D A Eisner

The University of Manchester, Manchester, England, United Kingdom

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Publications (223)1347.64 Total impact

  • David Eisner
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    ABSTRACT: Contraction of the heart results from an increase of cytoplasmic Ca concentration ([Ca2+]i), the so-called systolic Ca transient. Most of this results from the release of Ca from the sarcoplasmic reticulum (SR) through the Ryanodine Receptor (RyR). In turn, the amplitude of this Ca transient determines the contractility of the heart. In this lecture, I consider the factors which govern the size and stability of this Ca release. The amplitude of the Ca transient is a steep function of SR Ca resulting in a requirement for very precise beat-to-beat regulation of SR Ca content. This is achieved by a simple negative feedback mechanism in which an increase of SR Ca content increases the size the Ca transient resulting in a decrease of Ca influx on the L-type Ca current and an increase of efflux on Na-Ca exchange. Changing the activity of any of the Ca cycling proteins will change the steady state SR Ca content. This feedback mechanism has many consequences including the fact that a change of RyR open probability has a only a temporary effect on the amplitude of the Ca transient due to a compensating change of SR Ca content. The remainder of the article considers the link between intracellular Ca waves and arrhythmias. This is done in the context of catecholaminergic polymorphic ventricular tachycardia (CPVT). This is an inherited arrhythmia syndrome, in many cases due to a RyR mutation, where arrhythmias occur during exercise as a result of β-adrenergic stimulation. Ca waves only occur when the SR Ca content exceeds a threshold level. Our data shows that the threshold is reduced by the RyR mutation and the that adrenergic stimulation increases SR Ca content.This article is protected by copyright. All rights reserved
    Experimental physiology 08/2014; · 2.87 Impact Factor
  • D.J. Greensmith, L. Miller, D.A. Eisner
    Proc Physiol Soc, London; 07/2014
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    ABSTRACT: The incidence of atrial fibrillation (AF) has a steep relationship with age. AF prevalence in persons aged over 85 exceeds 15% in European cohorts. The basis for the exaggerated vulnerability of the atria to fibrillation in the elderly is incompletely understood. Previous work has shown that ageing is associated with a prolongation of action potential duration, a finding that could be expected to protect against re-entrant arrhythmias. Alternating beat to beat variation in action potential duration and amplitude occurs at high heart rates and has been associated with a history of AF in humans. We investigated whether isolated atrial myocytes from young and old sheep would exhibit differences in alternans behaviour.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A119-A120. · 6.02 Impact Factor
  • The Lancet 02/2014; 383:S93. · 39.21 Impact Factor
  • Circulation Research 09/2013; 113(8):958-61. · 11.09 Impact Factor
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    ABSTRACT: Over the last two decades, understanding of the mechanisms that underlie heart failure has grown enormously. One of the key concepts is that heart failure is associated with profound alterations in myocardial calcium handling and excitation-contraction coupling. Myocardial Ca handling Most of the calcium that activates contraction comes from the sarcoplasmic reticulum (SR). It leaves the SR through a specialized release channel known as the ryanodine receptor (RyR). The probability that a RyR is open and can therefore allow Ca to leave the SR into the cytoplasm is increased by an increase in the concentration of either cytosolic or SR (luminal) Ca concentration. During the normal heartbeat sarcolemmal Ca channels open and some of the entering Ca binds to the RyRs making them open thereby triggering the release of a much greater amount of Ca from the SR into the cytosol. This Ca release causes a rapid rise of cytosolic Ca to levels that activate the myofilaments and initiate contraction. After termination of release of Ca from the SR (because of closure of RyRs), cytosolic Ca levels decline rapidly and relaxation occurs. Ca is rapidly removed from the cytosol by two major Ca removal systems: the sarcoendoplasmic reticulum Ca ATPase (SERCA) and the sarcolemmal sodium /calcium exchanger (NCX). SERCA pumps Ca back into the SR while NCX pumps 1 Ca(2+) ion out in exchange for the influx of 3 Na(+) ions into the cell. This rapid cycle of Ca release and reuptake is known as the systolic Ca transient and it is one of the main factors that control force of contraction in the heart. It is worth emphasizing that the normal Ca transient depends on the RyRs being virtually closed in diastole, opening very briefly to produce the systolic increase of Ca and then closing to allow Ca to fall to resting levels.
