34 results found
Handa B, Li X, Aras KK, et al., Granger Causality-based analysis for classification of fibrillation mechanisms and localisation of rotational drivers, Circulation: Arrhythmia and Electrophysiology, ISSN: 1941-3084
Li X, Roney C, Handa B, et al., 2019, Standardised framework for quantitative analysisof fibrillation dynamics, Scientific Reports, Vol: 9, ISSN: 2045-2322
The analysis of complex mechanisms underlying ventricular fibrillation (VF) and atrial fibrillation (AF) requires sophisticatedtools for studying spatio-temporal action potential (AP) propagation dynamics. However, fibrillation analysis tools are oftencustom-made or proprietary, and vary between research groups. With no optimal standardised framework for analysis, resultsfrom different studies have led to disparate findings. Given the technical gap, here we present a comprehensive framework andset of principles for quantifying properties of wavefront dynamics in phase-processed data recorded during myocardial fibrillationwith potentiometric dyes. Phase transformation of the fibrillatory data is particularly useful for identifying self-perpetuating spiralwaves or rotational drivers (RDs) rotating around a phase singularity (PS). RDs have been implicated in sustaining fibrillation,and thus accurate localisation and quantification of RDs is crucial for understanding specific fibrillatory mechanisms. In thiswork, we assess how variation of analysis parameters and thresholds in the tracking of PSs and quantification of RDs couldresult in different interpretations of the underlying fibrillation mechanism. These techniques have been described and appliedto experimental AF and VF data, and AF simulations, and examples are provided from each of these data sets to demonstratethe range of fibrillatory behaviours and adaptability of these tools. The presented methodologies are available as an opensource software and offer an off-the-shelf research toolkit for quantifying and analysing fibrillatory mechanisms.
Handa BS, Li X, Mansfield CA, et al., 2019, Ventricular fibrosis spatial distribution and quantity is a key mechanistic determinant of ventricular fibrillation mechanisms, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 896-896, ISSN: 0195-668X
Handa BS, Li X, Roney C, et al., 2019, Enhanced gap junction coupling organised and terminated acute ventricular fibrillation in ex-vivo perfused hearts, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 3034-3034, ISSN: 0195-668X
Sattler S, Baxan N, Chowdhury R, et al., 2019, Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multi-parametric quantitative cardiac MRI, Disease Models & Mechanisms, Vol: 12, Pages: 1-10, ISSN: 1754-8403
Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the TLR-7 agonist Resiquimod induces auto-antibodies and systemic tissue damage including in the heart, and is used as an inducible mouse model of Systemic Lupus Erythematosus (SLE).Here, we show that over-activation of the TLR-7 pathway of viral recognition by Resiquimod-treatment of CFN mice induces severe thrombocytopenia and internal bleeding which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results to ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed a detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes.In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis will improve interpretation of disease mechanisms and diagnostic sensitivity.
Handa B, Li X, Mansfield C, et al., 2019, MYOCARDIAL FIBROSIS AND THE DEGREE OF GAP JUNCTION COUPLING DIRECTLY MODIFIES THE UNDERLYING MECHANISM OF FIBRILLATION, Annual Conference of the British-Cardiovascular-Society (BCS) - Digital Health Revolution, Publisher: BMJ PUBLISHING GROUP, Pages: A179-A180, ISSN: 1355-6037
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.
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., 2010, 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., 2010, 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
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: 1941-3149
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
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
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
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
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
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
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