In situ constructive myocardial remodeling of extracellular matrix patch enhanced with controlled growth factor release Akiko Tanaka, MD, PhD, Keigo.

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Discussion The Journal of Thoracic and Cardiovascular Surgery

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Akiko Tanaka, MD, PhD, Takeyoshi Ota, MD, PhD

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In situ constructive myocardial remodeling of extracellular matrix patch enhanced with controlled growth factor release Akiko Tanaka, MD, PhD, Keigo Kawaji, PhD, Amit R. Patel, MD, Yasuhiko Tabata, PhD, DMedSci, DPharm, Martin C. Burke, DO, Mahesh P. Gupta, PhD, Takeyoshi Ota, MD, PhD The Journal of Thoracic and Cardiovascular Surgery Volume 150, Issue 5, Pages 1280-1290.e2 (November 2015) DOI: 10.1016/j.jtcvs.2015.07.073 Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 CMR imaging. A, Peak longitudinal strain: The highest value in SIS-ECM-FGF-2 demonstrates significantly increased contractility compared with both SIS-ECM and Dacron patch groups. B, Mean longitudinal strain from end diastole to end systole: The peak of the Dacron patch was significantly delayed compared with the normal right ventricle, SIS-ECM-FGF-2, and SIS-ECM, implying passive “akinetic” movement of the patch area in conjunction with surrounding normal right ventricular contractility. C, Representative case of signal intensity curve: Relative maximum upslope (*normal right ventricle, †SIS-ECM-FGF-2) is calculated from the ration of maximum upslope of the target tissue to that of the left ventricular cavity (‡). D, Relative maximum upslope: The results indicate SIS-ECM-FGF-2 and SIS-ECM gained tissue perfusion. E, Representative figure of T1 maps generated from MOLLI images acquired before and after administration of a gadolinium contrast agent, and the reciprocal of each pixel value is taken to generate R1 maps. The ECV is calculated from the equation as described. F, ECM volume fractions. The results indicate that the patch area was remodeled with more viable tissue in the SIS-ECM-FGF-2 group compared with the SIS-ECM group, and the Dacron group mostly consisted of fibrous/edematous tissue. Group B, SIS-ECM-FGF-2. Group U, untreated SIS-ECM. Group D, Dacron patch. Normal RV, Self-control normal right ventricle. RV, Right ventricle; ECG, electrocardiogram; SIS-ECM-FGF-2, small intestine submucosa-extracellular matrix-basic fibroblast growth factor; SIS-ECM, small intestine submucosa-extracellular matrix; a.u, arbitrary units; MOLLI, modified Look-Locker inversion recovery; Gd, gadolinium; ECV, extracellular volume fraction. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 1280-1290.e2DOI: (10.1016/j.jtcvs.2015.07.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Electrophysiologic-anatomic mapping. This represents a right ventricular endocardial voltage map. Purple signifies normal voltage with values greater than 1.5 mV. The spectrum of colors (dark blue, light blue, and red) in the patch (inset) reveal a range in voltage from 0.5 to 1.5 mV compared with the surrounding native tissue of 7.01 mV. Voltage less than 0.5 mV is gray. RV, Right ventricle; 3D, 3-dimensional. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 1280-1290.e2DOI: (10.1016/j.jtcvs.2015.07.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Macro inspection. Intraoperative views (A, E, I), epicardial views at 60 days (B, F, J), endocardial views at 60 days (C, G, K), and cross-section views at 60 days (D, H, L) are demonstrated: A-D, SIS-ECM-FGF-2 patch. E-H, SIS-ECM patch. I-L, Dacron patch. SIS-ECM-FGF-2, Small intestine submucosa-extracellular matrix-basic fibroblast growth factor; SIS-ECM, small intestine submucosa-extracellular matrix. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 1280-1290.e2DOI: (10.1016/j.jtcvs.2015.07.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Histology and immunohistochemistry. SIS-ECM-FGF-2 (A-E): Homogenous distribution of repopulated host cells infiltrating through the entire layer of the patch is seen, including α-sarcomeric actinin and tropomyosin-positive cells, suggesting the presence of maturing cardiomyocytes. The endocardial surface is covered with a monolayer of endothelial cells (vWF-positive cells). SIS-ECM (F-J): Well-organized cells including monolayer of endothelial cells on the endocardial surface and layers of scattered α-sarcomeric actinin and tropomyosin-positive cells were observed. The repopulated cells were predominantly developed on the SIS-ECM sheet rather than infiltrating in the SIS-ECM layers. Dacron (K-O): Significant infiltration of lymphoid cells is observed, consistent with a foreign body response with no presence of vWF, α-sarcomeric actinin, or tropomyosin-positive cells. Black bar = 200 μm. White bar = 100 μm. SIS-ECM-FGF-2, Small intestine submucosa-extracellular matrix-basic fibroblast growth factor; SIS-ECM, small intestine submucosa-extracellular matrix. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 1280-1290.e2DOI: (10.1016/j.jtcvs.2015.07.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Real-time polymerase chain reaction. mRNA expression was normalized by the expression of a housekeeping gene (GAPDH). Comparison with normal myocardium: *P < .05. Comparison with SIS-ECM (U): †P < .05. Comparison with Dacron (D): ‡P < .05. SIS-ECM-FGF-2, Small intestine submucosa-extracellular matrix-basic fibroblast growth factor; SIS-ECM, small intestine submucosa-extracellular matrix; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; β-MYH, β-myosin heavy chain; SM22α, smooth muscle 22α; vWF, von Willebrand factor. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 1280-1290.e2DOI: (10.1016/j.jtcvs.2015.07.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 Capillary density. A-C, Representative vWF immunohistochemical staining in each patch. D, Capillary density *P < .05. SIS-ECM, Small intestine submucosa-extracellular matrix; SIS-ECM-FGF-2, small intestine submucosa-extracellular matrix-basic fibroblast growth factor. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 1280-1290.e2DOI: (10.1016/j.jtcvs.2015.07.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

The ECM patch enhanced with controlled release of growth factor. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 1280-1290.e2DOI: (10.1016/j.jtcvs.2015.07.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions