Gillian E Marshall

Publications (4)16.8 Total impact

• Article: Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes.

  A J Workman, G E Marshall, A C Rankin, G L Smith, J Dempster
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  ABSTRACT: Key points  The shape of the cardiac atrial action potential is influenced by the flow of a transient outward K(+) current (I(TO)) across atrial muscle cell membranes.  Whether changes in I(TO) could alter atrial cell action potentials in ways that could affect mechanisms of abnormal heart rhythms (arrhythmias) is unclear, because currently available I(TO) blocking drugs are non-selective.  We used the 'dynamic-clamp' technique, for the first time in atrial cells isolated from patients, and from rabbits, to electrically simulate selective changes in I(TO) during action potential recording.  We found that I(TO) decrease prolonged atrial cell action potential duration and, under β-adrenergic-stimulation, provoked abnormal membrane potential oscillations (afterdepolarisations) that were preventable by I(TO) increase or a β-blocker.  These results help us better understand the contribution of I(TO) to atrial cell action potential shape and mechanisms of arrhythmia, with potential implications for both the development and treatment of atrial fibrillation.
  The Journal of Physiology 06/2012; 590(Pt 17):4289-305. · 4.72 Impact Factor
• Article: Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade.

  Gillian E Marshall, Julie A Russell, James O Tellez, Pardeep S Jhund, Susan Currie, John Dempster, Mark R Boyett, Kathleen A Kane, Andrew C Rankin, Antony J Workman
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  ABSTRACT: Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K(+) currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K(+) currents (I(TO), I(KSUS) and I(K1)) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in I(TO) density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. I(K1) was reduced by 34% at -120 mV (p < 0.05). Neither I(KSUS), nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of I(TO)- and I(K1)-decrease could result in a 28% increase in APD(90). Chronic β-blockade did not alter mRNA or protein expression of the I(TO) pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in I(K1). A reduction in atrial I(TO) and I(K1) associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits.
  Pflügers Archiv - European Journal of Physiology 12/2011; 463(4):537-48. · 4.46 Impact Factor
• Article: Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF.

  Antony J Workman, Davide Pau, Calum J Redpath, Gillian E Marshall, Julie A Russell, John Norrie, Kathleen A Kane, Andrew C Rankin
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  ABSTRACT: Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear. This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF. Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique. The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 +/- 8 ms; 52 cells, 18 patients vs 233 +/- 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% +/- 4%, n = 15) than in those without LVSD (62% +/- 2%, n = 31; P <0.05). In cells from patients with LVEF <or= 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics. LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF.
  Heart rhythm: the official journal of the Heart Rhythm Society 05/2009; 6(4):445-51. · 4.56 Impact Factor
• Article: Post-operative atrial fibrillation is influenced by beta-blocker therapy but not by pre-operative atrial cellular electrophysiology.

  Antony J Workman, Davide Pau, Calum J Redpath, Gillian E Marshall, Julie A Russell, Kathleen A Kane, John Norrie, Andrew C Rankin
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  ABSTRACT: We investigated whether post-cardiac surgery (CS) new-onset atrial fibrillation (AF) is predicted by pre-CS atrial cellular electrophysiology, and whether the antiarrhythmic effect of beta-blocker therapy may involve pre-CS pharmacological remodeling. Atrial myocytes were obtained from consenting patients in sinus rhythm, just prior to CS. Action potentials and ion currents were recorded using whole-cell patch-clamp technique. Post-CS AF occurred in 53 of 212 patients (25%). Those with post-CS AF were older than those without (67 +/- 2 vs 62 +/- 1 years, P = 0.005). In cells from patients with post-CS AF, the action potential duration at 50% and 90% repolarization, maximum upstroke velocity, and effective refractory period (ERP) were 13 +/- 4 ms, 217 +/- 16 ms, 185 +/- 10 V/s, and 216 +/- 14 ms, respectively (n = 30 cells, 11 patients). Peak L-type Ca(2+) current, transient outward and inward rectifier K(+) currents, and the sustained outward current were -5.0 +/- 0.5, 12.9 +/- 2.4, -4.1 +/- 0.4, and 9.7 +/- 1.0 pA/pF, respectively (13-62 cells, 7-19 patients). None of these values were significantly different in cells from patients without post-CS AF (P > 0.05 for each, 60-279 cells, 29-86 patients), confirmed by multiple and logistic regression. In patients treated >7 days with a beta-blocker pre-CS, the incidence of post-CS AF was lower than in non-beta-blocked patients (13% vs 27%, P = 0.038). Pre-CS beta-blockade was associated with a prolonged pre-CS atrial cellular ERP (P = 0.001), by a similar degree (approximately 20%) in those with and without post-CS AF. Pre-CS human atrial cellular electrophysiology does not predict post-CS AF. Chronic beta-blocker therapy is associated with a reduced incidence of post-CS AF, unrelated to a pre-CS ERP-prolonging effect of this treatment.
  Journal of Cardiovascular Electrophysiology 11/2006; 17(11):1230-8. · 3.06 Impact Factor