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

Heart disease is the leading cause of death worldwide, with coronary heart disease causing one of every six deaths in the United States [1]. Following a myocardial infarction (MI), scar tissue gradually replaces myocardium that is lost through a process of collagen deposition and an increase in tensile strength of the tissue [2]. Borderzone myocardium becomes hypocontractile, leading to left ventricular dilation, increased left ventricle (LV) wall stress, and a decrease in ejection fraction [3]. LV dilation perpetuates infarct expansion, adverse ventricular remodeling, and dysfunction, which ultimately leads to heart failure. The deleterious remodeling of the LV after MI causes a significant change in its geometry, resulting in less efficient cardiomyocyte contraction and finally, a significant decline in cardiac pump efficiency [4,5]. Understanding the effect of a therapy on the passive mechanical properties of the myocardium is a key component of understanding its efficacy. Angiogenesis is a mechanism by which adverse ventricular remodeling can be limited. It has previously been shown that bone marrow-derived endothelial progenitor cells migrate toward ischemic tissue and incorporate into foci of neovascularization [6]. We formerly demonstrated the efficacy of a native protein, stromal cell-derived factor-1α (SDF), in providing an effective neovasculogenic therapy for ischemic cardiomyopathy [7]. Subsequently, we developed ESA, a computationally designed analog of SDF-1α, and demonstrated that intramyocardial injection enhances LV function by promoting angiogenesis and retention of the extracellular matrix (ECM) [8]. Angiogenesis in the borderzone reduces collagen deposition, limits infarct spreading, and thereby preserves healthy tissue. The differential collagen content in the borderzone has a significant effect on the tensile modulus of the tissue [9]. There has been significant interest among both the clinical and basic science communities in understanding the regional stresses in the heart. The LV free wall is a thick-walled complex fibrous structure, mainly consisting of myocyte and collagen fibers. The functional and structural complexity of the LV free wall poses a challenge to the application of biaxial biomechanical analysis to the passive tissue state. Myocardium is anisotropic in the fiber and cross-fiber directions, and exhibits both nonlinear elasticity and viscoelasticity, with strain-rate dependence. The fibrous structure also varies throughout the LV, with the direction and degree of anisotropy dependent on the location from which the biopsy was taken. Computing regional stresses in the LV require constitutive mathematical models of both the active and passive tissue states [10]. In this study, we sought to validate an experimental model of testing myocardium that combines viscoelastic properties with previously reported elastic properties, in order to better understand how ESA treatment alters the mechanics of myocardial tissue with a focus on the borderzone. Given our previous results [8,9], we hypothesized that injection of ESA into the borderzone of infarcted cardiac muscle would improve the viscoelastic properties of the ventricle, providing further evidence that ESA effects change at the tissue mechanics level, in addition to globally preserving LV function.