Regional mechanics determine collagen fiber structure in healing myocardial infarcts

Abstract

Following myocardial infarction, the mechanical properties of the healing infarct are an important determinant of heart function and the risk of progression to heart failure. In particular, mechanical anisotropy (having different mechanical properties in different directions) in the healing infarct can preserve pump function of the heart. Based on reports of different collagen structures and mechanical properties in various animal models, we hypothesized that differences in infarct size, shape, and/or location produce different patterns of mechanical stretch that guide evolving collagen fiber structure. We tested the effects of infarct shape and location using a combined experimental and computational approach. We studied mechanics and collagen fiber structure in cryoinfarcts in 53 Sprague-Dawley rats and found that regardless of shape or orientation, cryoinfarcts near the equator of the left ventricle stretched primarily in the circumferential direction and developed circumferentially aligned collagen, while infarcts at the apex stretched similarly in the circumferential and longitudinal direction and developed randomly oriented collagen. In a computational model of infarct healing, an effect of mechanical stretch on fibroblast and collagen alignment was required to reproduce the experimental results. We conclude that mechanical environment determines collagen fiber structure in healing myocardial infarcts. Our results suggest that emerging post-infarction therapies that alter regional mechanics will also alter infarct collagen structure, offering both potential risks and novel therapeutic opportunities.

Emergence of Collagen Orientation Heterogeneity in Healing Infarcts and an Agent-Based Model

“…We (4,14,21) and others (22) have reported a range of collagen fiber structures in healing infarcts in different animal models, and have shown that manipulating anisotropy in healing infarcts can improve left ventricular pump function (5,23). These prior studies focused on collagen content and alignment averaged over many microscopic fields; broadly, they show collagen fibers oriented in planes parallel to the epicardial surface, with a degree of overall alignment that depends strongly on the mechanical environment during scar formation (4).…”

“…We and others have quantified the collagen structure of healing myocardial infarcts and found that both collagen content and collagen fiber orientation vary widely across different experimental models (see a recent review by Richardson et al (3)). Our group proposed that differences in the average degree of structural anisotropy in healing infarcts arise from differences in regional mechanics during scar formation (4). During the course of these studies, we noticed that collagen orientation in many of the scars we examined appeared to vary significantly from region to region.…”

“…For each of the four time points, we imaged sections from the midwall of four to five infarcts under 20 magnification with automated image stitching (Aperio ScanScope). We then generated collagen orientation maps from the PSR-stained images using a previously published image-processing method (15) (MatFiber, code freely available at http://bme.virginia.edu/holmes) implemented in MATLAB (The MathWorks, Natick, MA) that was previously used by our group to quantify collagen alignment in healing infarcts (4,14,16). This code segmented each PSR-stained image into a grid of 12 mm  12 mm subregions, calculated intensity gradients within each subregion, and output a single angle for each subregion that was perpendicular to the maximum intensity gradient within that subregion (Fig.…”

“…One important difference compared with our previous modeling studies is that herein we simulated the infarct geometry in its full dimensions rather than scaling the problem, to maintain a physiologically accurate cell/infarct size ratio. Accordingly, we refit k rotation , k deposition , and k degradation to match the collagen content and alignment values measured in healing rat infarcts across a range of loading conditions (4,14). The model was solved using MATLAB.…”

Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression

“…It could also be due to the variation in the amount of isolated muscle fibres especially when considering the difficulty of precisely controlling the size of the infarct in the samples as we demonstrated in this study. Furthermore, the orientation of collagen was shown to vary according to the location of the infarct in the LV of a rat [37]; the collagen in a mid-ventricle infarct aligns mostly in the circumferential direction whereas collagen fibres are randomly oriented in an apical infarct. All or some of these factors may have contributed in the discrepancy between the two studies.…”