The 'Lambeth Conventions' is a guidance document, written in 1987 (Walker et al., 1988), intended to be of practical value in the investigation of experimental arrhythmias induced by ischaemia, ...infarction, and reperfusion. This is an update, expanded to include guidance on the study of supraventricular arrhythmias, drug-induced arrhythmias, heritable arrhythmias, and advances in our knowledge in core areas since 1987. We have updated the guidance on the design and execution of experiments and the definition, classification, quantification, and analysis of all types of arrhythmias. Investigators are encouraged to adopt the conventions and test their validity in the hope that this will improve uniformity and interlaboratory comparisons, aid clinical research, facilitate antiarrhythmic drug discovery and safety assessment, and improve antiarrhythmic drug deployment for different cardiac conditions. We note that there is a gap between some definitions proposed here and their conventional clinical counterparts, and encourage the research necessary to bridge that translational gap. A web link offers the chance to vote and comment on the new conventions (https://bscr.wufoo.com/forms/z7x0x5/).
This review focuses mainly on studies in non-ischemic animal models of heart failure. These animals develop ventricular arrhythmias, mostly non-sustained ventricular tachycardia, and often die ...suddenly. Clinical studies suggest that sudden death is due to ventricular tachycardia or fibrillation in about 50% of cases, the other half to bradyarrhythmias or electromechanical dissociation. Electrophysiologic changes in heart failure are not confined to the ventricles: the intrinsic sinus rate is reduced due to a downregulation of If and sensitivity to acetylcholine is enhanced by upregulation of the muscarinic receptor. Reduction of heart rate may be a protective mechanism since at rapid rates contractility is reduced and the likelihood for triggered activity due to delayed afterdepolarizations is enhanced. The beneficial effect of beta-adrenergic blockade in patients may be partly due to the reduction in sinus rate. Although the results of different studies often vary, the most consistent electrophysiological changes in the ventricles are prolongation of the action potential, especially at slow rates, a reduction in the transient outward current Ito, the rapid and slow components of the delayed rectifier Ikr and Iks, and the inward rectifier Ik1. Abnormalities in intracellular calcium handling play a major role in the genesis of delayed afterdepolarizations. Triggered activity based on delayed afterdepolarizations has been demonstrated in failing myocardium and are caused by spontaneous release of calcium from the sarcoplasmic reticulum (SR), especially in the presence of noradrenaline. Three factors combine to the enhanced propensity for the occurrence of delayed afterdepolarizations: (1) increased activity of the Na/Ca exchanger, (2) a reduced inward rectifier, (3) residual beta-adrenergic responsiveness required to raise the reduced sarcoplasmic calcium content to a level where spontaneous calcium release occurs. Early afterdepolarizations have also been demonstrated, especially in human myocytes from failing hearts in the presence of noradrenaline. Mapping experiments have shown that the ventricular arrhythmias are mainly due to non-reentrant mechanisms, most likely triggered activity based on delayed afterdepolarizations.
The relation between induction of arrhythmias and dispersion of repolarization is not completely understood.
The purpose of this study was to study the relation between heterogeneity in ...repolarization and arrhythmogenesis under conditions of selective regional action potential prolongation and shortening.
Pig hearts were perfused in a Langendorff setup. The left anterior descending artery (LAD) was cannulated and perfused. Sotalol (220 microM) was infused in the aortic cannula, and pinacidil (20 microM) was infused through the LAD, causing a gradient in repolarization time between the two myocardial regions. Premature stimulation was performed from the LAD region.
No transmural repolarization gradients developed after infusion of the drugs. High-density epicardial activation/repolarization mapping (176 unipolar electrodes, 2-mm interelectrode spacing) revealed a maximum repolarization gradient of approximately 120 ms over 14 mm. The critical parameter for differentiating between the occurrence of reentry and the mere occurrence of a line of activation block between the two myocardial regions (and no reentry) was not the magnitude of the repolarization gradient but the timing of arrival of the premature activation wave at the distal side of the line of activation block relative to the repolarization time of the premature beat proximal to the line of block. No spontaneous arrhythmias were observed despite the presence of the repolarization gradient.
It is not the repolarization gradient but the restitution characteristics of the tissue with the shorter action potential, in combination with the time of arrival of the premature wavefront at the distal side of the line of block, that determines the occurrence of reentry.
Background
Spontaneous ventricular premature contractions (PVCs) and ventricular tachycardia (VT) in the acute post infarct milieu is assumed to be due to automaticity. However, the mechanism has not ...been studied with intramural mapping.
Objective
To study the mechanism of spontaneous PVCs with high density intramural mapping in a canine model, and to test the hypothesis that post‐infarct PVCs and VT are due to re‐entry rather than automaticity.
Methods
In 15 anesthetized dogs, using 768 intramural unipolar electrograms, simultaneous recordings were made. After 20 min of stabilization, recordings were made during the first 10 min of ischemia, and activation maps of individual beats were constructed. Acute ischemia was produced by clamping the left anterior descending coronary artery proximal to the first diagonal branch.
