Publications
61 results found
Handa B, Lawal S, Wright IJ, et al., 2019, Interventricular differences in action potential duration restitution contribute to dissimilar ventricular rhythms in ex vivo perfused hearts, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X
Background: Dissimilar ventricular rhythms refer to the occurrence of different ventricular tachyarrhythmias in the right and left ventricles or different rates of the same tachyarrhythmia in the two ventricles.Objective: We investigated the inducibility of dissimilar ventricular rhythms, their underlying mechanisms, and the impact of anti-arrhythmic drugs (lidocaine and amiodarone) on their occurrence.Methods: Ventricular tachyarrhythmias were induced with burst pacing in 28 Langendorff-perfused Sprague Dawley rat hearts (14 control, 8 lidocaine, 6 amiodarone) and bipolar electrograms recorded from the right and left ventricles. Fourteen (6 control, 4 lidocaine, 4 amiodarone) further hearts underwent optical mapping of transmembrane voltage to study interventricular electrophysiological differences and mechanisms of dissimilar rhythms.Results: In control hearts, dissimilar ventricular rhythms developed in 8/14 hearts (57%). In lidocaine treated hearts, there was a lower cycle length threshold for developing dissimilar rhythms, with 8/8 (100%) hearts developing dissimilar rhythms in comparison to 0/6 in the amiodarone group. Dissimilar ventricular tachycardia (VT) rates occurred at longer cycle lengths with lidocaine vs. control (57.1 ± 7.9 vs. 36.6 ± 8.4 ms, p < 0.001). The ratio of LV:RV VT rate was greater in the lidocaine group than control (1.91 ± 0.30 vs. 1.76 ± 0.36, p < 0.001). The gradient of the action potential duration (APD) restitution curve was shallower in the RV compared with LV (Control - LV: 0.12 ± 0.03 vs RV: 0.002 ± 0.03, p = 0.015), leading to LV-to-RV conduction block during VT.Conclusion: Interventricular differences in APD restitution properties likely contribute to the occurrence of dissimilar rhythms. Sodium channel blockade with lidocaine increases the likelihood of dissimilar ventricular rhythms.
Cantwell C, Mohamied Y, Tzortzis K, et al., 2019, Rethinking multiscale cardiac electrophysiology with machine learning and predictive modelling, Computers in Biology and Medicine, Vol: 104, Pages: 339-351, ISSN: 0010-4825
We review some of the latest approaches to analysing cardiac electrophysiology data using machine learning and predictive modelling. Cardiac arrhythmias, particularly atrial fibrillation, are a major global healthcare challenge. Treatment is often through catheter ablation, which involves the targeted localised destruction of regions of the myocardium responsible for initiating or perpetuating the arrhythmia. Ablation targets are either anatomically defined, or identified based on their functional properties as determined through the analysis of contact intracardiac electrograms acquired with increasing spatial density by modern electroanatomic mapping systems. While numerous quantitative approaches have been investigated over the past decades for identifying these critical curative sites, few have provided a reliable and reproducible advance in success rates. Machine learning techniques, including recent deep-learning approaches, offer a potential route to gaining new insight from this wealth of highly complex spatio-temporal information that existing methods struggle to analyse. Coupled with predictive modelling, these techniques offer exciting opportunities to advance the field and produce more accurate diagnoses and robust personalised treatment. We outline some of these methods and illustrate their use in making predictions from the contact electrogram and augmenting predictive modelling tools, both by more rapidly predicting future states of the system and by inferring the parameters of these models from experimental observations.
Handa BS, Roney CH, Houston C, et al., 2018, Analytical approaches for myocardial fibrillation signals, Computers in Biology and Medicine, Vol: 102, Pages: 315-326, ISSN: 0010-4825
Atrial and ventricular fibrillation are complex arrhythmias, and their underlying mechanisms remain widely debated and incompletely understood. This is partly because the electrical signals recorded during myocardial fibrillation are themselves complex and difficult to interpret with simple analytical tools. There are currently a number of analytical approaches to handle fibrillation data. Some of these techniques focus on mapping putative drivers of myocardial fibrillation, such as dominant frequency, organizational index, Shannon entropy and phase mapping. Other techniques focus on mapping the underlying myocardial substrate sustaining fibrillation, such as voltage mapping and complex fractionated electrogram mapping. In this review, we discuss these techniques, their application and their limitations, with reference to our experimental and clinical data. We also describe novel tools including a new algorithm to map microreentrant circuits sustaining fibrillation.
