Francis L. Burton

Dispersion of ventricular repolarization and refractory period

Time for primary review 34 days. In their classic studies published in 1964, Han, Moe and co-workers [1,2] established an association between nonuniform recovery of excitability and lowered fibrillation threshold. They concluded that “those agencies known to favour the development of ventricular fibrillation were found to increase the temporal dispersion of recovery of excitability, whether the average refractory period was reduced … or increased…. The results emphasise the importance of nonuniformity of excitability and conduction velocity during the relative refractory period in the induction of turbulent impulse propagation.” The purpose of this review is to describe the basis of dispersion in recovery of excitability in the ventricle and its association with arrhythmogenesis. Ventricular tachyarrhythmias are readily generated not only in acute ischaemia/infarction but also in hearts that have undergone remodelling following myocardial infarction [3–5]. Life-threatening arrhythmias are commonly seen in patients with previous myocardial infarction in the absence of new ischaemic events, as evidenced by the ability to initiate sustained ventricular tachycardia by programmed stimulation [6]. The risk of ventricular arrhythmias and sudden death in heart failure is inversely proportional to the left ventricular ejection fraction [7]. However, the Veterans Heart Failure Trial and other studies suggest that the proportion of deaths that are sudden is higher in patients with less severe LV dysfunction [8]. Such individuals are less likely to die from pump failure, hence they are at greater relative (but not absolute) risk of sudden death in comparison with patients with advanced heart failure. The classical prerequisites for the development of reentry are the presence of a potential circuit around an anatomical obstacle, unidirectional block, and sufficiently slow conduction to enable recovery of excitability in time for reexcitation by the depolarizing wavefront [9]. A feature of this type of reentry is the presence … * Corresponding author. Tel.: +44-141-211-4722; fax: +44-141-552-4683 stuart.cobbe{at}clinmed.gla.ac.uk

Energy replacement attenuates the effects of prior moderate exercise on postprandial metabolism in overweight/obese men

Background:The extent to which exercise-induced changes to postprandial metabolism are dependant on the associated energy deficit is not known.Objective:To determine the effects of exercise, with and without energy replacement, on postprandial metabolism.Design:Each subject underwent three 2-day trials in random order. On day 1 of each trial subjects rested (control), walked at 50% maximal oxygen uptake to induce a net energy expenditure of 27 kJ kg−1 body mass (energy-deficit) or completed the same walk with the net energy expended replaced (energy-replacement). On day 2 subjects completed an 8.5-h metabolic assessment. For 3 days prior to day 2, subjects consumed an isocaloric diet, avoided planned exercise (apart from exercise interventions) and alcohol.Subjects:A total of 13 overweight/obese men (age: 40±8 years, body mass index: 31.1±3.0 kg m−2).Measurements:Postprandial triglyceride, insulin, glucose, non-esterified fatty acid and 3-hydroxybutyrate concentrations and substrate utilization rates were determined.Results:Energy-deficit lowered postprandial triglyceride concentrations by 14 and 10% compared with control and energy-replacement (P<0.05 for both). Energy-deficit increased postprandial 3-hydroxybutyrate concentrations by 40 and 19% compared with control and energy-replacement (P<0.05 for both). Postprandial insulin concentrations were 18 and 10% lower for energy-deficit and energy-replacement compared with control and 10% lower for energy-deficit than energy-replacement (P<0.05 for all). Postprandial fat oxidation increased by 30 and 14% for energy-deficit and energy-replacement compared to control and was 12% higher for energy-deficit than energy-replacement (P<0.05 for all).Conclusion:Exercise with energy replacement lowered postprandial insulinaemia and increased fat oxidation. However an exercise-induced energy deficit augmented these effects and was necessary to lower postprandial lipaemia.

Artery tertiary lymphoid organs control aorta immunity and protect against atherosclerosis via vascular smooth muscle cell Lymphotoxin β receptors

Summary Tertiary lymphoid organs (TLOs) emerge during nonresolving peripheral inflammation, but their impact on disease progression remains unknown. We have found in aged Apoe−/− mice that artery TLOs (ATLOs) controlled highly territorialized aorta T cell responses. ATLOs promoted T cell recruitment, primed CD4+ T cells, generated CD4+, CD8+, T regulatory (Treg) effector and central memory cells, converted naive CD4+ T cells into induced Treg cells, and presented antigen by an unusual set of dendritic cells and B cells. Meanwhile, vascular smooth muscle cell lymphotoxin β receptors (VSMC-LTβRs) protected against atherosclerosis by maintaining structure, cellularity, and size of ATLOs though VSMC-LTβRs did not affect secondary lymphoid organs: Atherosclerosis was markedly exacerbated in Apoe−/−Ltbr−/− and to a similar extent in aged Apoe−/−Ltbrfl/flTagln-cre mice. These data support the conclusion that the immune system employs ATLOs to organize aorta T cell homeostasis during aging and that VSMC-LTβRs participate in atherosclerosis protection via ATLOs.