Results
In all experiments ST‐T alternans was present. Spontaneous ventricular beats occurred in five of 15 dogs where the earliest ectopic activity was manifested in the endocardium, well within the ischemic zone. From there, activity spread rapidly along the subendocardium, with endo‐to epicardial spread along the non‐ischemic myocardium. Epicardial breakthrough always occurred at the border of the ischemic myocardium. In three dogs, delayed potentials were observed, which were earliest at the ischemic epicardium and extended transmurally with increasing delay towards the endocardium, where they culminated in a premature beat. A similar sequence was observed in VT that followed.
Conclusion
Graded responses that occur with each sinus beat intramurally, when able to propagate from epicardium to endocardium are the mechanism of PVCs and VT in post‐infarct myocardium.
Abstract
Aims
Enhanced sympathetic activity during acute ischaemia is arrhythmogenic, but the underlying mechanism is unknown. During ischaemia, a diastolic current flows from the ischaemic to the ...non-ischaemic myocardium. This ‘injury’ current can cause ventricular premature beats (VPBs) originating in the non-ischaemic myocardium, especially during a deeply negative T wave in the ischaemic zone. We reasoned that shortening of repolarization in myocardium adjacent to ischaemic myocardium increases the ‘injury’ current and causes earlier deeply negative T waves in the ischaemic zone, and re-excitation of the normal myocardium. We tested this hypothesis by activation and repolarization mapping during stimulation of the left stellate ganglion (LSG) during left anterior descending coronary artery (LAD) occlusion.
Methods and results
In nine pigs, five subsequent episodes of acute ischaemia, separated by 20 min of reperfusion, were produced by occlusion of the LAD and 121 epicardial local unipolar electrograms were recorded. During the third occlusion, left stellate ganglion stimulation (LSGS) was initiated after 3 min for a 30-s period, causing a shortening of repolarization in the normal myocardium by about 100 ms. This resulted in more negative T waves in the ischaemic zone and more VPBs than during the second, control, occlusion. Following the decentralization of the LSG (including removal of the right stellate ganglion and bilateral cervical vagotomy), fewer VPBs occurred during ischaemia without LSGS. During LSGS, the number of VPBs was similar to that recorded before decentralization.
Conclusion
LSGS, by virtue of shortening of repolarization in the non-ischaemic myocardium by about 100 ms, causes deeply negative T waves in the ischaemic tissue and VPBs originating from the normal tissue adjacent to the ischaemic border.
Graphical Abstract
The concept that the interval between the peak (T(peak)) and the end (T(end)) of the T wave (T(p-e)) is a measure of transmural dispersion of repolarization time is widely accepted but has not been ...tested rigorously by transmural mapping of the intact heart.
The purpose of this study was to test the relationship of T(p-e) to transmural dispersion of repolarization by correlating local repolarization times at endocardial, midmural, and epicardial sites in the left and right ventricles with the T wave of the ECG.
Local activation times, activation-recovery intervals, and repolarization times were measured at 98 epicardial sites and up to 120 midmural and endocardial sites in eight open-chest dogs. In four of the dogs, long-term cardiac memory was induced by 3 weeks of ventricular pacing at 130 bpm because previous data suggest that, in this setting, delayed epicardial repolarization increases transmural dispersion. The other four dogs were sham operated.
In sham dogs, T(p-e) was 41 +/- 2.2 ms (X +/- SEM), whereas the transmural dispersion of repolarization time was 2.7 +/- 4.2 ms (not significant between endocardium and epicardium). Cardiac memory was associated with evolution of a transmural gradient of 14.5 +/- 1.9 ms (P <.02), with epicardium repolarizing later than endocardium. The corresponding T(p-e) was 43 +/- 2.3 ms (not different from sham). In combined sham and memory dogs, T(p-e) intervals did not correlate with transmural dispersion of repolarization times. In contrast, dispersion of repolarization of the whole heart (measured as the difference between the earliest and the latest moment of repolarization from all left and right ventricular, endocardial, intramural, and epicardial recording sites) did correlate with T(p-e) (P <.0005, r = 0.98), although the latter underestimated total repolarization time by approximately 35%. The explanation for this finding is that parts of the heart fully repolarize before the moment of T(peak).
T(p-e) does not correlate with transmural dispersion of repolarization but is an index of total dispersion of repolarization.
Dispersion in repolarization is important for the genesis of the T wave, and for the induction of reentrant arrhtyhmias. Because the T wave differs across species our intent here is to review the ...epicardial, endocardial and transmural repolarization patterns contributing to repolarization in whole hearts from man, dog and pig. The major points we emphasize are: transmural repolarization time gradients are small and are directed from endocardium (early) to epicardium (late) in dog and human and from epicardium to endocardium in pig; the right ventricle tends to repolarize before the left ventricle and this difference is larger in dog than in pig; a negative relation between the activation times and the repolarization times is rare in man, and absent in dog and pig. Given the above, a large dispersion in repolarization between two myocardial areas does not lead to arrhythmias without a premature beat. Moreover, an arrhythmic substrate can be identified by a metric composed of activation times and repolarization times, the reentry vulnerability index, RVI.
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