Roney C, Ng FS, Debney M, et al., 2018, Determinants of new wavefront locations in cholinergic atrial fibrillation, EP-Europace, Vol: 20, Pages: iii3-iii15, ISSN: 1099-5129
AimsAtrial fibrillation (AF) wavefront dynamics are complex and difficult to interpret, contributing to uncertainty about the mechanisms that maintain AF. We aimed to investigate the interplay between rotors, wavelets, and focal sources during fibrillation.Methods and resultsArrhythmia wavefront dynamics were analysed for four optically mapped canine cholinergic AF preparations. A bilayer computer model was tuned to experimental preparations, and varied to have (i) fibrosis in both layers or the epicardium only, (ii) different spatial acetylcholine distributions, (iii) different intrinsic action potential duration between layers, and (iv) varied interlayer connectivity. Phase singularities (PSs) were identified and tracked over time to identify rotational drivers. New focal wavefronts were identified using phase contours. Phase singularity density and new wavefront locations were calculated during AF. There was a single dominant mechanism for sustaining AF in each of the preparations, either a rotational driver or repetitive new focal wavefronts. High-density PS sites existed preferentially around the pulmonary vein junctions. Three of the four preparations exhibited stable preferential sites of new wavefronts. Computational simulations predict that only a small number of connections are functionally important in sustaining AF, with new wavefront locations determined by the interplay between fibrosis distribution, acetylcholine concentration, and heterogeneity in repolarization within layers.ConclusionWe were able to identify preferential sites of new wavefront initiation and rotational activity, in order to determine the mechanisms sustaining AF. Electrical measurements should be interpreted differently according to whether they are endocardial or epicardial recordings.
Houston CPJ, Tzortzis KN, Roney C, et al., 2018, Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line, Journal of Molecular and Cellular Cardiology, Vol: 119, Pages: 155-164, ISSN: 0022-2828
Fibrillation is the most common arrhythmia observed in clinical practice. Understanding of the mechanisms underlying its initiation and maintenance remains incomplete. Functional re-entries are potential drivers of the arrhythmia. Two main concepts are still debated, the “leading circle” and the “spiral wave or rotor” theories. The homogeneous subclone of the HL1 atrial-derived cardiomyocyte cell line, HL1-6, spontaneously exhibits re-entry on a microscopic scale due to its slow conduction velocity and the presence of triggers, making it possible to examine re-entry at the cellular level.We therefore investigated the re-entry cores in cell monolayers through the use of fluorescence optical mapping at high spatiotemporal resolution in order to obtain insights into the mechanisms of re-entry.Re-entries in HL1-6 myocytes required at least two triggers and a minimum colony area to initiate (3.5 to 6.4 mm2). After electrical activity was completely stopped and re-started by varying the extracellular K+ concentration, re-entries never returned to the same location while 35% of triggers re-appeared at the same position. A conduction delay algorithm also allows visualisation of the core of the re-entries. This work has revealed that the core of re-entries is conduction blocks constituted by lines and/or groups of cells rather than the round area assumed by the other concepts of functional re-entry. This highlights the importance of experimentation at the microscopic level in the study of re-entry mechanisms.
Chowdhury RA, Tzortzis KN, Dupont E, et al., 2018, Concurrent micro- to macro-cardiac electrophysiology in myocyte cultures and human heart slices, Scientific Reports, Vol: 8, ISSN: 2045-2322
The contact cardiac electrogram is derived from the extracellular manifestation of cellular action potentials and cell-to-cell communication. It is used to guide catheter based clinical procedures. Theoretically, the contact electrogram and the cellular action potential are directly related, and should change in conjunction with each other during arrhythmogenesis, however there is currently no methodology by which to concurrently record both electrograms and action potentials in the same preparation for direct validation of their relationships and their direct mechanistic links. We report a novel dual modality apparatus for concurrent electrogram and cellular action potential recording at a single cell level within multicellular preparations. We further demonstrate the capabilities of this system to validate the direct link between these two modalities of voltage recordings.
