Publications by authors named "Konstantinos Tzortzis"

7 Publications

  • Page 1 of 1

Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling.

Pflugers Arch 2020 10 1;472(10):1435-1446. Epub 2020 Sep 1.

Faculty of Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far-field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting. Porcine (n = 9) and human (n = 4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. A total of 1 mM of carbenoxolone was administered at 5 ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed. We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt) increased between baseline and carbenoxolone (47.9 ± 4.1-67.2 ± 2.7 ms) indicating conduction slowing. The features with the largest percentage change between baseline and carbenoxolone were fractionation + 185.3%, endpoint amplitude - 106.9%, S-endpoint gradient + 54.9%, S point - 39.4%, RS ratio + 38.6% and (-dV/dt) - 20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00424-020-02446-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476990PMC
October 2020

Rethinking multiscale cardiac electrophysiology with machine learning and predictive modelling.

Comput Biol Med 2019 01 18;104:339-351. Epub 2018 Oct 18.

ElectroCardioMaths Group, Imperial College Centre for Cardiac Engineering, Imperial College London, London, UK; National Heart and Lung Institute, Imperial College London, South Kensington Campus, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiomed.2018.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334203PMC
January 2019

Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line.

J Mol Cell Cardiol 2018 06 7;119:155-164. Epub 2018 May 7.

Myocardial Function, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address:

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 mm). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004038PMC
June 2018

Concurrent micro- to macro-cardiac electrophysiology in myocyte cultures and human heart slices.

Sci Rep 2018 05 2;8(1):6947. Epub 2018 May 2.

Myocardial Function Section, National Heart and Lung Institute, Imperial College London, 4th floor Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-25170-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932023PMC
May 2018

A technique for visualising three-dimensional left atrial cardiac activation data in two dimensions with minimal distance distortion.

Annu Int Conf IEEE Eng Med Biol Soc 2015 ;2015:7296-9

Electro-anatomic mapping and medical imaging systems, used during clinical procedures for treatment of atrial arrhythmias, frequently record and display measurements on an anatomical surface of the left atrium. As such, obtaining a complete picture of activation necessitates simultaneous views from multiple angles. In addition, post-processing of three-dimensional surface data is challenging, since algorithms are typically applicable to planar or volumetric data. We applied a surface flattening methodology to medical imaging data and electro-anatomic mapping data to generate a two-dimensional representation that best preserves distances, since the calculation of many clinically relevant metrics, including conduction velocity and rotor trajectory identification require an accurate representation of distance. Distance distortions were small and improved upon exclusion of the pulmonary veins. The technique is demonstrated using maps of local activation time, based on clinical data, and plotting rotor-core trajectories, using simulated data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/EMBC.2015.7320076DOI Listing
September 2016

Bortezomib Amplifies Effect on Intracellular Proteasomes by Changing Proteasome Structure.

EBioMedicine 2015 Jul 28;2(7):642-8. Epub 2015 May 28.

Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom.

The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). Bortezomib inhibits protein degradation by inactivating proteasomes' active-sites. MM cells are exquisitely sensitive to Bortezomib - exhibiting a low-nanomolar IC(50) - suggesting that minimal inhibition of degradation suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, contrary to expectation, achieves severe inhibition of proteasome activity in MM cells: the degree of inhibition exceeds what one would expect from the small proportion of active-sites that Bortezomib inhibits. Our data indicate that Bortezomib achieves this severe inhibition by triggering secondary changes in proteasome structure that further inhibit proteasome activity. Comparing MM cells to other, Bortezomib-resistant, cancer cells shows that the degree of proteasome inhibition is the greatest in MM cells and only there leads to proteasome stress, providing an explanation for why Bortezomib is effective against MM but not other cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2015.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534688PMC
July 2015

Nuclear proteasomes carry a constitutive posttranslational modification which derails SDS-PAGE (but not CTAB-PAGE).

Biochim Biophys Acta 2014 Dec 2;1844(12):2222-8. Epub 2014 Sep 2.

Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom. Electronic address:

We report that subunits of human nuclear proteasomes carry a previously unrecognised, constitutive posttranslational modification. Subunits with this modification are not visualised by SDS-PAGE, which is used in almost all denaturing protein gel electrophoresis. In contrast, CTAB-PAGE readily visualises such modified subunits. Thus, under most experimental conditions, with identical samples, SDS-PAGE yielded gel electrophoresis patterns for subunits of nuclear proteasomes which were misleading and strikingly different from those obtained with CTAB-PAGE. Initial analysis indicates a novel modification of a high negative charge with some similarity to polyADP-ribose, possibly explaining compatibility with (positively-charged) CTAB-PAGE but not (negatively-charged) SDS-PAGE and providing a mechanism for how nuclear proteasomes may interact with chromatin, DNA and other nuclear components.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbapap.2014.08.013DOI Listing
December 2014