Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated
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NTEGRATIVE PHYSIOLOGY
Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling Joseph Brook 1 & Min-young Kim 1 & Simos Koutsoftidis 2 & David Pitcher 1 & Danya Agha-Jaffar 1 & Annam Sufi 1 & Catherine Jenkins 1 & Konstantinos Tzortzis 1 & Suofeiya Ma 1 & Richard J. Jabbour 1 & Charles Houston 1 & Balvinder S. Handa 1 & Xinyang Li 1 & Ji-Jian Chow 1 & Anand Jothidasan 3 & Poppy Bristow 4 & Justin Perkins 4 & Sian Harding 1 & Anil A Bharath 2 & Fu Siong Ng 1 & Nicholas S Peters 1 & Chris D Cantwell 2 & Rasheda A Chowdhury 1 Received: 11 March 2020 / Revised: 11 June 2020 / Accepted: 6 August 2020 / Published online: 1 September 2020 # The Author(s) 2020
Abstract 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)max 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)max − 20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates. Keywords Langendorff . Ex vivo model . Isolated heart . Contact electrogram . Gap junction uncoupling . Carbenoxolone
Background Ex vivo models * Rasheda A Chowdhury [email protected] 1
Faculty of Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
2
Faculty of Engineering, Imperial College London, South Kensington Campus, Exhibition Road, London SW7 2AZ, UK
3
Harefield Hospital, Hill End Road, Harefield UB9 6JH, UK
4
Royal Veterinary
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