    Circulation 07/2013; · 14.95 Impact Factor
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    ABSTRACT: The microcirculation is the site of gas and nutrient exchange. Control of central or local signals acting on the myocytes, pericytes and endothelial cells within it, is essential for health. Due to technical problems of accessibility, the mechanisms controlling Ca(2+) signalling and contractility of myocytes and pericytes in different sections of microvascular networks in situ have not been investigated. We aimed to investigate Ca(2+) signalling and functional responses, in a microcirculatory network in situ. Using live confocal imaging of ureteric microvascular networks, we have studied the architecture, morphology, Ca(2+) signalling and contractility of myocytes and pericytes. Ca(2+) signals vary between distributing arcade and downstream transverse and precapillary arterioles, are modified by agonists, with sympathetic agonists being ineffective beyond transverse arterioles. In myocytes and pericytes, Ca(2+) signals arise from Ca(2+) release from the sarcoplasmic reticulum through inositol 1,4,5-trisphosphate-induced Ca(2+) release and not via ryanodine receptors or Ca(2+) entry into the cell. The responses in pericytes are less oscillatory, slower and longer-lasting than those in myocytes. Myocytes and pericytes are electrically coupled, transmitting Ca(2+) signals between arteriolar and venular networks dependent on gap junctions and Ca(2+) entry via L-type Ca(2+) channels. Endothelial Ca(2+) signalling inhibits intracellular Ca(2+) oscillations in myocytes and pericytes via L-arginine/nitric oxide pathway and intercellular propagating Ca(2+) signals via EDHF. Increases of Ca(2+) in pericytes and myocytes constrict all vessels except capillaries. These data reveal the structural and signalling specializations allowing blood flow to be regulated by myocytes and pericytes.
    Cell calcium 07/2013; · 4.29 Impact Factor
  • Journal of Molecular and Cellular Cardiology 03/2013; · 5.15 Impact Factor
  • Journal of Molecular and Cellular Cardiology 03/2013; · 5.15 Impact Factor
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    ABSTRACT: The atria contribute 25 % to ventricular stroke volume and are the site of the commonest cardiac arrhythmia, atrial fibrillation (AF). The initiation of contraction in the atria is similar to that in ventricle involving a systolic rise of intracellular Ca(2+) concentration ([Ca(2+)](i)). There are, however, substantial inter-species differences in the way systolic Ca(2+) is regulated in atrial cells. These differences are a consequence of a well-developed and functionally relevant transverse (t) - tubule network in the atria of large mammals including man and its virtual absence in smaller laboratory species such as the rat. Where t-tubules are absent the systolic Ca(2+) transient results from a 'fire-diffuse-fire' sequential recruitment of Ca(2+) release sites from the cell edge to the centre and hence marked spatiotemporal heterogeneity of systolic Ca(2+). Conversely the well-developed t-tubule network in large mammals ensures a near synchronous rise of [Ca(2+)](i). In addition to synchronizing the systolic rise of [Ca(2+)](i) the presence of t-tubules in the atria of large mammals, by virtue of localization of the L-type Ca(2+) channels and Na(+)-Ca(2+) exchanger antiporters on the t-tubules, may serve to respectively accelerate changes in the amplitude of the systolic Ca(2+) transient during inotropic manoeuvres and lower diastolic [Ca(2+)](i). On the other hand, the presence of t-tubules and thence wider cellular distribution of the Na(+)-Ca(2+) exchanger may predispose the atria of large mammals to Ca(2+) dependent delayed after-depolarisations (DADs); this may be a determining factor in why the atria of large mammals spontaneously develop and maintain AF.
    Cardiovascular Research 02/2013; · 5.81 Impact Factor
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    ABSTRACT: This article reviews the consequences of the need for the cardiac cell to be in calcium flux balance in the steady state. We first discuss how this steady state condition affects the control of resting [Ca(2+)](i). The next section considers how sarcoplasmic retirculum (SR) Ca content is controlled by a feedback mechanism whereby changes of SR Ca affect the amplitude of the Ca transient and this, in turn, controls sarcolemmal Ca fluxes. Subsequent sections review the effects of altering the activity of individual Ca handling proteins. Increasing the activity of the SR Ca-ATPase (SERCA) increases both the amplitude and rate constant of decay of the systolic Ca transient. The Ca flux balance condition requires that this must be achieved with no change of Ca efflux placing constraints on the magnitude of change of amplitude and decay rate. We analyze the quantitative dependence of Ca transient amplitude and SR content on SERCA activity. Increasing the open probability of the RyR during systole is predicted to have no steady state effect on the amplitude of the systolic Ca transient. We discuss the effects of changing the amplitude of the L-type Ca current in the context of both triggering Ca release from the SR and loading the cell with calcium. These manoeuvres are considered in the context of the effects of β-adrenergic stimulation. Finally, we review calcium flux balance in the presence of Ca waves.
