The effects of cardiac stretch on atrial fibroblasts: analysis of the evidence and potential role in atrial fibrillation

Abstract

Atrial fibrillation (AF) is an important clinical problem. Chronic pressure/volume overload of the atria promotes AF, particularly via enhanced extracellular matrix (ECM) accumulation manifested as tissue fibrosis. Loading of cardiac cells causes cell stretch that is generally considered to promote fibrosis by directly activating fibroblasts, the key cell type responsible for ECM production. The primary purpose of this article is to review the evidence regarding direct effects of stretch on cardiac fibroblasts, specifically: (i) the similarities and differences among studies in observed effects of stretch on cardiac fibroblast function; (ii) the signalling pathways implicated; and (iii) the factors that affect stretch-related phenotypes. Our review summarizes the most important findings and limitations in this area and gives an overview of clinical data and animal models related to cardiac stretch, with particular emphasis on the atria. We suggest that the evidence regarding direct fibroblast activation by stretch is weak and inconsistent, in part because of variability among studies in key experimental conditions that govern the results. Further work is needed to clarify whether, in fact, stretch induces direct activation of cardiac fibroblasts and if so, to elucidate the determining factors to ensure reproducible results. If mechanical load on fibroblasts proves not to be clearly profibrotic by direct actions, other mechanisms like paracrine influences, the effects of systemic mediators and/or the direct consequences of myocardial injury or death, might account for the link between cardiac stretch and fibrosis. Clarity in this area is needed to improve our understanding of AF pathophysiology and assist in therapeutic development.

Keywords: Atrial fibrillation; Cardiac fibroblast; Fibrosis; Mechanical strain; Pressure overload; Stretch.

Graphical abstract

Figure 1

Schematic of processes believed to be involved in AF-promoting responses to stretch. Conditions leading to atrial stretch and its consequences are shown at the top. These lead to atrial stretch, either directly via altered atrial load (primary or secondary to ventricular overload) or indirectly by affecting atrial function and causing atrial cardiomyopathy. Atrial stretch in itself causes cellular consequences that lead to atrial cardiomyopathy. Atrial cardiomyopathy leads to AF and can impair atrial function sufficiently to lead to atrial failure. CM, cardiomyocyte; ECM, extracellular matrix; FB, fibroblast; P/V, pressure/volume; SAC, stretch-activated channel.

Figure 2

Schematic of biochemical and functional changes in response to stretch and modifying factors. αSMA, alpha-smooth muscle actin; AP1, activator protein 1; ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; GPCR, G-protein-coupled receptor; JNK, c-Jun N-terminal kinase; p38, p38 mitogen-activated protein kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog family member A.

Figure 3

Factors that can affect the results of cardiac fibroblast stretch studies.

Figure 4

Schematic representing (top) the relative percentage use of different key conditions (species, age/stage and stretch device) across different studies reviewed in this paper; and (bottom) different types of stretch pattern used in research on stretch effects on fibroblasts. (A–C) Pie charts indicating the percentage of various species (A), age/stage of fibroblasts (B), and type of stretch devices (C) that were used in the in vitro stretch studies reviewed in the present paper. (D–H) Schematics showing the types of stretch patterns used for in vitro studies of stretch effects on fibroblasts. The solid arrows indicate the direction of applied stretch. (D, E) Uniaxial (linear) stretch. (F, G) Biaxial stretch. (H) Isotropic, equibiaxial stretch.