The Electro‐Mechanical window: a risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias

Linde, H. van der; Deuren, Bruno Van; Somers, Yves; Loenders, Brigitte; Towart, R.; Gallacher, D.

doi:10.1111/j.1476-5381.2010.00934.x

Cited by 79 publications

(104 citation statements)

References 41 publications

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“…More recently, these clinical findings were substantiated by animal studies, which demonstrate that the negative EM window markedly increases susceptibility to life-threatening ventricular tachyarrhythmia, such as torsade de pointes [6], [8]–[9]. In a canine model of long QT syndrome, a negative EM window was found to be a prerequisite for VT initiation [6]. In anesthetized guinea-pigs, administration of drugs with known high proarrhythmic potential (i.e., quinidine, haloperidol, and domperidone) was found to induce a negative EM window, whereas safe antiarrhythmics such as amiodarone, verapamil and diltiazem produced no effect [8]–[9].…”

Section: Discussionmentioning

confidence: 89%

“…Importantly, in patients with healed myocardial infarction, the long-term survival rate was found to be 2.6-fold lower in a patient subgroup with a negative EM window, thereby indicating that this parameter may be used to predict the mortality risk in coronary artery disease [3]. More recently, these clinical findings were substantiated by animal studies, which demonstrate that the negative EM window markedly increases susceptibility to life-threatening ventricular tachyarrhythmia, such as torsade de pointes [6], [8]–[9]. In a canine model of long QT syndrome, a negative EM window was found to be a prerequisite for VT initiation [6].…”

Section: Discussionmentioning

confidence: 95%

“…The EM window was calculated as the difference between the Q-P end interval and the QT interval on ECG, as described previously [6], [8]–[9], [26]. The measurements were performed both during steady-state pacing and extrasystolic stimulation (Figure 1).…”

Section: Methodsmentioning

confidence: 99%

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Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

Osadchii

2014

PLoS ONE

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Normal hearts exhibit a positive time difference between the end of ventricular contraction and the end of QT interval, which is referred to as the electromechanical (EM) window. Drug-induced prolongation of repolarization may lead to the negative EM window, which was proposed to be a novel proarrhythmic marker. This study examined whether abnormal changes in the EM window may account for arrhythmogenic effects produced by hypokalemia. Left ventricular pressure, electrocardiogram, and epicardial monophasic action potentials were recorded in perfused hearts from guinea-pig and rabbit. Hypokalemia (2.5 mM K+) was found to prolong repolarization, reduce the EM window, and promote tachyarrhythmia. Nevertheless, during both regular pacing and extrasystolic excitation, the increased QT interval invariably remained shorter than the duration of mechanical systole, thus yielding positive EM window values. Hypokalemia-induced arrhythmogenicity was associated with slowed ventricular conduction, and shortened effective refractory periods, which translated to a reduced excitation wavelength index. Hypokalemia also evoked non-uniform prolongation of action potential duration in distinct epicardial regions, which resulted in increased spatial variability in the repolarization time. These findings suggest that arrhythmogenic effects of hypokalemia are not accounted for by the negative EM window, and are rather attributed to abnormal changes in ventricular conduction times, refractoriness, excitation wavelength, and spatial repolarization gradients.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 95%

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Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

Osadchii

2014

PLoS ONE

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“…1 In follow-up studies, conscious dogs (n¼6; telemetered) showed comparable baseline values to anaesthetised dogs (n¼20): QT¼250 vs 252 ms, QLVPend¼347 vs 339 ms and EMw¼+96 vs +87 ms, respectively. To compare the EMw in conscious and anaesthetised dogs after IKs blockade.…”

mentioning

confidence: 89%

06 Possible role of the ultra-rapid delayed rectifier potassium current (IKur) in action potential repolarisation in rabbit heart