    Journal of Molecular and Cellular Cardiology 12/2012; · 5.15 Impact Factor
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    ABSTRACT: Rationale: Spontaneous Ca(2+) release from the sarcoplasmic reticulum (SCR) can cause delayed afterdepolarizations (DADs) and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation leading to SCR. Objective: We aimed to determine ionic mechanisms controlling BVR under these conditions. Methods and Results: Membrane potentials and cell shortening or Ca(2+) transients were recorded from isolated canine left-ventricular myocytes in the presence of isoproterenol. Action-potential (AP) durations following DADs were significantly prolonged. Addition of I(Ks) blockade led to further AP prolongation after SCR and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, CaMKII inhibition, or by using Mg(2+) or flecainide, eliminated DADs and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring I(CaL) with and without prior SCR indicated that I(CaL) was increased during Ca(2+)-induced Ca(2+) release after SCR, and this contributes to AP prolongation. Prolongation of QT, T(peak)-T(end) intervals and left-ventricular monophasic AP duration of beats following aftercontractions occurred prior to torsades de pointes in an in-vivo dog model of drug-induced long-QT1 syndrome. Conclusions: SCR contributes to increased BVR by interspersed prolongation of AP duration, which is exacerbated during I(Ks) blockade. Attenuation of Ca(2+)-induced Ca(2+) release by SCR underlies AP prolongation via increased I(CaL). These data provide novel insights into arrhythmogenic mechanisms during β-adrenergic stimulation besides triggered activity and illustrate the importance of I(Ks) function in preventing excessive BVR.
    Circulation Research 11/2012; · 11.09 Impact Factor
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    ABSTRACT: Mammalian ventricular myocytes are characterized by the presence of an extensive transverse (t) tubule network which is responsible for the synchronous rise of intracellular Ca(2+) concentration ([Ca(2+)](i)) during systole. Disruption to the ventricular t-tubule network occurs in various cardiac pathologies and leads to heterogeneous changes of [Ca(2+)](i) which is thought to contribute to the reduced contractility and increased susceptibility to arrhythmias of the diseased ventricle. Here we review evidence that, despite the long-held dogma of atrial cells having no or very few t-tubules, there is indeed an extensive and functionally significant t-tubule network present in atrial myocytes of large mammals including man. Moreover, the atrial t-tubule network is highly plastic in nature and undergoes far more extensive remodeling in heart disease than is the case in the ventricle with profound consequences for the resulting systolic Ca(2+) transient. In addition to considering the functional role of the t-tubule network in the healthy and diseased atria we also provide an overview of recent data concerning the putative factors controlling the formation of t-tubules and conclude by posing some important questions that currently remain to be addressed and whether or not targeting t-tubules offers potential novel therapeutic possibilities for heart disease.
    Journal of Molecular and Cellular Cardiology 11/2012; 58. · 5.15 Impact Factor
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    David A Eisner, Yatong Li, Stephen O'Neill
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    ABSTRACT: The aim of was to investigate the propagation of calcium waves between cells and determine whether this synchronizes alternating Ca release between cells. Experiments were carried out on electrically coupled cell pairs; spontaneous Ca waves were produced by elevating external Ca. There was a significant difference in the ability of these waves to propagate between cells depending on the orientation of the pairs. Although almost all pairs connected by side to side contacts showed propagating Ca release, this was very uncommon in end to end cell pairs. Confocal studies showed that there was a gap at the intercalated disc consisting of cell membranes and a region of cytoplasm devoid of sarcoplasmic reticulum. This gap was 2.3 μm in length and is suggested to interfere with Ca wave propagation. The gap measured was much smaller between side to side contacts: 1.5 μm and so much less likely to interfere with propagation. Subsequent experiments investigated the synchronization between cells of calcium alternans produced by small depolarizing pulses. Although this alternation results from beat to beat alternation of intracellular Ca wave propagation, there was no evidence that propagation of Ca waves between cells contributed to synchronization of this alternans.
