Sympathetic modulation of the long QT syndrome

Transcription

1 European Heart Journal (2002) 23, doi: /euhj , available online at on Sympathetic modulation of the long QT syndrome See Eur Heart J 2002; 23: for the article to which this Editorial refers The long QT syndrome (LQTS) is characterized by the appearance of long QT intervals in the ECG, torsade de pointes (TdP) arrhythmias, and a relatively high risk for sudden cardiac death [1,3]. Genetic studies have identified seven genotypes responsible for congenital LQTS, characterized by mutations in six different ion channel genes located on chromosomes 3, 7,11, 17 and 21 [4 8]. These mutations result in defects in the sodium channel (SCN5A, LQT3) [4], the rapidly activating delayed rectifier channel (I Kr ) (HERG, LQT2 or KCNE2, LQT6) [9,10], the slowly activating delayed rectifier channel (I Ks ) (KvLQT1, LQT1 or KCNE1, LQT5) [7,11,12] and the inward rectifier current (I K1 ) (Kir2.1, LQT7) [8]. It is generally recognized that most, but not all, patients with LQTS experience cardiac events during increased sympathetic activation induced or mimicked by pharmacological agents, physical exercise, stress or emotion. Carriers of KCNQ1 gene mutations have been shown to develop 68% of events during physical exercise or emotional stress and only 9% at rest [13]. Swimming-related cardiac events occur almost exclusively in LQT1 patients [14,16]. In contrast, LQT2 patients commonly develop TdP following an auditory stimulus or a sudden startle [17] and LQT3 patients have a higher probability of developing events at rest or during sleep (49%) [13]. These observations are consistent with our current mechanistic understanding of the ionic and cellular substrates underlying the different genetic variants of LQTS, as discussed below. The tachyarrhythmia typically encountered in congenital LQTS is TdP, an atypical polymorphic ventricular tachycardia. Torsade de Pointes has been shown to develop under conditions that predispose to the development of early afterdepolarizations (EADs) in isolated Purkinje fibres and M cells, suggesting a role for EAD-induced triggered activity in the genesis of TdP [18,19]. While an EAD-induced extrasystole is believed to be responsible for the premature beat that initiates TdP, consensus is building in favour of circus movement reentry as the mechanism responsible for the maintenance of the arrhythmia [20 42].Inthe canine left ventricular wedge preparation, a drop in perfusate temperature can eliminate all sources of focal activity; although TdP no longer occurs spontaneously, the arrhythmia can be readily induced by a single premature stimuli applied to the epicardium, the site of briefest refractoriness, demonstrating the persistence of a substrate for reentry in the form of a transmural dispersion of repolarization [20]. Recent studies have demonstrated that QT prolongation alone, if not accompanied by an increase in transmural or transseptal dispersion of repolarization, is not in itself sufficient to cause TdP [32,43,44], supporting the thesis that QT prolongation is not the cause of TdP arrhythmias [20,45]. This premise is also supported by a recent study by Gbadebo and co-workers demonstrating that W-7, a calmodulin inhibitor, can prevent TdP in a rabbit model of LQTS, without abbreviating the QT interval [46]. These studies point to transmural (including transseptal) dispersion of repolarization as the principal substrate for the development of the TdP [20,22,45]. Whereas in vivo experiments point to macroreentry as the basis for TdP [31], experiments in the arterially perfused wedge suggest that reentrant activity underlying TdP can occur in a more limited volume of tissue via an intramural reentrant circuit ( cm 3 ) [21,32,33]. The hypothesis proposed to explain the development of LQTS-related TdP maintains that the various mutations that underlie the syndrome amplify the transmural dispersion of repolarization (TDR) by producing a net reduction in repolarizing current (Fig. 1). Conditions leading to a reduction in I Kr (e.g. LQT2) or augmentation of late I Na (e.g. LQT3) amplify transmural electrical heterogeneities by producing a preferential prolongation of the M cell action potential. Thus, QT interval prolongation is accompanied by a dramatic increase in TDR, which creates a vulnerable window for the development of reentry across the ventricular wall. The reduction in net repolarizing current also predisposes to the development of EAD-induced triggered activity in M and Purkinje cells, which provide the extrasystole that triggers TdP when it arrives during the vulnerable period. β adrenergic agonists further amplify transmural heterogeneity (transiently) in the case of I Kr block and LQT2, but reduce it in the case of I Na promoters and LQT3 [43,47]. In contrast, conditions leading to a reduction in I Ks (e.g. LQT1) cause a homogeneous prolongation of action potential duration (APD) throughout the ventricular wall, leading to a prolongation of the QT interval but with no increase in transmural dispersion of repolarization. Torsade de Pointes does not occur spontaneously nor can it be induced by programmed stimulation under these conditions until a β adrenergic agonist 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