The electrophysiological and mechanical effects of 2,3-butane-dione monoxime and cytochalasin-D in the Langendorff perfused rabbit heart.

Procedures that reduce contraction are used to facilitate optical measurements of membrane potential, but it is unclear to what extent they affect the excitability of the heart. This study has examined the electrophysiological consequences of a range of extracellular [Ca2+] (0.7–2.5 mmol l−1), 2,3‐butane‐dione monoxime (BDM; 1–20 mmol l−1) and cytochalasin‐D (Cyto‐D; 1–5 μmol l−1). Methods. Monophasic action potentials (MAPs) were recorded from the basal epicardial surface of the left ventricle of isolated rabbit hearts. Conduction delay (CD) and time to 90% repolarisation of the monophasic action potential (MAPD90) were measured. The effects of BDM and Cyto‐D on restitution were studied at a [Ca2+] of 1.9 mmol l−1. Restitution curves for MAPD90 were generated using a standard S1–S2 protocol. Results. All manoeuvres decreased left ventricular developed pressure (LVDP): 0.7 mmol l−1 Ca2+ to 74.0 ± 6.1%, 20 mmol l−1 BDM to 4.5 ± 1.0%, and 5 μmol l−1 Cyto‐D to 12.8 ± 3.5% of control value. CD decreased from a control value (33.3 ± 1.0 ms, n= 16) to 93.0 ± 2.2% in 0.7 mmol l−1 Ca2+, but increased to 133.7 ± 10.5% in 20 mmol l−1 BDM and 127.4 ± 10.6% in 5 μmol l−1 Cyto‐D. At 350 ms pacing cycle length, MAPD90 (control = 119.6 ± 1.7 ms n= 16) was prolonged by reduced extracellular [Ca2+]. BDM had no effects on MAPD90 at control pacing rates. Cyto‐D caused a significant prolongation (to 115.0 ± 3.0% of control, n= 6) at the highest concentration studied (5 μmol l−1). Both BDM (20 mmol l−1) and Cyto‐D (3 μmol l−1) flattened the restitution curves but neither agent altered maximum MAPD90. Conclusions. Extracellular [Ca2+] of 1.9 mmol l−1 in conjunction with a moderate dose of Cyto‐D (3 μmol l−1) reduced contractility with minimal effects on action potential duration and conduction at a fixed pacing cycle length. However, both BDM and Cyto‐D had pronounced effects on electrical restitution.

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 ± 5 vs. epi: 147 ± 4 ms; P < 0.05). During epicardial stimulation, this gradient reversed (epi: 162 ± 4 vs. endo: 148 ± 6 ms; P < 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall.

The link between repolarisation alternans and ventricular arrhythmia: does the cellular phenomenon extend to the clinical problem?

T-wave alternans is considered a potentially useful clinical marker for the risk of ventricular arrhythmia in patients with heart disease. Cellular repolarisation alternans is thought to underlie T-wave alternans, and moreover, to cause re-entrant ventricular arrhythmia. This review examines the experimental and clinical evidence linking repolarisation alternans and T-wave alternans with the occurrence of ventricular arrhythmia. Repolarisation alternans, manifest as alternating changes in action potential duration, is observed in isolated ventricular cardiomyocytes and in multicellular preparations. Its underlying causes are discussed particularly with respect to the role of intracellular Ca(2+). The repolarisation alternans observed at the single cell level is compared to the alternating behaviour observed in isolated multicellular preparations including the perfused ventricular wedge and Langendorff perfused heart. The evidence concerning spatial differences in repolarisation alternans is considered, particularly the situation where adjacent regions of myocardium exhibit repolarisation alternans of different phases. This extreme behaviour, known as discordant alternans, is thought to produce marked gradients of repolarisation that can precipitate unidirectional block and re-entrant ventricular arrhythmias. Finally, the difficulties in extrapolating between experimental models of alternans and arrhythmias and the clinical manifestation are discussed. The areas where experimental evidence is weak are highlighted, and areas for future research are outlined.

