IRUS Total

Remodelling of adult cardiac tissue subjected to physiological and pathological mechanical load in vitro

File Description SizeFormat 
cvab084.pdfPublished version1.59 MBAdobe PDFView/Open
Title: Remodelling of adult cardiac tissue subjected to physiological and pathological mechanical load in vitro
Authors: Pitoulis, FG
Nunez-Toldra, R
Xiao, K
Kit-Anan, W
Mitzka, S
Jabbour, RJ
Harding, SE
Perbellini, F
Thum, T
De Tombe, PP
Terracciano, CM
Item Type: Journal Article
Abstract: Aims: Cardiac remodelling is the process by which the heart adapts to its environment. Mechanical load is a major driver of remodelling. Cardiac tissue culture has been frequently employed for in vitro studies of load-induced remodelling; however, current in vitro protocols (e.g. cyclic stretch, isometric load, and auxotonic load) are oversimplified and do not accurately capture the dynamic sequence of mechanical conformational changes experienced by the heart in vivo. This limits translational scope and relevance of findings. Methods and results: We developed a novel methodology to study chronic load in vitro. We first developed a bioreactor that can recreate the electromechanical events of in vivo pressure–volume loops as in vitro force–length loops. We then used the bioreactor to culture rat living myocardial slices (LMS) for 3 days. The bioreactor operated based on a 3-Element Windkessel circulatory model enabling tissue mechanical loading based on physiologically relevant parameters of afterload and preload. LMS were continuously stretched/relaxed during culture simulating conditions of physiological load (normal preload and afterload), pressure-overload (normal preload and high afterload), or volume-overload (high preload & normal afterload). At the end of culture, functional, structural, and molecular assays were performed to determine load-induced remodelling. Both pressure- and volume-overloaded LMS showed significantly decreased contractility that was more pronounced in the latter compared with physiological load (P < 0.0001). Overloaded groups also showed cardiomyocyte hypertrophy; RNAseq identified shared and unique genes expressed in each overload group. The PI3K-Akt pathway was dysregulated in volume-overload while inflammatory pathways were mostly associated with remodelling in pressure-overloaded LMS. Conclusion: We have developed a proof-of-concept platform and methodology to recreate remodelling under pathophysiological load in vitro. We show that LMS cultured in our bioreactor remodel as a function of the type of mechanical load applied to them.
Issue Date: 1-Feb-2022
Date of Acceptance: 8-Mar-2021
URI: http://hdl.handle.net/10044/1/88552
DOI: 10.1093/cvr/cvab084
ISSN: 0008-6363
Publisher: European Society of Cardiology
Start Page: 814
End Page: 827
Journal / Book Title: Cardiovascular Research
Volume: 118
Issue: 3
Copyright Statement: © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: British Heart Foundation
British Heart Foundation
Funder's Grant Number: FS/18/37/33642
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
Myocardial remodelling
Pressure overload
Volume overload
In vitro cardiac tissue culture
Mechanical load
Myocardial slices
In vitro cardiac tissue culture
Mechanical load
Myocardial remodelling
Myocardial slices
Pressure overload
Volume overload
1102 Cardiorespiratory Medicine and Haematology
Cardiovascular System & Hematology
Publication Status: Published
Online Publication Date: 2021-03-16
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine

This item is licensed under a Creative Commons License Creative Commons