Sanchez-Alonso JL, Schobesberger S, Poulet CE, et al., 2018, Function of L-Type Calcium Channel Microdomain in Human Myocytes from Hearts with Ischemic versus Dilated Cardiomyopathies, 62nd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 638A-638A, ISSN: 0006-3495
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- Citations: 1
Roney CH, Cantwell CD, Qureshi NA, et al., 2016, Rotor tracking using phase of electrograms recorded during atrial fibrillation, Annals of Biomedical Engineering, Vol: 45, Pages: 910-923, ISSN: 1573-9686
Extracellular electrograms recorded during atrial fibrillation (AF) are challenging to interpret due to the inherent beat-to-beat variability in amplitude and duration. Phase mapping represents these voltage signals in terms of relative position within the cycle, and has been widely applied to action potential and unipolar electrogram data of myocardial fibrillation. To date, however, it has not been applied to bipolar recordings, which are commonly acquired clinically. The purpose of this study is to present a novel algorithm for calculating phase from both unipolar and bipolar electrograms recorded during AF. A sequence of signal filters and processing steps are used to calculate phase from simulated, experimental, and clinical, unipolar and bipolar electrograms. The algorithm is validated against action potential phase using simulated data (trajectory centre error <0.8 mm); between experimental multi-electrode array unipolar and bipolar phase; and for wavefront identification in clinical atrial tachycardia. For clinical AF, similar rotational content (R (2) = 0.79) and propagation maps (median correlation 0.73) were measured using either unipolar or bipolar recordings. The algorithm is robust, uses standard signal processing techniques, and accurately quantifies AF wavefronts and sources. Identifying critical sources, such as rotors, in AF, may allow for more accurate targeting of ablation therapy and improved patient outcomes.
Ng FS, Kalindjian JM, Cooper SA, et al., 2016, Enhancement of Gap Junction Function During Acute Myocardial Infarction Modifies Healing and Reduces Late Ventricular Arrhythmia Susceptibility, JACC. Clinical electrophysiology, Vol: 2, Pages: 574-582, ISSN: 2405-5018
Objectives: To investigate the effects of enhancing gap junction (GJ) coupling during acute myocardial infarction (MI) on the healed infarct scar morphology and late post-MI arrhythmia susceptibility. Background: Increased heterogeneity of myocardial scarring after MI is associated with greater arrhythmia susceptibility. We hypothesized that short-term enhancement of GJ coupling during acute MI can produce more homogeneous infarct scars, reducing late susceptibility to post-MI arrhythmias. Methods: Following arrhythmic characterisation of the rat 4-week post-MI model (n=24), a further 27 Sprague-Dawley rats were randomised to receive rotigaptide to enhance GJ coupling (n=13) or saline control (n=14) by osmotic minipump immediately prior to, and for the first 7 days following surgical MI. At 4 weeks post-MI, hearts were explanted for ex vivo programmed electrical stimulation (PES) and optical mapping. Heterogeneity of infarct border zone (IBZ) scarring was quantified by histomorphometry. Results: Despite no detectable difference in infarct size at 4 weeks post-MI, rotigaptide-treated hearts had reduced arrhythmia susceptibility during PES (Inducibility score: rotigaptide 2.40.8, control 5.00.6, p=0.02) and less heterogeneous IBZ scarring (standard deviation of IBZ Complexity Score: rotigaptide 1.10.1, control 1.40.1, p=0.04), associated with an improvement in IBZ conduction velocity (rotigaptide 43.13.4 cm/s, control 34.82.0 cm/s, p=0.04). Conclusions: Enhancement of GJ coupling for only 7 days at the time of acute MI produced more homogeneous IBZ scarring and reduced arrhythmia susceptibility at 4 weeks post-MI. Short-term GJ modulation at the time of MI may represent a novel treatment strategy to modify the healed infarct scar morphology and reduce late post-MI arrhythmic risk.
