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Papers by Godfrey Smith

Cardiovascular Research, Jun 21, 2022

(i) Pseudo-ECG recorded from a Langendorff-perfused rabbit heart under aLQTS conditions during pa... more (i) Pseudo-ECG recorded from a Langendorff-perfused rabbit heart under aLQTS conditions during pacing at 2000ms showing induction of TdP by spontaneous PVCs. (ii) Contour maps showing APD90 for a paced beat and AT of the subsequent PVC with contiguous single-pixel AP traces taken from dashed line plotted with estVm and expanded to show the temporal relationship between the peak of the EAD (blue dashed line), the peak VG (red dashed line) and the earliest upstroke of the PVC (dark grey dashed line). (iii) Simulations of the border of a prolonged AP island, showing the initiation of a PVC at the border of the long APD region with propagation into the normal APD region with ICaL and INa traces sampled at 1mm spacing from the border. (iv) Superimposed AP traces showing abolition of PVCs with nifedipine in the presence of EADs and APD prolongation, with doseresponse for anti-arrhythmic effect of nifedipine and recapitulation with reduction of gCaL in simulations.

The Journal of Physiology, Jun 12, 2019

Early-afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of... more Early-afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of cardiac arrhythmias. Ventricular EADs involve reactivation of a Ca 2+ current (I CaL) in its 'window region' voltage range. However, electrical mechanisms of atrial EADs, a potential cause of atrial fibrillation, are poorly understood. r Atrial cells were obtained from consenting patients undergoing heart surgery, as well as from rabbits. I CaL was blocked with nifedipine and then a hybrid patch clamp/mathematicalmodelling technique, 'dynamic clamping' , was used to record action potentials at the same time as injecting an artificial, modifiable, I CaL (I CaL,D-C). r Progressively widening the I CaL,D-C window region produced EADs of various types, dependent on window width. EAD production was strongest upon moving the activation (vs. inactivation) side of the window. r EADs were then induced by a different method: increasing I CaL,D-C amplitude and/or K + channel-blockade (4-aminopyridine). Narrowing of the I CaL,D-C window by ß10 mV abolished these EADs. r Atrial I CaL window narrowing is worthy of further testing as a potential anti-atrial fibrillation drug mechanism.

British Journal of Pharmacology, Aug 11, 2017

BACKGROUND AND PURPOSE Human ether-ago go related gene (hERG; K v 11.1) channel inhibition is a w... more BACKGROUND AND PURPOSE Human ether-ago go related gene (hERG; K v 11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro-arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The interference from accompanying block of Ca v 1.2 and Na v 1.5 channels was investigated along with an in silico AP model. EXPERIMENTAL APPROACH Drug-induced changes in APD were assessed in hiPSC-CMs using voltage-sensitive dyes. The IC 50 values for dofetilide and 13 derivatives on hERG current were estimated in an HEK293 expression system. The relative potency of each drug on APD was estimated by calculating the dose (D 150) required to prolong the APD at 90% (APD 90) repolarization by 50%. KEY RESULTS The D 150 in hiPSC-CMs was linearly correlated with IC 50 of hERG current. In silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, and these compounds also inhibited Ca v 1.2 and/or Na v 1.5 in a channel statedependent manner. Adding Ca v 1.2 and Na v 1.2 block to the in silico model recapitulated the direction but not the extent of the APD change. CONCLUSIONS AND IMPLICATIONS Potency of hERG current inhibition correlates linearly with an index of APD in hiPSC-CMs. The compounds that do not correlate have additional effects including concomitant block of Ca v 1.2 and/or Na v 1.5 channels. In silico simulations of hiPSC-CMs APs confirm the principle of the multiple ion channel effects. Abbreviations APD, action potential duration; CiPA, comprehensive in vitro proarrhythmia assay; hERG, human ether-ago go related gene; hiPSC-CMs, human-induced pluripotent stem cell-derived cardiomyocytes; I Kr , delayed rectifier potassium current; TdP, torsade de pointes This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Biomolecules, Apr 14, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Mathematical Medicine and Biology: A Journal of the IMA

Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinge... more Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a mul...