    The Journal of Physiology 10/2012; · 4.38 Impact Factor
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    ABSTRACT: This study investigated the mechanisms underlying the propagation of cytoplasmic calcium waves and the genesis of systolic Ca(2+) alternans in cardiac myocytes lacking transverse tubules (t-tubules). These correspond to atrial cells of either small mammals or large mammals that have lost their t-tubules due to disease-induced structural remodeling (e.g., atrial fibrillation). A mathematical model was developed for a cluster of ryanodine receptors distributed on the cross section of a cell that was divided into 13 elements with a spatial resolution of 2 μm. Due to the absence of t-tubules, L-type Ca(2+) channels were only located in the peripheral elements close to the cell-membrane surface and produced Ca(2+) signals that propagated toward central elements by triggering successive Ca(2+)-induced Ca(2+) release (CICR) via Ca(2+) diffusion between adjacent elements. Under control conditions, the Ca(2+) signals did not fully propagate to the central region of the cell. However, with modulation of several factors responsible for Ca(2+) handling, such as the L-type Ca(2+) channels (Ca(2+) influx), SERCA pumps (sarcoplasmic reticulum (SR) Ca(2+) uptake), and ryanodine receptors (SR Ca(2+) release), Ca(2+) wave propagation to the center of the cell could occur. These simulation results are consistent with previous experimental data from atrial cells of small mammals. The model further reveals that spatially functional heterogeneity in Ca(2+) diffusion within the cell produced a steep relationship between the SR Ca(2+) content and the cytoplasmic Ca(2+) concentration. This played an important role in the genesis of Ca(2+) alternans that were more obvious in central than in peripheral elements. Possible association between the occurrence of Ca(2+) alternans and the model parameters of Ca(2+) handling was comprehensively explored in a wide range of one- and two-parameter spaces. In addition, the model revealed a spontaneous second Ca(2+) release in response to a single voltage stimulus pulse with SR Ca(2+) overloading and augmented Ca(2+) influx. This study provides what to our knowledge are new insights into the genesis of Ca(2+) alternans and spontaneous second Ca(2+) release in cardiac myocytes that lack t-tubules.
    Biophysical Journal 04/2012; 102(7):1471-82. · 3.83 Impact Factor
  • Heart Rhythm 11/2011; 8(11):1823-1823. · 4.92 Impact Factor
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    ABSTRACT: Changes of the activity of the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) affect the amplitude of the systolic Ca(2+) transient and thence cardiac contractility. This is thought to be due to alterations of SR Ca(2+) content. Recent work on mice in which the expression of SERCA is decreased found that a large reduction of SERCA expression resulted in a proportionately much smaller decrease of SR Ca(2+) content. The aim of the current work was to investigate the quantitative nature of the dependence of both the amplitude of the systolic Ca(2+) transient and SR Ca(2+) content on SERCA activity during acute partial inhibition of SERCA. Experiments were performed on rat ventricular myocytes. Brief application of thapsigargin (1 μm) resulted in a decrease of SERCA activity as measured from the rate of decay of the systolic Ca(2+) transient. This was accompanied by a decrease in the amplitude of the systolic Ca(2+) transient which was linearly related to that of SERCA activity. However, the fractional decrease in the SR Ca(2+) content was much less than that of SERCA activity. On average SR Ca(2+) content was proportional to SERCA activity raised to the 0.38 ± 0.07 power. This shallow dependence of SR content on SERCA activity arises because Ca(2+) release is a steep function of SR Ca(2+) content. In contrast SR Ca(2+) content was increased 4.59 ± 0.40 (n = 8)-fold by decreasing ryanodine receptor opening with tetracaine (1 mm). Therefore a modest decrease of SR Ca(2+) content results in a proportionately larger fall of Ca(2+) release from the SR which can balance a larger initiating decrease of SERCA. In conclusion, the shallow dependence of SR Ca(2+) content on SERCA activity is expected for a system in which small changes of SR Ca(2+) content produce larger effects on the amplitude of the systolic Ca(2+) transient.
