Copyright © 2007, European Society of Cardiology
Drug-induced torsades de pointes — A form of mechano-electric feedback?
Department of Cardiology and Angiology and Centre for Interdisciplinary Clinical Research (IZKF), University Hospital Münster, 48129 Münster, Germany
*Tel.: +49 251 83 46034; fax: +49 251 83 47864. fabritzl{at}uni-muenster.de
Received 22 August 2007; accepted 24 August 2007
See article by Gallacher et al. [1] (pages 247–256) in this issue.
In this issue of Cardiovascular Research, Gallacher et al. report findings on a novel canine model of drug-induced long-QT syndrome [1]. In this model, torsades de pointes (TdP) arrhythmia was induced in anaesthetised dogs by bolus injections of the β-adrenoreceptor agonist isoproterenol during selective inhibition of the slow component of the delayed-rectifier potassium current IKs by HMR1556. Isoproterenol induced TdP in 94% of dogs tested. Authors examined the interaction of putative mechanisms of induction of TdP. Blockade of IKs mimics the functional effects of the genetic alterations found in long-QT syndrome type I. The β-adrenergic challenge caused action potential prolongation and increased spatial [2–4] and temporal [2] dispersion of repolarisation. Systolic aftercontractions, measured as small increases in left ventricular systolic pressure, preceded the onset of TdP (see Fig. 4 in the manuscript). TdP and aftercontractions were able to be suppressed by either β-adrenoreceptor blockade by esmolol or calcium channel blockade by verapamil, as expected [5,6].
The simultaneous real-time recording of surface ECG, several monophasic action potentials (MAP), and pressure from both ventricles in the dog gives us valuable insight into the relationship between putative markers of proarrhythmia in the beating heart. QT interval and action potential duration were prolonged by IKs blockade. β-Adrenoreceptor stimulation further prolonged ventricular action potential duration, and temporal [2] and spatial [2–4] dispersion of repolarisation were increased. This "paradoxical" prolongation of action potential duration is thought to contribute to TdP in patients with long-QT syndrome type I [7].
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1. Excitation–contraction coupling or mechano-electric feedback? |
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 Top 1. Excitation-contraction... 2. The trigger mattersReferences |
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Authors observed transient increases in left ventricular pressure concurring with early afterdepolarisations (EADs) and TdP in the MAP recordings. Aftercontractions preceded TdP? This does not look like a novel finding at first glance [8]. But authors have more to say: They suggest that aftercontractions may have preceded and possibly initiated EADs and, finally, may have initiated the arrhythmia. Do aftercontractions kick off TdP? In the ECG, we are used to talking about contraction although we describe electrical activity: We say "extrasystole" or "extra beat" and assume that the contraction is just following the electrical activity. Gallacher et al. propose the opposite: They claim that in this model, the aftercontraction may initiate the EAD, and they thereby add a provocative thought to current discussions of electro-mechanic and mechano-electric feedback. It is well known that stretch-induced depolarisations can trigger premature ventricular electrical activations [9,10]. EADs may potentially arise from diastolic calcium overload and spontaneous or force-induced calcium release [5,6,8]. Interestingly, Volders et al. already reported isoproterenol-induced early aftercontractions preceding EADs a decade ago in canine cardiomyocytes [11]. EADs could hence represent an electrical activity initiated by force.
Both MAP and pressure recordings shown are of good quality. Nonetheless, there are technical concerns about the timing of events: Aftercontractions may be initiated by local afterdepolarisations. The MAPs may not have been recorded from the site of origin of the EAD. A pressure rise, in contrast, is measured globally in the LV and will therefore be recorded irrespective of the site of electrical activity.
If we assume that contraction is a surrogate parameter for intracellular calcium binding to the contractile filaments, then the observations by Gallacher et al. suggest that a calcium release sufficient to lead to a contraction of the left ventricle may be essential to the initiation of TdP. EADs and TdP are also elicited in unloaded, Langendorff-perfused isolated beating hearts [4–6], suggesting mechanical force may not be a prerequisite for TdP. To study the potential relevance of mechanical load and the origin of EADs initiating TdP, further studies using detailed mapping techniques, calcium imaging, and pressure measurements may be of use. While this is technically challenging, the questions raised by the observations of Gallacher et al. require such comprehensive physiological studies in the intact beating heart.
In patients with congenital long-QT syndrome, a prolonged and double-peak pattern of systolic wall movement was detected during echocardiography that may reflect EADs [12]. It would be most interesting to study these phenomena using MAPs in patients, and it is unfortunate that the MAP catheter is currently not produced for human studies because of regulatory restrictions.
The strength of the present model is the integration of methods for recording of spontaneous arrhythmias in vivo; a weakness is the use of anaesthesia which may alter autonomic regulation, even if authors have chosen drugs shown to affect autonomic tone less than others. Proarrhythmic parameters have also been assessed using MAPs in the dog model of chronic AV nodal block. These hearts develop electrical remodelling, including remodelling of IKs and β-adrenergic activation [13], and increased susceptibility for drug-induced TdP arrhythmias if challenged with IKs or IKr blockers [2]. Marked hypertrophy or failure is sufficient to elicit similar ventricular arrhythmias in beating hearts [5,6,8].
Some diagnostics are difficult to perform in vivo and the isolated heart set up can be a valuable alternative to the whole organism. The isolated heart is, however, devoid of autonomous innervation. An isolated heart preparation with a mostly intact nervous system has been developed to address this shortcoming [14]. The isolated heart setup allows for simultaneous, detailed electrical and mechanical recordings of spontaneous arrhythmias in transgenic models [4,6,15], models of acquired proarrhythmia [5,8], and even in explanted human hearts of heart transplant recipients [16].
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2. The trigger matters |
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Top1. Excitation-contraction...2. The trigger mattersReferences |
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The model used by Gallacher et al. shows how important the trigger is to elicit TdP. During drug administration alone, dispersion was increased, but TdP did not occur without the trigger of EADs and aftercontractions with β-adrenergic stimulation. In the end, it may not matter much at what sort of dispersion we look — temporal, transmural, interventricular, global — as long as our eye catches the trigger, and this might work best in physiological models like beating hearts — alive and kicking. Integrative physiological studies will help us understand the trigger for TdP.
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References |
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Top1. Excitation-contraction...2. The trigger mattersReferences |
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