Ng FS, Lyon AR, Shadi IT, et al., 2015, Gap Junctional Uncoupling with Carbenoxolone Slows Conduction and Increases Vulnerability to Ventricular Arrhythmias in Structurally Normal Hearts: An Optical Mapping Study, British Cardiovascular Society Annual Conference 2010, Pages: A5-A6
Ng FS, Lyon AR, Shadi IT, et al., 2015, Modulation of Gap Junctional Coupling as an Anti-Arrhythmic Strategy to Prevent Reperfusion Ventricular Fibrillation, SET for Britain 2010 (House of Commons, UK Parliament)
Ng FS, Roney CH, Debney MT, et al., 2015, Anatomical and functional determinants of preferential rotor locations and stability in atrial fibrillation, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 568-568, ISSN: 0195-668X
Kirubakaran S, Chowdhury RA, Hall MCS, et al., 2015, Fractionation of electrograms is caused by colocalized conduction block and connexin disorganization in the absence of fibrosis as AF becomes persistent in the goat model, HEART RHYTHM, Vol: 12, Pages: 397-408, ISSN: 1547-5271
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- Citations: 10
Dhillon PS, Chowdhury RA, Patel PM, et al., 2014, Relationship between connexin expression and gap-junction resistivity in human atrial myocardium, Circulation: Arrhythmia and Electrophysiology, Vol: 7, Pages: 321-329, ISSN: 1941-3084
Background—The relative roles of the gap-junctional proteins connexin40 (Cx40) and connexin43 (Cx43) in determining human atrial myocardial resistivity is unknown. In addressing the hypothesis that changing relative expression of Cx40 and Cx43 underlies an increase in human atrial myocardial resistivity with age, this relationship was investigated by direct ex vivo measurement of gap-junctional resistivity and quantitative connexin immunoblotting and immunohistochemistry.Methods and Results—Oil-gap impedance measurements were performed to determine resistivity of the intracellular pathway (Ri), which correlated with total Cx40 quantification by Western blotting (rs=0.64, P<0.01, n=20). Specific gap-junctional resistivity (Rj) correlated not only with Western immunoquantification of Cx40 (rs=0.63, P=0.01, n=20), but also more specifically, with the Cx40 fraction localized to the intercalated disks on immunohistochemical quantification (rs=0.66, P=0.02, n=12). Although Cx43 expression showed no correlation with resistivity values, the proportional expression of the 2 connexins, (Cx40/[Cx40+Cx43]) correlated with Ri and Rj (rs=0.58, P<0.01 for Ri and rs=0.51, P=0.02 for Rj). Advancing age was associated with a rise in Ri (rs=0.77, P<0.0001), Rj (rs=0.65, P<0.001, n=23), Cx40 quantity (rs=0.54, P=0.01, n=20), and Cx40 gap–junction protein per unit area of en face disk (rs=0.61, P=0.02, n=12).Conclusions—Cx40 is associated with human right atrial gap-junctional resistivity such that increased total, gap-junctional, and proportional Cx40 expression increases gap-junctional resistivity. Accordingly, advancing age is associated with an increase in Cx40 expression and a corresponding increase in gap-junctional resistivity. These findings are the first to demonstrate this relationship and a mechanistic explanation for changing atrial conduction and age-related arrhythmic tendency.