International Journal of Molecular Sciences

Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results i... more Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals ...

International Journal of Molecular Sciences, 2021

The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiC... more The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) complicates their use for therapeutic and pharmacological purposes. An insufficient inward rectifying current (IK1) and the presence of a funny current (if) cause spontaneous electrical activity. This study tests the hypothesis that the co-culturing of hiCMs with a human embryonic kidney (HEK) cell-line expressing the Kir2.1 channel (HEK-IK1) can generate an electrical syncytium with an adult-like cardiac electrophysiology. The mechanical activity of co-cultures using different HEK-IK1:hiCM ratios was compared with co-cultures using wildtype (HEK–WT:hiCM) or hiCM alone on days 3–8 after plating. Only ratios of 1:3 and 1:1 showed a significant reduction in spontaneous rate at days 4 and 6, suggesting that IK1 was influencing the electrophysiology. Detailed analysis at day 4 revealed an increased incidence of quiescent wells or sub-areas. Electrical activity showed a decreased action p...

The Journal of Physiology, 2021

Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CM) in monolayers interact mech... more Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CM) in monolayers interact mechanically via cell–cell and cell–substrate adhesion. Spatiotemporal features of contraction were analysed in hiPSC‐CM monolayers (1) attached to glass or plastic (Young's modulus (E) >1 GPa), (2) detached (substrate‐free) and (3) attached to a flexible collagen hydrogel (E = 22 kPa). The effects of isoprenaline on contraction were compared between rigid and flexible substrates. To clarify the underlying mechanisms, further gene expression and computational studies were performed. HiPSC‐CM monolayers exhibited multiphasic contractile profiles on rigid surfaces in contrast to hydrogels, substrate‐free cultures or single cells where only simple twitch‐like time‐courses were observed. Isoprenaline did not change the contraction profile on either surface, but its lusitropic and chronotropic effects were greater in hydrogel compared with glass. There was no significant difference between...

JCI Insight, 2021

Calcium transients. GCaMP6f EHTs were analyzed using standard methods (see Supplemental Methods),... more Calcium transients. GCaMP6f EHTs were analyzed using standard methods (see Supplemental Methods), and parameters were calculated in pClamp. GCaMP6f cells were obtained courtesy of the Conklin laboratory (Gladstone Institutes,

Journal of Cardiovascular Pharmacology, 2021

The use of voltage sensitive dye di-4-ANEPPS and video-based contractility measurements to assess... more The use of voltage sensitive dye di-4-ANEPPS and video-based contractility measurements to assess drug effects on excitation-contraction coupling in human induced pluripotent stem cell-derived cardiomyocytes.

Cryobiology, 2021

The Supporting Institutions listed above contribute to the cost of publication of this Journal, b... more The Supporting Institutions listed above contribute to the cost of publication of this Journal, but they are not owners or publishers and have no responsibility for its content or policies. Mathematical papers intended for publication in the Pacific Journal of Mathematics should be in typed form or offset-reproduced (not dittoed), double spaced with large margins. Please do not use built up fractions in the text of the manuscript. However, you may use them in the displayed equations. Underline Greek letters in red, German in green, and script in blue. The first paragraph must be capable of being used separately as a synopsis of the entire paper. In particular it should contain no bibliographic references. Please propose a heading for the odd numbered pages of less than 35 characters. Manuscripts, in triplicate, may be sent to any one of the editors.

Cardiovascular Research, 2018

Moderate therapeutic hypothermia procedures are used in post-cardiac arrest care, while in surgic... more Moderate therapeutic hypothermia procedures are used in post-cardiac arrest care, while in surgical procedures, lower core temperatures are often utilized to provide cerebral protection. Involuntary reduction of core body temperature takes place in accidental hypothermia and ventricular arrhythmias are recognized as a principal cause for a high mortality rate in these patients. We assessed both clinical and experimental literature through a systematic literature search in the PubMed database, to review the effect of hypothermia on cardiac electrophysiology. From included studies, there is common experimental and clinical evidence that progressive cooling will induce changes in cardiac electrophysiology. The QT interval is prolonged and appears more sensitive to decreases in temperature than the QRS interval. Severe hypothermia is associated with more pronounced changes, some of which are proarrhythmic. This is supported clinically where severe accidental hypothermia is commonly asso...

Frontiers in physiology, 2018

Increasing age is the most important risk factor for atrial fibrillation (AF). Very high doses of... more Increasing age is the most important risk factor for atrial fibrillation (AF). Very high doses of exercise training might increase AF risk, while moderate levels seem to be protective. This study aimed to examine the effects of age on vulnerability to AF and whether long-term aerobic interval training (AIT) could modify these effects. Nine months old, male Sprague-Dawley rats were randomized to AIT for 16 weeks (old-ex) or to a sedentary control group (old-sed), and compared to young sedentary males (young-sed). After the intervention, animals underwent echocardiography, testing of exercise capacity (VO), and electrophysiology with AF induction before electrophysiology. Fibrosis quantification, immunohistochemistry and western blotting of atrial tissue were performed. Sustained AF was induced in 4 of 11 old-sed animals, but none of the old-ex or young-sed rats ( = 0.006). VO was lower in old-sed, while old-ex had comparable results to young-sed. Fibrosis was increased in old-sed ( =...

Frontiers in physiology, 2017

Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications in diseas... more Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications in disease modeling, cell therapy, drug screening and personalized medicine. Computational models can be used to interpret experimental findings in iPSC-CMs, provide mechanistic insights, and translate these findings to adult cardiomyocyte (CM) electrophysiology. However, different cell lines display different expression of ion channels, pumps and receptors, and show differences in electrophysiology. In this exploratory study, we use a mathematical model based on iPSC-CMs from Cellular Dynamic International (CDI, iCell), and compare its predictions to novel experimental recordings made with the Axiogenesis Cor.4U line. We show that tailoring this model to the specific cell line, even using limited data and a relatively simple approach, leads to improved predictions of baseline behavior and response to drugs. This demonstrates the need and the feasibility to tailor models to individual cell lines,...

Circulation, Jan 13, 2017

Background -Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. P... more Background -Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes following MI; however, the functional role of Runx1 in the heart is unknown. Methods -To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole heart, cardiomyocyte and molecular levels. Results -Runx1 deficient mice were protected against adverse cardiac remodeling post-MI, maintaining ventricular wall thickness and contractile...

British journal of pharmacology, Jan 6, 2017

hERG (Kv11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG chann... more hERG (Kv11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro-arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in hiPSC-CMs. The interference from accompanying block of Cav1.2 and Nav1.5 channels was investigated along with an in-silico action potential (AP) model. Drug-induced changes in APD were assessed in hiPSC-CMs using voltage sensitive dyes. The half-maximal inhibitory concentrations (IC50 ) of hERG current by dofetilide and 13 derivatives were estimated in a HEK293 expression system. The relative potency of the drug on APD was estimated by calculating the drug dose (D150 ) required to prolong the APD at 90% (APD90 ) repolarisation by 50%. The D150 in hiPSC-CMs was linearly correlated with IC50 of hERG current...

Biophysical Journal, 2014

Biophysical Journal, 2015

Journal of Biophotonics, 2013

Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk ... more Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk 2-photon excitation fluorescence microscopy enables deeper high-resolution imaging of voltage and Ca2+ in intact mice, rat, and rabbit hearts

Frontiers in Physiology, 2014

Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively lit... more Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO 2 , pH 6.7) increased the time of earliest activation (T act) from 100.5 ± 7.9 to 166.1 ± 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37 • C). T act increased at shorter PCL, and the hypercapnic solution prolonged T act further: at 150 ms PCL, T act was prolonged from 131.0 ± 5.2 to 174.9 ± 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis.