Technical Brief

Bioengineered Stromal Cell-Derived Factor-1α Analogue Delivered as an Angiogenic Therapy Significantly Restores Viscoelastic Material Properties of Infarcted Cardiac Muscle

[+] Author and Article Information
Alen Trubelja, John W. MacArthur, George Hung, William Hiesinger, Pavan Atluri

Division of Cardiovascular Surgery,
Department of Surgery,
University of Pennsylvania School of Medicine,
Philadelphia, PA 19104

Joseph J. Sarver

School of Biomedical Engineering,
Science & Health Systems,
Drexel University,
Philadelphia, PA 19104

Jeffrey E. Cohen, Yasuhiro Shudo, Jay Patel, Bryan B. Edwards

Department of Cardiothoracic Surgery,
Stanford University School of Medicine,
Stanford, CA 94305

Alexander S. Fairman

Division of Cardiovascular Surgery,
Department of Surgery,
University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Scott M. Damrauer

Division of Vascular Surgery,
Department of Surgery,
University of Pennsylvania School of Medicine,
Philadelphia, PA 19104

Y. Joseph Woo

Department of Cardiothoracic Surgery,
Stanford University School of Medicine,
Stanford, CA 94305
e-mail: joswoo@stanford.edu

Manuscript received December 20, 2013; final manuscript received May 15, 2014; accepted manuscript posted May 23, 2014; published online June 2, 2014. Assoc. Editor: Hai-Chao Han.

J Biomech Eng 136(8), 084501 (Jun 02, 2014) (5 pages) Paper No: BIO-13-1583; doi: 10.1115/1.4027731 History: Received December 20, 2013; Revised May 15, 2014; Accepted May 23, 2014

Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-α analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

Copyright © 2014 by ASME
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Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Borden, W. B., Bravata, D. M., Dai, S., Ford, E. S., Fox, C. S., Franco, S., Fullerton, H. J., Gillespie, C., Hailpern, S. M., Heit, J. A., Howard, V. J., Huffman, M. D., Kissela, B. M., Kittner, S. J., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Magid, D., Marcus, G. M., Marelli, A., Matchar, D. B., McGuire, D. K., Mohler, E. R., Moy, C. S., Mussolino, M. E., Nichol, G., Paynter, N. P., Schreiner, P. J., Sorlie, P. D., Stein, J., Turan, T. N., Virani, S. S., Wong, N. D., Woo, D., and Turner, M. B., 2013, “Heart Disease and Stroke Statistics—2013 Update: A Report From the American Heart Association,” Circulation, 127(1), pp. e6–e245. [CrossRef]
Pfeffer, M. A., and Braunwald, E., 1990, “Ventricular Remodeling After Myocardial Infarction. Experimental Observations and Clinical Implications,” Circulation, 81(4), pp. 1161–1172. [CrossRef]
Shimkunas, R., Zhang, Z., Wenk, J. F., Soleimani, M., Khazalpour, M., Acevedo-Bolton, G., Wang, G., Saloner, D., Mishra, R., Wallace, A. W., Ge, L., Baker, A. J., Guccione, J. M., and Ratcliffe, M. B., 2013, “Left Ventricular Myocardial Contractility Is Depressed in the Borderzone After Posterolateral Myocardial Infarction,” Ann. Thorac. Surg., 95(5), pp. 1619–1625. [CrossRef]
Nelson, D. M., Ma, Z., Fujimoto, K. L., Hashizume, R., and Wagner, W. R., 2011, “Intra-Myocardial Biomaterial Injection Therapy in the Treatment of Heart Failure: Materials, Outcomes and Challenges,” Acta Biomater., 7(1), pp. 1–15. [CrossRef]
Burlew, B. S., and Weber, K. T., 2002, “Cardiac Fibrosis as a Cause of Diastolic Dysfunction,” Herz, 27(2), pp. 92–98. [CrossRef]
Takahashi, T., Kalka, C., Masuda, H., Chen, D., Silver, M., Kearney, M., Magner, M., Isner, J. M., and Asahara, T., 1999, “Ischemia- and Cytokine-Induced Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells for Neovascularization,” Nat. Med., 5(4), pp. 434–438. [CrossRef]
Woo, Y. J., Grand, T. J., Berry, M. F., Atluri, P., Moise, M. A., Hsu, V. M., Cohen, J., Fisher, O., Burdick, J., Taylor, M., Zentko, S., Liao, G., Smith, M., Kolakowski, S., Jayasankar, V., Gardner, T. J., and Sweeney, H. L., 2005, “Stromal Cell-Derived Factor and Granulocyte-Monocyte Colony-Stimulating Factor Form a Combined Neovasculogenic Therapy for Ischemic Cardiomyopathy,” J. Thoracic Cardiovasc. Surg., 130(2), pp. 321–329. [CrossRef]
Hiesinger, W., Perez-Aguilar, J. M., Atluri, P., Marotta, N. A., Frederick, J. R., Fitzpatrick, J. R., III, McCormick, R. C., Muenzer, J. R., Yang, E. C., Levit, R. D., Yuan, L. J., Macarthur, J. W., Saven, J. G., and Woo, Y. J., 2011, “Computational Protein Design to Reengineer Stromal Cell-Derived Factor-1alpha Generates an Effective and Translatable Angiogenic Polypeptide Analog,” Circulation, 124(11 Suppl), pp. S18–S26. [CrossRef]
MacArthur, J. W., Jr., Trubelja, A., Shudo, Y., Hsiao, P., Fairman, A. S., Yang, E., Hiesinger, W., Sarver, J. J., Atluri, P., and Woo, Y. J., 2013, “Mathematically Engineered Stromal Cell-Derived Factor-1alpha Stem Cell Cytokine Analog Enhances Mechanical Properties of Infarcted Myocardium,” J. Thorac. Cardiovasc. Surg., 145(1), pp. 278–284. [CrossRef]
Sacks, M. S., 2000, “Biaxial Mechanical Evaluation of Planar Biological Materials,” J. Elast., 61(1–3), pp. 199–246. [CrossRef]
Hiesinger, W., Frederick, J. R., Atluri, P., McCormick, R. C., Marotta, N., Muenzer, J. R., and Woo, Y. J., 2010, “Spliced Stromal Cell-Derived Factor-1alpha Analog Stimulates Endothelial Progenitor Cell Migration and Improves Cardiac Function in a Dose-Dependent Manner After Myocardial Infarction,” J. Thorac. Cardiovasc. Surg., 140(5), pp. 1174–1180. [CrossRef]
Beason, D. P., Abboud, J. A., Kuntz, A. F., Bassora, R., and Soslowsky, L. J., 2011, “Cumulative Effects of Hypercholesterolemia on Tendon Biomechanics in a Mouse Model,” J. Orthop. Res., 29(3), pp. 380–383. [CrossRef]
Gimbel, J. A., Sarver, J. J., and Soslowsky, L. J., 2005, “The Effect of Overshooting the Target Strain on Estimating Viscoelastic Properties From Stress Relaxation Experiments,” ASME J. Biomech. Eng., 126(6), pp. 844–848. [CrossRef]
Miller, K. S., Edelstein, L., Connizzo, B. K., and Soslowsky, L. J., 2012, “Effect of Preconditioning and Stress Relaxation on Local Collagen Fiber Re-Alignment: Inhomogeneous Properties of Rat Supraspinatus Tendon,” ASME J. Biomech. Eng., 134(3), p. 031007. [CrossRef]
Yao, J., Varner, V. D., Brilli, L. L., Young, J. M., Taber, L. A., and Perucchio, R., 2012, “Viscoelastic Material Properties of the Myocardium and Cardiac Jelly in the Looping Chick Heart,” ASME J. Biomech. Eng., 134(2), p. 024502. [CrossRef]
Sarver, J. J., Robinson, P. S., and Elliott, D. M., 2003, “Methods for Quasi-Linear Viscoelastic Modeling of Soft Tissue: Application to Incremental Stress-Relaxation Experiments,” ASME J. Biomech. Eng., 125(5), pp. 754–758. [CrossRef]
Fomovsky, G. M., and Holmes, J. W., 2010, “Evolution of Scar Structure, Mechanics, and Ventricular Function After Myocardial Infarction in the Rat,” Am. J. Physiol.: Heart Circ. Physiol., 298(1), pp. H221–H228. [CrossRef]
Wenk, J. F., Sun, K., Zhang, Z., Soleimani, M., Ge, L., Saloner, D., Wallace, A. W., Ratcliffe, M. B., and Guccione, J. M., 2011, “Regional Left Ventricular Myocardial Contractility and Stress in a Finite Element Model of Posterobasal Myocardial Infarction,” ASME J. Biomech. Eng., 133(4), p. 044501. [CrossRef]
Lee, L. C., Wenk, J. F., Klepach, D., Zhang, Z., Saloner, D., Wallace, A. W., Ge, L., Ratcliffe, M. B., and Guccione, J. M., 2011, “A Novel Method for Quantifying In-Vivo Regional Left Ventricular Myocardial Contractility in the Border Zone of a Myocardial Infarction,” ASME J. Biomech. Eng., 133(9), p. 094506. [CrossRef]
Fomovsky, G. M., Thomopoulos, S., and Holmes, J. W., 2010, “Contribution of Extracellular Matrix to the Mechanical Properties of the Heart,” J. Mol. Cell. Cardiol., 48(3), pp. 490–496. [CrossRef]
Pai, S., Vawter, P. T., and Ledoux, W. R., 2013, “The Effect of Prior Compression Tests on the Plantar Soft Tissue Compressive and Shear Properties,” ASME J. Biomech. Eng., 135(9), p. 094501. [CrossRef]
Sullivan, K. E., and Black, L. D., 2013, “The Role of Cardiac Fibroblasts in Extracellular Matrix-Mediated Signaling During Normal and Pathological Cardiac Development,” ASME J. Biomech. Eng., 135(7), p. 071001. [CrossRef]
Connizzo, B. K., Sarver, J. J., Birk, D. E., Soslowsky, L. J., and Iozzo, R. V., 2013, “Effect of Age and Proteoglycan Deficiency on Collagen Fiber Re-Alignment and Mechanical Properties in Mouse Supraspinatus Tendon,” ASME J. Biomech. Eng., 135(2), p. 021019. [CrossRef]
Ohtani, T., Mohammed, S. F., Yamamoto, K., Dunlay, S. M., Weston, S. A., Sakata, Y., Rodeheffer, R. J., Roger, V. L., and Redfield, M. M., 2012, “Diastolic Stiffness as Assessed by Diastolic Wall Strain Is Associated With Adverse Remodelling and Poor Outcomes in Heart Failure With Preserved Ejection Fraction,” Eur. Heart J., 33(14), pp. 1742–1749. [CrossRef]


Grahic Jump Location
Fig. 3

(a) The bilinear region of the ramp to failure was identified for each specimen and analyzed separately from the linear elastic region. A bilinear curve was fit to the data and used to calculate the break point and transition strain. (b) The difference in the break point between the two best fit lines in the bilinear region was quantified. *p = 0.0110 and **p = 0.0042.

Grahic Jump Location
Fig. 2

(a) Samples were all preloaded to 0.05 N, at which point gauge length was set. The three incremental stress-relaxation ramps were analyzed to determine the viscoelastic properties of the muscle. (b) The peak and the equilibrium locations of the ramp. (c) The load data for each ramp were normalized using the peak and equilibrium loads in order to calculate the relaxation rate for the last 5% of each cycle. (d) The relaxation rates for each stress-relaxation ramp were analyzed independently for each experimental group. The trend of the ESA treatment group relaxing faster than the saline group is apparent at each increment (p = 0.2165 for the first increment and p = 0.2804 for the second increment). *p = 0.0284 and **p = 0.0065.

Grahic Jump Location
Fig. 1

(a) Representative image of a sham control heart. Specimens were excised from the LV in line from apex to base (white dashed lines). (b) Ventricular biopsies were mounted to an Instron 5543 material testing system. The purple squares indicate the ROIs used for strain analysis.




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