Cui

Wilson

Turner

et al. 2010

Heart

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The ultra-rapid delayed rectifier K+ current (IKur) plays an important role in early cardiac action potential repolarisation in a number of species. Although the rabbit heart has proven useful for studying cardiac repolarisation, the role of IKur in rabbit heart is less well known, as is the potential contribution of this ion channel to drug-induced changes in repolarisation. The aim of this study was to investigate the effects of 4-aminopyridine (4-AP) and 2-isopropyl-5-methylcyclohexyl diphenylphosphine oxide (DPO-1) on action potential duration (APD) in isolated rabbit atria and ventricular papillary muscles. Intracellular action potentials were recorded at 36–37°C and APD was measured at 20, 50 and 90% repolarisation (APD20, 50 and 90). Exposure to 4-AP at 50 μM for 30 min caused a significant prolongation in APD20 of 29.0±3.3% and 39.4±9.4% in left atria and right ventricular papillary muscles, respectively (stimulated at 1 Hz). In contrast, late repolarisation was less affected; increases in APD90 were 8.6±2.8% and 18.7±5.0% for atria and papillary muscles, respectively. The prolongation was reverse frequency dependent (0.2–1 Hz). Similarly, application of DPO-1 at 0.3 μM for 30 min significantly prolonged APD20 by 21.9±8.8% and 45.8±23.0% in atria and papillary muscles, respectively. APD90 was less affected, with increases of 10.8±2.2 and 25.2±13.2% in atria and papillary muscles, respectively. In conclusion, it is likely that IKur may play a functional role in repolarisation in rabbit in both atria and ventricle.

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“…Drug-induced cardiotoxicity is a major concern to the pharmacological industry and it is one of the main reasons for non-approval, re-labelling, warnings and withdrawal of pharmaceutical compounds from the market. 1 Doxorubicin is an anthracycline antibiotic used in cancer therapy. Although issues relating to Doxorubicin and cardiac safety have been well established in normal conditions, the effects of this drug on the myocardium during ischaemia-reperfusion have not been investigated in detail to date.…”

mentioning

confidence: 99%

04 The bronchodilator salbutamol is associated with increased myocardial injury in a pre-clinical heart attack model

Nagra

Maddock

Hussain

2010

Heart

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Salbutamol is widely used to treat symptoms of chest tightness commonly associated with Asthma. Recent studies have associated increased in morbidity and mortality in asthmatic patients with underlying heart disease currently being treated with salbutamol. The study aimed to investigate the effects of salbutamol on the myocardium subjected to ischaemia-reperfusion (I/R). Langendorff hearts were subjected to control or I/R in the absence or presence of salbutamol (1–100 nM)±CGP-12177 (β1 adrenoceptor antagonist) or ICI 118551 (β2 adrenoceptor antagonist). Hearts underwent triphenyl tetrazolium staining for infarct size assessment. Isolated cardiomyocytes were exposed to simulated I/R in the absence or presence of salbutamol (1 pM–1 μM)±CGP-12177 or ICI 118551. Cellular injury was determined by measurement of viability, apoptosis and necrosis using flow cytometry. Hypercontracture was also assessed in cardiomyocytes subjected to oxidative stress in the absence or presence of salbutamol. Salbutamol (100 nM) significantly increased infarct size to risk ratio (%) compared to controls (76±3% vs 51±2%, p<0.001, respectively). Administration of salbutamol in the presence of the CGP-12177 or ICI 118551 completely reversed the cardio-toxic effects of salbutamol (63±4%, p<0.01, 50±2%, p<0.001, respectively). Salbutamol significantly increased apoptosis/necrosis compared to non-treated cardiomyocytes subjected to hypoxia/reoxygenation, the cardio-toxic effect of salbutamol abrogated by CGP-12177 and ICI 118551. Salbutamol also reduced hypercontracture time in cardiomyocytes subjected to oxidative stress. This study is the first to identify the cardiotoxic effects of salbutamol in a pre-clinical heart attack model. Further studies are being investigated to determine the mechanism of action of the myocardial injury associated with salbutamol.

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The Electro‐Mechanical window: a risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias

Cited by 79 publications

References 41 publications

Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

06 Possible role of the ultra-rapid delayed rectifier potassium current (IKur) in action potential repolarisation in rabbit heart

04 The bronchodilator salbutamol is associated with increased myocardial injury in a pre-clinical heart attack model

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