Background-To treat cardiac injuries created by myocardial infarcts, current approaches seek to add cells and/or synthetic extracellular matrices to the damaged ventricle to restore function. Because definitive myocardial regeneration remains undemonstrated, we propose that cardiac changes observed from implanted materials may result from altered mechanisms of the ventricle. Methods and Results-We exploited a validated finite element model of an ovine left ventricle with an anteroapical infarct to examine the short-term effect of injecting material to the left ventricular wall. The model's mesh and regional material properties were modified to simulate expected changes. Three sets of simulations were run: (1) single injection to the anterior border zone; (2) therapeutic multiple border zone injections; and (3) injection of material to the infarct region.Results indicate that additions to the border zone decrease end-systolic fiber stress proportionally to the fractional volume added, with stiffer materials improving this attenuation. As a potential therapy, small changes in wall volume (Ϸ4.5%) reduce elevated border zone fiber stresses from mean end-systole levels of 28.2 kPa (control) to 23.3 kPa (treatment), similar to levels of 22.5 kPA computed in remote regions. In the infarct, injection improves ejection fraction and the stroke volume/end-diastolic volume relationship but has no effect on the stroke volume/end-diastolic pressure relationship. Conclusions-Simulations indicate that the addition of noncontractile material to a damaged left ventricular wall has important effects on cardiac mechanics, with potentially beneficial reduction of elevated myofiber stresses, as well as confounding changes to clinical left ventricular metrics.

Heart failure continues to present a significant medical and economic burden throughout the developed world. Novel treatments involving the injection of polymeric materials into the myocardium of the failing left ventricle (LV) are currently being developed, which may reduce elevated myofiber stresses during the cardiac cycle and act to retard the progression of heart failure. A finite element (FE) simulation-based method was developed in this study that can automatically optimize the injection pattern of the polymeric "inclusions" according to a specific objective function, using commercially available software tools. The FE preprocessor TRUEGRID((R)) was used to create a parametric axisymmetric LV mesh matched to experimentally measured end-diastole and end-systole metrics from dogs with coronary microembolization-induced heart failure. Passive and active myocardial material properties were defined by a pseudo-elastic-strain energy function and a time-varying elastance model of active contraction, respectively, that were implemented in the FE software LS-DYNA. The companion optimization software LS-OPT was used to communicate directly with TRUEGRID((R)) to determine FE model parameters, such as defining the injection pattern and inclusion characteristics. The optimization resulted in an intuitive optimal injection pattern (i.e., the one with the greatest number of inclusions) when the objective function was weighted to minimize mean end-diastolic and end-systolic myofiber stress and ignore LV stroke volume. In contrast, the optimization resulted in a nonintuitive optimal pattern (i.e., 3 inclusions longitudinallyx6 inclusions circumferentially) when both myofiber stress and stroke volume were incorporated into the objective function with different weights.

Background Left ventricular (LV) wall stress reduction is a cornerstone in treating heart failure. Large animal models and computer simulations indicate that adding non-contractile material to the damaged LV wall can potentially reduce myofiber stress. We sought to quantify the effects of a novel implantable hydrogel (Algisyl-LVR™) treatment in combination with coronary artery bypass grafting (i.e. Algisyl-LVR™+CABG) on both LV function and wall stress in heart failure patients. Methods and results Magnetic resonance images obtained before treatment (n=3), and at 3 months (n=3) and 6 months (n=2) afterwards were used to reconstruct the LV geometry. Cardiac function was quantified using end-diastolic volume (EDV), end-systolic volume (ESV), regional wall thickness, sphericity index and regional myofiber stress computed using validated mathematical modeling. The LV became more ellipsoidal after treatment, and both EDV and ESV decreased substantially 3 months after treatment in all patients; EDV decreased from 264±91 ml to 146±86 ml and ESV decreased from 184±85 ml to 86±76 ml. Ejection fraction increased from 32±8% to 47±18% during that period. Volumetric-averaged wall thickness increased in all patients, from 1.06±0.21 cm (baseline) to 1.3±0.26 cm (3 months). These changes were accompanied by about a 35% decrease in myofiber stress at end-of-diastole and at end-of-systole. Post-treatment myofiber stress became more uniform in the LV. Conclusions These results support the novel concept that Algisyl-LVR™+CABG treatment leads to decreased myofiber stress, restored LV geometry and improved function.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of the cells' electrophysiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for adult cells based on changes in optical measurements of action potentials and Ca 2+ transients made in stem cell derived cardiac microtissues. This methodology quantifies ion channel changes through the inversion of data into a mathematical model, and maps this response to an adult phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation. Here, we utilize an updated action potential model to represent both hiPSC-CMs and adult cardiomyocytes, apply an IC50-based model of dose-dependent drug effects, and introduce a continuation-based optimization algorithm for analysis of dose escalation measurements using five drugs with known effects. The improved methodology can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodology is a step towards employing computational procedures to elucidate drug effects in adult cardiomyocytes for new drugs using stem cell-derived experimental tissues.

A potently active multivalent form of the protein Sonic hedgehog (Shh) was produced by bioconjugation of a modified recombinant form of Shh to the linear polymers poly(acrylic acid) (pAAc) and hyaluronic acid (HyA) via a two-step reaction exploiting carboimiide and maleimide chemistry. Efficiency of the conjugation was approximately 75% even at stoichiometric ratios of 30 Shh molecules per linear HyA chain (i.e., 30:1 Shh/HyA). Bioactivity of the conjugates was tested via a cellular assay across a range of stoichiometric ratios of Shh molecules to HyA linear chains, which was varied from 0.6:1 Shh/HyA to 22:1 Shh/HyA. Results indicate that low conjugation ratios decrease Shh bioactivity and high ratios increase this activity beyond the potency of monomeric Shh, with approximately equal activity between monomeric soluble Shh and conjugated Shh at 7:1 Shh/HyA. In addition, high-ratio constructs increased angiogenesis determined by the in vivo chick chorioallantoic membrane (CAM) assay. These results are captured by a kinetic model of multiple interactions between the Shh/HyA conjugates and cell surface receptors resulting in higher cell signaling at lower bulk Shh concentrations.