2 Editorials 1247 Figure 1 Proposed cellular mechanism for the development of torsade de pointes in the long QT syndrome. is introduced. Isoproterenol dramatically increases transmural dispersion of repolarization and refractoriness under these conditions by abbreviating the APD of epicardium and endocardium, thus creating a vulnerable window that an EAD-induced triggered response can invade to generate TdP. Evidence in support of this hypothetical scheme derives in part from experimental studies conducted using the arterially perfused canine ventricular wedge preparation. Correlation of electrocardiographic activity recorded across the wedge with the transmembrane action potentials from individual cell types indicates that differences in the time course of repolarization of the three predominant ventricular myocardial cell types give rise to voltage gradients responsible for the manifestation of the T wave in the ECG [33,35,48]. Preferential prolongation of APD in cells from the M region appears to underlie LQTS, contributing to the development of long QT intervals, abnormal T waves and TdP. Studies employing the wedge have developed experimental models to assess the contribution of electrical heterogeneity across the ventricular wall to the manifestation of the T wave under conditions of acquired LQTS mimicking the different genetic defects that have been linked to the congenital syndrome (Fig. 2). The electrocardiographic T wave patterns described in the wedge are similar to those observed in patients with the respective genotype [49,50]. I Ks block with Chromanol 293B has been used to mimic the LQT1 form of LQTS. I Ks block alone produces a homogeneous prolongation of repolarization across the ventricular wall, but does not induce arrhythmias. The addition of isoproterenol leads to abbreviation of epicardial and endocardial APD with little or no change in the APD of the M cell, resulting in a marked augmentation of TDR and the development of spontaneous and stimulation-induced TdP [32]. These cellular changes generally give rise to a broad based T wave and a long QT interval characteristic of LQT1. The development of TdP in this model is exquisitely sensitive to β adrenergic stimulation consistent with the high sensitivity of congenital LQTS, LQT1 in particular, to sympathetic stimulation [1 3,51 54]. In the wedge model of LQT1, I Ks block alone produces a homogeneous prolongation of APD, thus prolonging the QT interval without an increase in TDR. Torsade de Pointes does not occur under these conditions. The introduction of an adrenergic agent, isoproterenol, leads to further prolongation of M cell APD (due to a predominant action to increase I Na-Ca ), but an abbreviation of the APD of epicardium and endocardium (due to a predominant effect of isoproterenol to increase I Ks,

3 1248 Editorials Figure 2 Transmembrane action potentials and transmural electrocardiograms (ECG) in control and LQT1 (A), LQT2 (B), and LQT3 (C) models of LQTS (arterially perfused canine left ventricular wedge preparations). Isoproterenol+chromanol 293B an I Ks blocker, d-sotalol+low [K + ] 0, and ATX-II an agent that slows inactivation of late I Na, are used to mimic the LQT1, LQT2 and LQT3 syndromes, respectively. Panels A C depict action potentials simultaneously recorded from endocardial (Endo), M and epicardial (Epi) sites together with a transmural ECG. BCL=2000 ms. In all cases, the peak of the T wave in the ECG is coincident with the repolarization of the epicardial action potential, whereas the end of the T wave is coincident with the repolarization of the M cell action potential. Repolarization of the endocardial cell is intermediate between that of the M cell and epicardial cell. Transmural dispersion of repolarization across the ventricular wall, defined as the difference in the repolarization time between M and epicardial cells, is denoted below the ECG traces. (A) Isoproterenol (100 nm) in the presence of chromanol 293B (30 μm) produces a preferential prolongation of the action potential duration (APD) of the M, resulting in an accentuated transmural dispersion of repolarization. (B) d-sotalol (100 μm) in the presence of low potassium (2 mm) gives rise to low-amplitude T waves with a notched or bifurcated appearance due to a very significant slowing of repolarization. (C) ATX-II (20 nm) markedly prolongs the QT interval, widens the T wave, and causes a sharp rise in the dispersion of repolarization. ATX-II also produces a marked delay in onset of the T wave due to relatively large effects of the drug on the APD of epicardium and endocardium. Panels D F: Effect of isoproterenol in the LQT1, LQT2 and LQT3 models. In LQT1, isoproterenol (Iso) produces a persistent prolongation of the APD 90 of the M cell and of the QT interval (at both 2 and 10 min), whereas the APD 90 of the epicardial cell is always abbreviated, resulting in a persistent increase in TDR (D). In LQT2, isoproterenol initially prolongs (2 min) and then abbreviates the QT interval and the APD 90 of the M cell to the control level (10 min), whereas the APD 90 of epicardial cell is always abbreviated, resulting in a transient increase in TDR (E). In LQT3, isoproterenol produced a persistent abbreviation of the QT interval and the APD 90 of both M and epicardial cells (at both 2 and 10 min), resulting in a persistent decrease in TDR (F). *P< vs Control; P<0 0005, P<0 005, P<0 05, vs 293B, d-sotalol (d-sot) or ATX-II. (Modified from references [32,33,43] with permission.)