    The Journal of Physiology 08/2011; 589(Pt 19):4723-9. · 4.38 Impact Factor
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    ABSTRACT: Reduced inotropic responsiveness is characteristic of heart failure (HF). This study determined the cellular Ca2+ homeostatic and molecular mechanisms causing the blunted β-adrenergic (β-AR) response in HF.We induced HF by tachypacing in sheep; intracellular Ca2+ concentration was measured in voltage-clamped ventricular myocytes. In HF, Ca2+ transient amplitude and peak L-type Ca2+ current (ICa-L) were reduced (to 70 ± 11% and 50 ± 3.7% of control, respectively, P <0.05) whereas sarcoplasmic reticulum (SR) Ca2+ content was unchanged. β-AR stimulation with isoprenaline (ISO) increased Ca2+ transient amplitude, ICa-L and SRCa2+ content in both cell types; however, the response of HF cells was markedly diminished (P <0.05).Western blotting revealed an increase in protein phosphatase levels (PP1, 158 ± 17% and PP2A, 188 ± 34% of control, P <0.05) and reduced phosphorylation of phospholamban in HF (Ser16, 30 ± 10% and Thr17, 41 ± 15% of control, P <0.05). The β-AR receptor kinase GRK-2 was also increased in HF (173 ± 38% of control, P <0.05). In HF, activation of adenylyl cyclase with forskolin rescued the Ca2+ transient, SR Ca2+ content and SR Ca2+ uptake rate to the same levels as control cells in ISO. In conclusion, the reduced responsiveness of the myocardium to β-AR agonists in HF probably arises as a consequence of impaired phosphorylation of key intracellular proteins responsible for regulating the SR Ca2+ content and therefore failure of the systolic Ca2+ transient to increase appropriately during β-AR stimulation.
    The Journal of Physiology 03/2011; 589(Pt 6):1367-82. · 4.38 Impact Factor
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    ABSTRACT: In this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca(2+) wave development during β-adrenergic stimulation. SERCA2 knockout mice (KO) were used 6 days after cardio-specific gene deletion, with left ventricular SERCA2a abundance reduced by 54 ± 9% compared with SERCA2(flox/flox) controls (FF) (P < 0.05). Ca(2+) waves occurred in fewer KO than FF myocytes (40 vs. 68%, P < 0.05), whereas the addition of isoproterenol (ISO) induced waves in an equal percentage of myocytes (82 vs. 64%). SERCA2-dependent Ca(2+) reuptake was slower in KO (-ISO, KO vs. FF: 15.4 ± 1.2 vs. 21.1 ± 1.4 s(-1), P < 0.05), but equal during ISO (+ISO, KO vs. FF: 21.9 ± 3.3 vs. 27.7 ± 2.7 s(-1)). Threshold SR Ca(2+) content for wave development was lower in KO (-ISO, KO vs. FF: 126.6 ± 10.3 vs. 159.3 ± 7.1 µmol/L, P < 0.05) and was increased by ISO only in FF (+ISO, KO vs. FF: 131.7 ± 8.7 vs. 205.5 ± 20.4 µmol/L, P < 0.05). During ISO, Ca(2+)/calmodulin-dependent kinase II (CaMKII)-dependent phosphorylation of RyR in KO was 217 ± 21% of FF (P < 0.05), and SR Ca(2+) leak indicated higher RyR open probability in KO. CaMKII inhibition decreased Ca(2+) spark frequency in KO by 44% (P < 0.05) but not in FF. Mathematical modelling predicted that increased Ca(2+) sensitivity of RyR in KO could account for increased Ca(2+) wave probability during ISO. In ventricular cardiomyocytes with reduced SERCA2 abundance, Ca(2+) wave development following β-adrenergic stimulation is potentiated. We suggest that this is caused by a CaMKII-dependent shift in the balance between SERCA2-dependent Ca(2+) reuptake and threshold SR Ca(2+) content.
    Cardiovascular Research 02/2011; 90(3):503-12. · 5.81 Impact Factor
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    Katharine Dibb, David Eisner
    The Journal of Physiology 12/2010; 588(Pt 24):4849. · 4.38 Impact Factor

Publication Stats

7k Citations
1,347.64 Total Impact Points


  • 1992–2014
    • The University of Manchester
      • • Manchester Medical School
      • • Faculty of Medical and Human Sciences
      Manchester, England, United Kingdom
  • 1985–2013
    • University of Maryland, Baltimore
      • Department of Physiology
      Baltimore, Maryland, United States
  • 2009
    • National Heart, Lung, and Blood Institute
      • Translational Medicine Branch
      Maryland, United States
    • Oslo University Hospital
      • Institute for Experimental Medical Research
      Oslo, Oslo, Norway
  • 1994–2005
    • University of Bristol
      • School of Physiology and Pharmacology
      Bristol, England, United Kingdom
    • University of Glasgow
      • Division of Physiology
      Glasgow, SCT, United Kingdom
  • 1991–2004
    • University of Liverpool
      • Department of Cellular and Molecular Physiology
      Liverpool, England, United Kingdom
  • 1985–1995
    • University College London
      • Department of Clinical Physiology
      London, ENG, United Kingdom
  • 1979
    • University of Oxford
      Oxford, England, United Kingdom