Dias P, Desplantez T, El-Harasis MA, et al., 2014, Characterisation of Connexin Expression and Electrophysiological Properties in Stable Clones of the HL-1 Myocyte Cell Line, PLOS ONE, Vol: 9, ISSN: 1932-6203
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- Citations: 26
Dhillon PS, Gray R, Kojodjojo P, et al., 2013, Relationship Between Gap-Junctional Conductance and Conduction Velocity in Mammalian Myocardium, CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY, Vol: 6, Pages: 1208-1214, ISSN: 1941-3149
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- Citations: 50
Zaman JAB, Al-Aidarous S, Patel PM, et al., 2013, The contact electrogram and its architectural determinants in atrial fibrillation, Spring Meeting for Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 118-118, ISSN: 0140-6736
Al-Aidarous SI, Roney CH, Peters FMD, et al., 2012, CONDUCTION BLOCK INDUCED BY ACIDOSIS IN HL-1 MOUSE ATRIAL MYOCYTES CAN BE REVERSED BY ADMINISTERING THE GAP JUNCTIONAL COUPLER ROTIGAPTIDE, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: B M J PUBLISHING GROUP, Pages: A66-A66, ISSN: 1355-6037
Roney CH, Ng FS, Chowdhury RA, et al., 2012, Hysteresis of cardiac action potential duration restitution occurs in the absence of calcium transient duration hysteresis - a dual optical mapping study of ex vivo rat hearts, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S63-S63, ISSN: 0008-6363
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- Citations: 1
Ng FS, Cooper SA, Chowdhury RA, et al., 2011, Short-term enhancement of gap junctional coupling during early myocardial infarction modifies late susceptibility to ventricular arrhythmias, EUROPEAN HEART JOURNAL, Vol: 32, Pages: 797-797, ISSN: 0195-668X
Ng FS, Owusu-Agyei AA, Chang ETY, et al., 2010, ZP1210, a Novel Gap Junction Modulator, Attenuates Conduction Slowing and Prevents Cx43 Dephosphorylation During Metabolic Stress, American Heart Association (AHA) Scientific Sessions 2010, Pages: A13633-A13633
Hussain W, Patel PM, Chowdhury RA, et al., 2010, The Renin-Angiotensin System Mediates the Effects of Stretch on Conduction Velocity, Connexin43 Expression, and Redistribution in Intact Ventricle, JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Vol: 21, Pages: 1276-1283, ISSN: 1045-3873
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- Citations: 18
Ng FS, Lyon AR, Shadi IT, et al., 2010, Modulation of gap junctional coupling as an antiarrhythmic strategy to prevent reperfusion ventricular arrhythmias, 6th Congress of the European Cardiac Arrhythmia Society, Publisher: Springer Verlag, Pages: 173-174, ISSN: 1572-8595
Dhillon PS, Gray R, Kojodjojo P, et al., 2009, The Relationship Between Gap Junction Conductance and Conduction Velocity in Intact Myocardium, 82nd Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S621-S621, ISSN: 0009-7322
Roosen A, Wu C, Sui G, et al., 2009, Characteristics of Spontaneous Activity in the Bladder Trigone, EUROPEAN UROLOGY, Vol: 56, Pages: 346-353, ISSN: 0302-2838
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- Citations: 30
Roosen A, Datta SN, Chowdhury RA, et al., 2009, Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment, EUROPEAN UROLOGY, Vol: 55, Pages: 1440-1449, ISSN: 0302-2838
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- Citations: 61
Chowdhury RA, Inuabasi L, Jabr RI, et al., 2007, Multiple anatomical changes in a goat model of atrial fibrillation are associated with conduction velocity abnormalities at 3 months, EUROPEAN HEART JOURNAL, Vol: 28, Pages: 801-802, ISSN: 0195-668X
Chowdhury RA, Aguiar-Martins Y, Patel PM, et al., 2007, Changes in atrial connexin40 And 43 are apparent after 2 months of atrial fibrillation in a goat model, EUROPEAN HEART JOURNAL, Vol: 28, Pages: 803-803, ISSN: 0195-668X
Chowdhury RA, Aguiar-Martins Y, Patel PM, et al., 2006, Changes in atrial connexin40 and 43 are apparent after 2 months of atrial fibrillation in a goat-model, 79th Annual Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 237-237, ISSN: 0009-7322
Chowdhury RA, Kaba RA, Patel PM, et al., 2006, Changes in connexin43 immunolabelling are not associated with changes in connexin45 or connexin40 labelling in the canine infarct border zone, 28th Congress of the European-Society-of-Cardiology/World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 720-721, ISSN: 0195-668X
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