Effect of sustained stretch on dispersion of ventricular fibrillation intervals in normal rabbit hearts

OBJECTIVE To determine the effect of acute left ventricular dilatation on refractoriness in normal hearts. METHODS During sustained ventricular fibrillation (VF) in isolated perfused hearts, recording of local activation time yields VF intervals which provide an index of local refractoriness. Simultaneous measurement from multiple sites enables study of spatial aspects of changes in refractoriness. We studied the effects of stretch on the magnitude and dispersion of changes in VF interval in 10 isolated, Langendorff-perfused rabbit hearts using a flexible epicardial array containing 240 unipolar electrodes. The left ventricular pressure was increased from 0 to 40 mmHg by inflation of an intraventricular balloon during sustained VF. RESULTS The current threshold for VF induction fell from 64 +/- 11 mA to 43 +/- 11 mA (mean +/- SE, P < 0.01) following ventricular dilatation. Mean VF interval at 0 mmHg was 79.8 +/- 1.3 ms and fell to 70.2 +/- 1.7 ms (P < 0.01) at 40 mmHg. There was a corresponding increase in dispersion of VF interval (coefficient of variation) from 8.13 +/- 0.8 to 13.3 +/- 0.8 (P < 0.01). There was regional heterogeneity in the areas of greatest reduction in VF interval, which varied between hearts. Following balloon inflation there was an increase in the number of activation waves. CONCLUSIONS Acute ventricular dilatation produces spatially heterogeneous changes in refractoriness which would predispose to the maintenance of reentrant arrhythmias.

Optical and electrical recordings from isolated coronary-perfused ventricular wedge preparations

The electrophysiological heterogeneity that exists across the ventricular wall in the mammalian heart has long been recognized, but remains an area that is incompletely understood. Experimental studies of the mechanisms of arrhythmogenesis in the whole heart often examine the epicardial surface in isolation and thereby disregard transmural electrophysiology. Significant heterogeneity exists in the electrophysiological properties of cardiomyocytes isolated from different layers of the ventricular wall, and given that regional heterogeneities of membrane repolarization properties can influence the electrophysiological substrate for re-entry, the diversity of cell types and characteristics spanning the ventricular wall is important in the study of arrhythmogenesis. For these reasons, coronary-perfused left ventricular wedge preparations have been developed to permit the study of transmural electrophysiology in the intact ventricle. Since the first report by Yan and Antzelevitch in 1996, electrical recordings from the transmural surface of canine wedge preparations have provided a wealth of data regarding the cellular basis for the electrocardiogram, the role of transmural heterogeneity in arrhythmogenesis, and differences in the response of the different ventricular layers to drugs and neurohormones. Use of the wedge preparation has since been expanded to other species and more recently it has also been widely used in optical mapping studies. The isolated perfused wedge preparation has become an important tool in cardiac electrophysiology. In this review, we detail the methodology involved in recording both electrical and optical signals from the coronary-perfused wedge preparation and review the advances in cardiac electrophysiology achieved through study of the wedge.

Alternans of action potential duration and amplitude in rabbits with left ventricular dysfunction following myocardial infarction.

T-wave alternans may predict the occurrence of ventricular arrhythmias in patients with left ventricular dysfunction and experimental work has linked discordant repolarization alternans to the induction of re-entry. The aim of this study was to examine the occurrence of transmural repolarization alternans and to investigate the link between alternans and ventricular arrhythmia in rabbits with left ventricular dysfunction following myocardial infarction. Optical mapping was used to record action potentials from the transmural surface of left ventricular wedge preparations from normal and post-infarction hearts during a progressive reduction in pacing cycle length at 30 and 37°C. Data were analyzed using custom software, including spectral analysis. There were no significant differences in baseline transmural electrophysiology between the groups. Post-infarction hearts had a lower threshold for both repolarization alternans (286 vs. 333 bpm, p<0.05) and ventricular arrhythmias (79 vs. 19%, p<0.01) during rapid pacing, which was not accounted for by increased transmural discordant alternans. In VF-prone hearts, alternans in optical action potential amplitude was observed and increased until 2:1 block occurred. The degree of optical action potential amplitude alternans (12.0 ± 7.0 vs. 1.8 ± 0.3, p<0.05), but not APD(90) alternans (1.4 ± 0.6 vs. 1.1 ± 0.1, p>0.05) was associated with VF inducibility during rapid pacing. Post-infarction hearts are more vulnerable to transmural alternans and ventricular arrhythmias at rapid rates. Alternans in optical action potential amplitude was associated with conduction block and VF. The data suggest that changes in optical action potential amplitude may underlie a mechanism for alternans-associated ventricular arrhythmia in left ventricular dysfunction.

Heterogeneity of Ventricular Fibrillation Dominant Frequency During Global Ischemia in Isolated Rabbit Hearts

Introduction : Ventricular fibrillation (VF) studies show that ECG‐dominant frequency (DF) decreases as ischemia develops. This study investigates the contribution of the principle ischemic metabolic components to this decline.