4 Editorials 1249 which is more abundant in these cell types), resulting in a further prolongation of QT and a dramatic increase in TDR. It is only under these conditions that TdP is observed to occur either spontaneously or following programmed electrical stimulation (PES). With continued exposure (10 min) the effect of isoproterenol on I Ks intensifies, resulting in an abbreviation of APD of all three cell types. Thus, the immediate effects of isoproterenol are maintained but reduced in steady-state (Fig. 2) [32,43]. I Kr block with d-sotalol was used to mimic LQT2 and the most common acquired (drug-induced) form of LQTS. In this model, a greater prolongation of the M cell action potential (due to an intrinsically weaker net repolarizing current in this cell type) and slowing of phase three of the action potential of all three cell types results in a low amplitude T wave, long QT interval, large transmural dispersion of repolarization and the development of spontaneous as well as stimulation-induced TdP. The addition of hypokalaemia further accentuates the reduction in the amplitude of the T wave, giving rise to a deeply notched or bifurcated appearance, similar to that commonly seen in patients with the LQT2 syndrome [33,35]. Isoproterenol further exaggerates transmural dispersion of repolarization, thus increasing the incidence of TdP [43]. It is noteworthy that the effects of a β adrenergic agent (epinephrine) to augment transmural dispersion has now been demonstrated in clinical cases of LQT1 and LQT2 using Tpeak-Tend [55] as a measure of transmural dispersion of repolarization [56].Inthe LQT2 model, TdP can occur in the absence of a sympathetic influence. The addition of isoproterenol leads to further prolongation of M cell APD (due to a predominant action to increase I Na-Ca ), but an abbreviation of the APD of epicardium and endocardium (due to a predominant effect of isoproterenol to increase I Ks which is more abundant in these cell types), resulting in a further prolongation of QT and an increase in TDR. Under these conditions, TdP occurs more readily, both spontaneously and in response to PES. With continued exposure (10 min) the effect of isoproterenol on I Ks intensifies resulting in a further abbreviation of APD of epicardium and endocardium and a dramatic abbreviation of APD of the M cell, restoring both QT and TDR to near normal levels. Torsade de Pointes does not occur spontaneously nor can it be induced after 10 min of exposure to isoproterenol. Thus, the arrhythmogenic effects observed after acute exposure to isoproterenol are reversed in steady-state. Torsade de Pointes either occurs during the initial sympathetic surge or does not occur at all (Fig. 2) [33,43]. This sharp biphasic response to isoproterenol may explain why LQT2 patients develop cardiac events following a startle or auditory stimulus [17]. Augmentation of late I Na with ATX-II has been used to mimic LQT3 [33,57]. ATX-II, a sea anemone toxin, markedly prolongs the QT interval, delays the onset of the T wave, in some cases also widening it, and causes a sharp rise in transmural dispersion of repolarization as a result of a greater prolongation of the APD of the M cell. The greater effect of ATX-II to prolong the M cell is likely due to the presence of a larger late sodium current in the M cell [58]. A relatively long delay in the onset of the T wave, due to the relatively large effect of ATX-II on epicardial and endocardial APD, is observed consistent with the late-appearing T wave pattern and long isoelectric ST segment observed in patients with LQT3. Concordant with the clinical presentation of the LQT3 syndrome, the wedge model displays a steep rate dependence of the QT interval and develops TdP at slow rates. In the ATX-II model of LQT3, β adrenergic stimulation with isoproterenol, reduces transmural dispersion of repolarization by abbreviating the APD of the M cell more than that of epicardium or endocardium. Transmural dispersion of repolarization is thus reduced, as is the incidence of TdP. While the β adrenergic blocker propranolol is protective in LQT1 and LQT2 wedge models, it exerts an opposite effect in LQT3, acting to amplify transmural dispersion and to promote TdP (Fig. 2) [33,43]. It is noteworthy that differences in