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  • Journal article
    Houston CPJ, Tzortzis KN, Roney C, Saglietto A, Pitcher DS, Cantwell C, Chowdhury RA, Ng FS, Peters NS, Dupont Eet 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.

  • Journal article
    Ciaccio EJ, Coromilas J, Wit AL, Peters NS, Garan Het al., 2018,

    Source-sink mismatch causing functional conduction block in re-entrant ventricular tachycardia

    , JACC: Clinical Electrophysiology, Vol: 4, Pages: 1-16, ISSN: 2405-5018

    Ventricular tachycardia (VT) caused by a re-entrant circuit is a life-threatening arrhythmia that at present cannot always be treated adequately. A realistic model of re-entry would be helpful to accurately guide catheter ablation for interruption of the circuit. In this review, models of electrical activation wavefront propagation during onset and maintenance of re-entrant VT are discussed. In particular, the relationship between activation mapping and maps of transition in infarct border zone thickness, which results in source-sink mismatch, is considered in detail and supplemented with additional data. Based on source-sink mismatch, the re-entry isthmus can be modeled from its boundary properties. Isthmus boundary segments with large transitions in infarct border zone thickness have large source-sink mismatch, and functional block forms there during VT. These alternate with segments having lesser thickness change and therefore lesser source-sink mismatch, which act as gaps, or entrance and exit points, to the isthmus during VT. Besides post-infarction substrates, the source-sink model is likely applicable to other types of volumetric changes in the myocardial conducting medium, such as when there is presence of fibrosis or dissociation of muscle fibers.

  • Journal article
    Kapnisi M, Mansfield C, Marijon C, Guex AG, Perbellini F, Bardi I, Humphrey EJ, Puetzer J, Mawad D, Koutsogeorgis DC, Stuckey DJ, Terracciano CM, Harding SE, Stevens MMet al., 2018,

    Auxetic cardiac patches with tunable mechanical and conductive properties toward treating myocardial infarction

    , Advanced Functional Materials, Vol: 28, ISSN: 1616-301X

    An auxetic conductive cardiac patch (AuxCP) for the treatment of myocardial infarction (MI) is introduced. The auxetic design gives the patch a negative Poisson's ratio, providing it with the ability to conform to the demanding mechanics of the heart. The conductivity allows the patch to interface with electroresponsive tissues such as the heart. Excimer laser microablation is used to micropattern a re‐entrant honeycomb (bow‐tie) design into a chitosan‐polyaniline composite. It is shown that the bow‐tie design can produce patches with a wide range in mechanical strength and anisotropy, which can be tuned to match native heart tissue. Further, the auxetic patches are conductive and cytocompatible with murine neonatal cardiomyocytes in vitro. Ex vivo studies demonstrate that the auxetic patches have no detrimental effect on the electrophysiology of both healthy and MI rat hearts and conform better to native heart movements than unpatterned patches of the same material. Finally, the AuxCP applied in a rat MI model results in no detrimental effect on cardiac function and negligible fibrotic response after two weeks in vivo. This approach represents a versatile and robust platform for cardiac biomaterial design and could therefore lead to a promising treatment for MI.

  • Journal article
    Broyd CJ, Hernández-Pérez F, Segovia J, Echavarría-Pinto M, Quirós-Carretero A, Salas C, Gonzalo N, Jiménez-Quevedo P, Nombela-Franco L, Salinas P, Núñez-Gil I, Del Trigo M, Goicolea J, Alonso-Pulpón L, Fernández-Ortiz A, Parker K, Hughes A, Mayet J, Davies J, Escaned Jet al., 2018,

    Identification of capillary rarefaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients

    , European Heart Journal, Vol: 39, Pages: 1807-1814, ISSN: 1522-9645

    Aims: Techniques for identifying specific microcirculatory structural changes are desirable. As such, capillary rarefaction constitutes one of the earliest changes of cardiac allograft vasculopathy (CAV) in cardiac allograft recipients, but its identification with coronary flow reserve (CFR) or intracoronary resistance measurements is hampered because of non-selective interrogation of the capillary bed. We therefore investigated the potential of wave intensity analysis (WIA) to assess capillary rarefaction and thereby predict CAV. Methods and results: Fifty-two allograft patients with unobstructed coronary arteries and normal left ventricular (LV) function were assessed. Adequate aortic pressure and left anterior descending artery flow measurements at rest and with intracoronary adenosine were obtained in 46 of which 2 were lost to follow-up. In a subgroup of 15 patients, simultaneous RV biopsies were obtained and analysed for capillary density. Patients were followed up with 1-3 yearly screening angiography. A significant relationship with capillary density was noted with CFR (r = 0.52, P = 0.048) and the backward decompression wave (BDW) (r = -0.65, P < 0.01). Over a mean follow-up of 9.3 ± 5.2 years patients with a smaller BDW had an increased risk of developing angiographic CAV (hazard ratio 2.89, 95% CI 1.12-7.39; P = 0.03). Additionally, the index BDW was lower in those who went on to have a clinical CAV-events (P = 0.04) as well as more severe disease (P = 0.01). Conclusions: Within cardiac transplant patients, WIA is able to quantify the earliest histological changes of CAV and can predict clinical and angiographic outcomes. This proof-of-concept for WIA also lends weight to its use in the assessment of other disease processes in which capillary rarefaction is involved.

