrossRef][Medline]
[11] Jensen BT, Larroude CE, Rasmussen LP, Holstein-Rathlou NH, Hojgaard MV, Agner E, et al. Beat-to-beat QT dynamics in healthy subjects. Ann Noninvasive Electrocardiol (2004) 9:3–11.[CrossRef][Web of Science][Medline]
[12] Stramba-Badiale M, Priori SG, Napolitano C, Locati EH, Vinolas X, Haverkamp W, et al. Gene-specific differences in the circadian variation of ventricular repolarization in the long QT syndrome: a key to sudden death during sleep? Ital Heart J (2000) 1:323–8.[Medline]
[13] Gilmour RF Jr, Riccio ML, Locati EH, Maison-Blanche P, Coumel P, Schwartz PJ. Time- and rate-dependent alterations of the QT interval precede the onset of torsade de pointes in patients with acquired QT prolongation. J Am Coll Cardiol (1997) 30:209–17.[Abstract]
[14] Noda T, Shimizu W, Satomi K, Suyama K, Kurita T, Aihara N, et al. Classification and mechanism of torsade de pointes initiation in patients with congenital long QT syndrome. Eur Heart J (2004) 25:2149–54.
[15] Takahashi N, Ito M, Inoue T, Koumatsu K, Takeshita Y, Tsumabuki S, et al. Torsades de pointes associated with acquired long QT syndrome: observation of 7 cases. J Cardiol (1993) 23:99–106.[Web of Science][Medline]
[16] Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation (1998) 98:1928–36.
[17] Zabel M, Portnoy S, Franz MR. Electrocardiographic indexes of dispersion of ventricular repolarization: an isolated heart validation study. J Am Coll Cardiol (1995) 25:746–52.[Abstract]
[18] Di Diego JM, Belardinelli L, Antzelevitch C. Cisapride-induced transmural dispersion of repolarization and torsade de pointes in the canine left ventricular wedge preparation during epicardial stimulation. Circulation (2003) 108:1027–33.
[19] Nalivaiko E, De Pasquale CG, Blessing WW. Ventricular arrhythmias triggered by alerting stimuli in conscious rabbits pre-treated with dofetilide. Basic Res Cardiol (2004) 99:142–51.[CrossRef][Web of Science][Medline]
[20] Antzelevitch C. Modulation of transmural repolarization. Ann NY Acad Sci (2005) 1047:314–23.[CrossRef][Web of Science][Medline]
[21] Curtis MJ. Torsades de pointes: arrhythmia, syndrome, or chimera? A perspective in the light of the Lambeth Conventions. Cardiovasc Drugs Ther (1991) 5:191–200.[Web of Science][Medline]
[22] Jenzer HR, Hagemeijer F. Quinidine syncope: torsade de pointes with low quinidine plasma concentrations. Eur J Cardiol (1976) 4:447–51.[Web of Science][Medline]
[23] Smith WM, Gallagher JJ. "Les torsade de pointes": an unusual ventricular arrhythmia. Ann Intern Med (1980) 93:578–84.
[24] Antzelevitch C. Role of transmural dispersion of repolarization in the genesis of drug-induced torsade de pointes. Heart Rhythm (2005) 2:S9–15.[Web of Science][Medline]
[25] van Opstal JM, Schoenmakers M, Verduyn SC, de Groot SH, Leunissen JD, Der Hulst FF, et al. Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation (2001) 104:2722–7.
[26] January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res (1989) 64:977–90.
[27] Choi BR, Burton F, Salama G. Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome. J Physiol (2002) 543:615–31.
[28] Antzelevitch C. Cellular basis and mechanism underlying normal and abnormal myocardial repolarization and arrhythmogenesis. Ann Med (2004) 36(Suppl 1):5–14.[CrossRef][Web of Science][Medline]
[29] Fedida D, Orth PM, Hesketh JC, Ezrin AM. The role of late I and antiarrhythmic drugs in EAD formation and termination in Purkinje fibers. J Cardiovasc Electrophysiol (2006) 17:S71–8.[CrossRef][Medline]
[30] Chinushi M, Restivo M, Caref EB, El Sherif N. Electrophysiological basis of arrhythmogenicity of QT/T alternans in the long-QT syndrome: tridimensional analysis of the kinetics of cardiac repolarization. Circ Res (1998) 83:614–28.