the effect of isoproterenol on APD in pharmacologic models that mimic LQT2 (dofetilide) and LQT3 (anthopleurin A) have also been demonstrated in experimental studies employing isolated guinea pig myocytes [59]. The dynamic responses to isoproterenol in the different LQTS wedge models are similar to those observed in response to epinephrine in patients with the LQT1, LQT2 and LQT3 forms of the long QT syndrome as elegantly demonstrated by Noda et al.in this issue. The authors recorded a 12-lead ECG from 12 LQT1, 10 LQT2, 6 LQT3 and 13 normal controls before and after a bolus injection of epinephrine (0 1 μg.kg 1 ), followed by continuous infusion (0 1 μg.kg 1. min 1 ). β blocker therapy was discontinued for at least five half-lives before the study was performed. Epinephrine, rather than isoproterenol was used because abbreviation of RR is less pronounced with the former. The longest QT interval that could be reliably measured was used for analysis and the same lead was measured before and after epinephrine. Bazzett s method was used to calculate the corrected QT (QTc). In LQT1 patients, epinephrine increased QTc by 32% at its peak effect (first 2 min) and the effect was maintained although at a lower level (17%) at steady state. In LQT2 patients, epinephrine increased QTc by 24% at its peak effect, but the effect quickly dissipated and QTc was not

5 1250 Editorials significantly augmented at steady state. In LQT3 and control patients, epinephrine increased QTc by 11% and 16% at its peak effect, and abbreviated to values that were not significantly different from baseline at steady state. While the dynamic results are qualitatively similar to those recorded in the respective models in the wedge, the responses were more accentuated with respect to the epinephrine-induced QTc prolongation. These differences may be due to any one of a long list of factors, including the fact that epinephrine (a combined α and β adrenergic agonist) was used in the clinical study, whereas isoproterenol (a β adrenergic agonist) was used in the experimental studies. The use of Bazzett s formula to calculate QTc may also have led to an overestimation of the QT prolongation. The author s note that when Fridericia s formula was used for correction of QT, epinephrine did not significantly prolong QT in either LQT3 or control patients. These observations provide important insights into the different sensitivites of the different genotypes of the long QT syndrome to sympathetic stimulation. The persistent effect of isoproterenol or epinephrine to prolong QT and TDR in LQT1 may provide an explanation as to why cardiac events are most frequently observed after exercise or emotion, when plasma catecholamine levels are elevated. The abrupt and transient response to catecholamines in LQT2 may explain why cardiac events are closely associated with a sympathetic surge as after a startle or loud noise. Finally, the lack of QT response or decrease in TDR (wedge) in response to isoproterenol or epinephrine in LQT3, appears consistent with the observation that cardiac events are more common at rest or during sleep. These results also highlight the importance of assessing the dynamic rather than just the steady state response to sympathetic stimuli in LQTS patients. The sensitivity to adrenergic agents has been exploited in the diagnosis of the LQTS among carriers whose phenotype is not immediately obvious on the basis of the resting ECG [61]. Recently, a systematic evaluation of the effectiveness of epinephrine in unmasking LQTS has been performed in patients with known genotypes [62,63]. In the study by Ackerman and co-workers, epinephrine was effective in identifying LQT1 patients with a baseline QTc that was non-diagnostic (QTc <460 ms), but was not effective in identifying concealed LQT2 or LQT3. The study by Shimizu and co-workers showed epinephrine to be capable of unmasking both LQT1 and LQT2 syndrome. In the latter, epinephrine prolonged the interval QT only transiently soon after the administration of the drug, consistent with the biphasic time course illustrated in the study by Noda et al. [60]. C. ANTZELEVITCH Masonic Medical Research Laboratory, Utica, New York, U.S.A. References [1] Schwartz PJ. 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