  • Conference paper
    Arnold AD, Shun-Shin MJ, Keene D, Howard J, Lefroy DC, Davies DW, Lim PH, Kanagaratnam P, Koa-Wing M, Wright IJ, Qureshi NA, Tanner MA, Muthumala AG, Linton N, Peters NS, Francis DP, Whinnett ZIet al., 2018,

    His bundle pacing can overcome left bundle branch block to produce greater improvements in acute haemodynamic function and ventricular activation than biventricular pacing

    , Heart Rhythm Society Scientific Sessions, Publisher: Elsevier, Pages: S40-S41, ISSN: 1547-5271
  • Journal article
    Chowdhury RA, Tzortzis KN, Dupont E, Selvadurai S, Perbellini F, Cantwell C, Ng FS, Simon A, Terracciano C, Peters NSet 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.

  • Journal article
    McGillivray MF, Cheng W, Peters NS, Christensen Ket al., 2018,

    Machine learning methods for locating re-entrant drivers from electrograms in a model of atrial fibrillation

    , ROYAL SOCIETY OPEN SCIENCE, Vol: 5, ISSN: 2054-5703

    Mapping resolution has recently been identified as a key limitation in successfully locating the drivers of atrial fibrillation (AF). Using a simple cellular automata model of AF, we demonstrate a method by which re-entrant drivers can be located quickly and accurately using a collection of indirect electrogram measurements. The method proposed employs simple, out-of-the-box machine learning algorithms to correlate characteristic electrogram gradients with the displacement of an electrogram recording from a re-entrant driver. Such a method is less sensitive to local fluctuations in electrical activity. As a result, the method successfully locates 95.4% of drivers in tissues containing a single driver, and 95.1% (92.6%) for the first (second) driver in tissues containing two drivers of AF. Additionally, we demonstrate how the technique can be applied to tissues with an arbitrary number of drivers. In its current form, the techniques presented are not refined enough for a clinical setting. However, the methods proposed offer a promising path for future investigations aimed at improving targeted ablation for AF.

  • Journal article
    Wright PT, Bhogal N, Diakonov I, Pannell L, Perera R, Bork N, Schobesberger S, Lucarelli C, Faggian G, Alvarez-Laviada A, Zaccolo M, Kamp TJ, Balijepalli R, Lyon A, Harding SE, Nikolaev V, Gorelik Jet al., 2018,

    Cardiomyocyte membrane structure and cAMP compartmentation produce anatomical variation in β2AR-cAMP responsiveness in murine hearts

    , Cell Reports, Vol: 23, Pages: 459-469, ISSN: 2211-1247

    Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β2-adrenoceptor (β2AR) stimulation, which may underlie the development of Takotsubo cardiomyopathy. However, both cell types produce comparable cytosolic amounts of the second messenger cAMP. We investigated this discrepancy using nanoscale imaging techniques and found that, structurally, basal cardiomyocytes have more organized membranes (higher T-tubular and caveolar densities). Local membrane microdomain responses measured in isolated basal cardiomyocytes or in whole hearts revealed significantly smaller and more short-lived β2AR/cAMP signals. Inhibition of PDE4, caveolar disruption by removing cholesterol or genetic deletion of Cav3 eliminated differences in local cAMP production and equilibrated the contractile response to β2AR. We conclude that basal cells possess tighter control of cAMP because of a higher degree of signaling microdomain organization. This provides varying levels of nanostructural control for cAMP-mediated functional effects that orchestrate macroscopic, regional physiological differences within the heart.

  • Journal article
    Ciaccio EJ, Peters NS, Garan H, 2018,

    Effects of refractory gradients and ablation on fibrillatory activity

    , COMPUTERS IN BIOLOGY AND MEDICINE, Vol: 95, Pages: 175-187, ISSN: 0010-4825

    BackgroundThe mechanisms involved in onset, maintenance, and termination of atrial fibrillation are not well understood. A biophysical model could be useful to determine how the events unfold.MethodA two-dimensional cellular automaton consisting of 576 × 576 grid nodes was implemented to demonstrate the types of electrical activity that may occur in compromised atrial substrate. Electrical activation between nodes was made anisotropic (2:1), and the refractory period (RP) was adjusted from 74 to 192 ms in the spatial domain. Presence of collagen fibers were simulated as short lines of conduction block at many random grid sites, while ablation lesions were delineated as longer lines of block. An S1-S2 pulse from one grid corner was utilized to initiate simulated electrical activity. Simulations were done in which 1. no ablation lines, 2. random ablation lines, and 3. parallel ablation lines were added to the grid to determine how this affected the formation and annihilation of rotational activity after S1-S2 stimulation.ResultsAs the premature (S2) wavefront traversed the grid, rotational activity formed near boundaries where wavefronts propagated from shorter to longer refractory regions, causing unidirectional block, and were anchored by fiber clusters. Multiple wavelets appeared when wavefronts originating from different driving rotational features collided, and/or by their encounter with RP discontinuities. With the addition of randomly orientated simulated ablation lesions, followed by reinduction of fibrillatory activity, mean activation interval (AI) prolonged from a baseline level of 144.2 ms–160.3 ms (p < 0.001 in most comparisons). During fibrillatory activity, when parallel ablation lines were added to short RP regions, AI prolonged to 150.4 ms (p < 0.001), and when added to long RP regions, AI prolonged to 185.3 ms (p < 0.001). In all cases, AI prolongation after simulated ablation resulted from reduced number and/or from the isolatio

  • Journal article
    Hou H, Zhao Z, Machuki JO, Zhang L, Zhang Y, Fu L, Wu J, Liu Y, Harding SE, Sun Het al., 2018,

    Estrogen deficiency compromised the beta(2)AR-Gs/Gi coupling: implications for arrhythmia and cardiac injury

    , PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 470, Pages: 559-570, ISSN: 0031-6768

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