[31] Martin RL, McDermott JS, Salmen HJ, Palmatier J, Cox BF, Gintant GA. The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block. J Cardiovasc Pharmacol (2004) 43:369–79.[CrossRef][Web of Science][Medline]
[32] Prystowsky EN. Effects of bepridil on cardiac electrophysiologic properties. Am J Cardiol (1992) 69:63D–67D.[Medline]
[33] Singh BN. Safety profile of bepridil determined from clinical trials in chronic stable angina in the United States. Am J Cardiol (1992) 69:68D–74D.[CrossRef][Medline]
[34] Yoshiga Y, Shimizu A, Yamagata T, Hayano T, Ueyama T, Ohmura M, et al. Beta-blocker decreases the increase in QT dispersion and transmural dispersion of repolarization induced by bepridil. Circ J (2002) 66:1024–8.[CrossRef][Web of Science][Medline]
[35] Sato N, Nishimura M, Kawamura Y, Ward CA, Kikuchi K. Block of Na+ channel by bepridil in isolated guinea-pig ventricular myocytes. Eur J Pharmacol (1996) 314:373–9.[CrossRef][Web of Science][Medline]
[36] Chouabe C, Drici MD, Romey G, Barhanin J. Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs. Therapie (2000) 55:195–202.[Web of Science][Medline]
[37] Kane KA, Berdeja Garcia GY, Sanchez-Perez S, Pastelin G. Electrophysiological effects of lidocaine, L-chlorpheniramine, and bepridil on normal and ouabain-intoxicated canine Purkinje fibers. J Cardiovasc Pharmacol (1983) 5:109–15.[Web of Science][Medline]
[38] Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation (2004) 110:904–10.
[39] Siddiqui MA, Keam SJ. Ranolazine: a review of its use in chronic stable angina pectoris. Drugs (2006) 66:693–710.[CrossRef][Web of Science][Medline]
[40] Brendorp B, Pedersen O, Torp-Pedersen C, Sahebzadah N, Kober L. A benefit–risk assessment of class III antiarrhythmic agents. Drug Saf (2002) 25:847–65.[CrossRef][Web of Science][Medline]
[41] Milberg P, Ramtin S, Monnig G, Osada N, Wasmer K, Breithardt G, et al. Comparison of the in vitro electrophysiologic and proarrhythmic effects of amiodarone and sotalol in a rabbit model of acute atrioventricular block. J Cardiovasc Pharmacol (2004) 44:278–86.[CrossRef][Web of Science][Medline]
[42] Singh BN. Amiodarone: a multifaceted antiarrhythmic drug. Curr Cardiol Rep (2006) 8:349–55.[CrossRef][Medline]
[43] Roden DM. Long QT syndrome: reduced repolarization reserve and the genetic link. J Intern Med (2006) 259:59–69.[CrossRef][Web of Science][Medline]
[44] Smetana P, Pueyo E, Hnatkova K, Batchvarov V, Laguna P, Malik M. Individual patterns of dynamic QT/RR relationship in survivors of acute myocardial infarction and their relationship to antiarrhythmic efficacy of amiodarone. J Cardiovasc Electrophysiol (2004) 15:1147–54.[CrossRef][Web of Science][Medline]
[45] Rudy Y, Silva JR. Computational biology in the study of cardiac ion channels and cell electrophysiology. Q Rev Biophys (2006) 39:57–116.[CrossRef][Web of Science][Medline]
[46] Roden DM, Yang T. Protecting the heart against arrhythmias: potassium current physiology and repolarization reserve. Circulation (2005) 112:1376–8.
[47] Silva J, Rudy Y. Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve. Circulation (2005) 112:1384–91.
[48] Jost N, Virag L, Bitay M, Takacs J, Lengyel C, Biliczki P, et al. Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation (2005) 112:1392–9.
[49] Shamgar L, Ma L, Schmitt N, Haitin Y, Peretz A, Wiener R, et al. Calmodulin is essential for cardiac IKS channel gating and assembly: impaired function in long-QT mutations. Circ Res (2006) 98:1055–63.
[50] Tsuji Y, Zicha S, Qi XY, Kodama I, Nattel S. Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-rectifier changes. Circulation (2006) 113:345–55.
[51] So PP, Hu XD, Backx PH, Puglisi JL, Dorian P. Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles. Br J Pharmacol (2006) 148:255–63.[CrossRef][Web of Science][Medline]
[52] Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res (2003) 58:32–45.
[53] Hondeghem LM. Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs. J Cardiovasc Electrophysiol (2006) 17:337–40.[CrossRef][Web of Science][Medline]
[54] Shah RR, Hondeghem LM. Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm (2005) 2:758–72.[CrossRef][Web of Science][Medline]
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