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. 2019 Nov 14;9(1):16744.
doi: 10.1038/s41598-019-53351-7.

Biomechanical assessment of remote and postinfarction scar remodeling following myocardial infarction

Mihaela Rusu  1 , Katrin Hilse  2 , Alexander Schuh  3 , Lukas Martin  4 , Ioana Slabu  5 , Christian Stoppe  4 , Elisa A Liehn  2   6
Affiliations

Biomechanical assessment of remote and postinfarction scar remodeling following myocardial infarction

Mihaela Rusu et al. Sci Rep. .

Abstract

The importance of collagen remodeling following myocardial infarction (MI) is extensively investigated, but little is known on the biomechanical impact of fibrillar collagen on left ventricle post-MI. We aim to identify the significant effects of the biomechanics of types I, III, and V collagen on physio-pathological changes of murine hearts leading to heart failure. Immediately post-MI, heart reduces its function (EF = 40.94 ± 2.12%) while sarcomeres' dimensions are unchanged. Strikingly, as determined by immunohistochemistry staining, type V collagen fraction significantly grows in remote and scar for sustaining de novo-types I and III collagen fibers' assembly while hindering their enzymatic degradation. Thereafter, the compensatory heart function (EF = 63.04 ± 3.16%) associates with steady development of types I and III collagen in a stiff remote (12.79 ± 1.09 MPa) and scar (22.40 ± 1.08 MPa). In remote, the soft de novo-type III collagen uncoils preventing further expansion of elongated sarcomeres (2.7 ± 0.3 mm). Once the compensatory mechanisms are surpassed, the increased turnover of stiff type I collagen (>50%) lead to a pseudo-stable biomechanical regime of the heart (≅9 MPa) with reduced EF (50.55 ± 3.25%). These end-characteristics represent the common scenario evidenced in patients suffering from heart failure after MI. Our pre-clinical data advances the understanding of the cause of heart failure induced in patients with extended MI.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Representative two-dimensional murine cardiac echocardiography measurements. (A) Long axis B-mode image showing the tip of the left ventricle cavity, the papillary muscle, and the origin of the aorta. The cursor placed in front of the papillary muscle, towards the apex, indicates the exact position where the M-mode images were recorded. (B) Long axis M-mode image showing the left ventricle movement during the cardiac cycle and an example of left ventricle -cavity and -walls measurements (left side of the image). (C) Left ventricular activity fraction, EF [%] (black line, left y axis) and FS [%] (red line, right y axis) during the healing post-MI period of 28 days, (D) Left ventricle wall thickness measured in M-Mode at different time points after MI; closed circle: systole, open circle: diastole (**p < 0.01, ***p < 0.001, ****p < 0.0001).
Figure 2
Figure 2
Total collagen distribution and turnover in infarct scar vs. remote tissue within the healing period up to 28 days post-MI. (A) Gomori’s Trichrome staining images of control and remote vs. (B) scar. Scale bar: 50 μm. (C) Time dependent measurements of total collagen amount in remote and control vs. scar within 28 days post-MI. The red and blue lines are guides to the eye. Collagen accumulates significantly in the infarct scar vs. remote and control. After 7 days post-MI, collagen increases linearly in remote and decreases linearly in the infract scar. (*p < 0.5, ***p < 0.001, ****p < 0.0001).
Figure 3
Figure 3
Immunohistological characteristics of types I, III, and V collagen in control and remote vs. scar within the healing period of 28 days post-MI. Spatial distribution of type I collagen in remote (A-left) and scar (A-right), type III collagen in remote (B-left) and scar (B-right), and type V collagen in remote (C-left) and scar (C-right) control (upper panels). Scale bar: 50 μm. Time variation of the amount of types I, III, and V collagen in remote (D–F) and in scar (G–I). The collagen amount is normalized by the total amount of type I, III, and V collagen in remote and scar. (*p < 0.5, ***p < 0.001, ****p < 0.0001).
Figure 4
Figure 4
Odd and even dyssynchronous contraction of sarcomeres in remote tissue vs. control within 21 days post-MI. (A) High-resolution AFM image topology of sarcomeres in control and remote areas (20 topological lines per image with n = 256 samples/image line) separated by transversal structures of Z bands (green head arrows). The globule-like subsurface structures displayed in between sarcomeres indicate mitochondria (M, red head arrows). Scale bar: 10 μm x 10 μm for control and 20 μm x 20 μm for remote area, respectively. (B) Typical example of topology of sarcomeres in control tissue reveals structures with a periodicity of (2.0 ± 0.7) μm. (C) Time dependent variation of sarcomere length (δ) in remote vs. control. Comparisons for statistical significance at all time points were performed relative to control values. (D) Time-dependent stiffness variation of sarcomeres in remote vs. control tissues (***p < 0.001, ****p < 0.0001).
Figure 5
Figure 5
Bio-mechanical characteristics of control (open circle) vs. remote and scar regions. (filled circle) (A) Representative force (F) vs. displacement (d) retraction curves recorded on control, scar and remote regions of mice heart tissue. The differences in the slopes of F-d curves indicate different elastic properties (stiffness) of the heart tissue. (B) Time dependent biomechanics modification of the E-Modulus (E) in control and remote vs. infarct scar. In the inflammatory phase (7–21 days post-MI) infarct scar undergoes a maximum tension compared to the remote region and it returns at its initial values at 28 days post-MI (****p < 0.0001).
Figure 6
Figure 6
Contour plots displaying the fraction of I, III, and V collagen for different parameter fields of EF (%) and tissue stiffness. Contour plots of the expression of type I collagen in remote (A) and scar (B), of the expression of type III collagen in remote (C) and scar (D), and of the expression of type V collagen in remote (E) and scar (F). Hue color gradients assign the minimum and maximum expression values for type I collagen (A,B), type III collagen (C,D) and type V collagen (E,F) respectively in remote and scar regions. The inset values represent post-MI days that indicate the maximum expression values for each collagen type.
Figure 7
Figure 7
Schematic overview of remote remodelling after MI. (A) Early after MI, higher expression of types V and I collagen partially hinders relaxation-contraction of sarcomeres, increasing the remote stiffness and decreasing the sarcomeres’ length. (B) Type V collagen supports the biosynthesis of a soft and thin type III collagen fibers. Thus, tissue stiffness decreases while sarcomeres elongate to maintain the heart pump function at increased mechanical overload. (C) In the late remodeling phase, the synthesis of type I collagen allows the recovery of tissue compliance and sarcomeres’ length. Blue arrows indicate the reduction - elongation of sarcomeres’ dimensions. The thick blue and grey light lines denote M bands and Z disks of sarcomeres.
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