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Original Articles: Adult Cardiac

Modification of Infarct Material Properties Limits Adverse Ventricular Remodeling

^a Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia
^c Department of Surgery, University of Pennsylvania, Philadelphia
^d Department of Bioengineering, University of Pennsylvania, Philadelphia
^b Engineered Tissue Mechanics and Mechanobiology Laboratory, Department of Bioengineering, Swanson School of Engineering, McGowan Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Accepted for publication April 14, 2011.

^_* Address correspondence to Dr Robert Gorman, Gorman Cardiovascular Research Group, Glenolden Research Laboratory, University of Pennsylvania, 500 S Ridgeway Ave, Glenolden, PA 19036 (Email: gormanr{at}uphs.upenn.edu).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background: Infarct expansion after myocardial infarction (MI) is an important phenomenon that initiates and sustains adverse left ventricular (LV) remodeling. We tested the hypothesis that infarct modification by material-induced infarct stiffening and thickening limits infarct expansion and LV remodeling.

Methods: Anteroapical infarction was induced in 21 sheep. Sheep were randomized to injection of saline (2.6 mL) or tissue filler material (2.6 mL) into the infarct within 3 hours of MI. Animals were monitored for 8 weeks with echocardiography to assess infarct expansion and global LV remodeling. Morphometric measurements were performed of excised hearts to quantify infarct thickness. Regional blood flow was assessed with colored microspheres. Infarct material properties were measured using biaxial tensile testing.

Results: Compared with controls at 8 weeks, treatment animals had less infarct expansion, reduced LV dilatation (LV systolic volumes: 60.8 ± 4.3 vs 80.3 ± 6.9 mL; p < 0.05), greater ejection fraction (0.310 ± 0.026 vs 0.276 ± 0.013; p < 0.05), thicker infarcts (5.5 ± 0.2 vs 2.2 ± 0.3 mm; p < 0.05), and greater infarct blood flow (0.22 ± 0.04 vs 0.11 ± 0.03 mL/min/g; p < 0.05). The longitudinal peak strain in the treatment group was less (0.05014 ± 0.0141) than the control group (0.1024 ± 0.0101), indicating increased stiffness of the treated infarcts.

Conclusions: Durable infarct thickening and stiffening can be achieved by infarct biomaterial injection, resulting in the amelioration of infarct expansion and global LV remodeling. Further material optimization will allow for clinical translation of this novel treatment paradigm.

	Introduction

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Studies of the biomechanical response of the left ventricle (LV) to myocardial infarction (MI) have identified infarct expansion (ie, stretching) as an important phenomenon that initiates and sustains a progressive pathologic process that ultimately results in LV dilatation, loss of global contractile function, symptomatic heart failure, and death [1–3]. This maladaptive infarction-induced ventricular remodeling is a complex process that is, in its initial phase, a largely mechanical problem manifest by abnormal myocardial stress patterns; however, with time, these abnormal stress distributions lead to inherent biologic changes in the myocardium that become difficult to reverse by any means once established [3–6].

Given our understanding that the mechanical phenomenon of infarct expansion initiates the adverse LV remodeling that leads to heart failure, we hypothesized, more than a decade ago, that physical restraint of the infarct would limit adverse remodeling. In a series of experiments using surgical mesh materials in large-animal infarct models, we confirmed the beneficial effects of mechanically restraining infarcts early after an MI [7–13]. As a result, our group and others have begun to develop and test materials that can be introduced directly into the infarct to prevent its expansion. Several substances have shown promise; however, little work has been performed to optimize material design or to elucidate the mechanism by which infarct expansion is reduced [14–18].

In this study we tested the hypothesis that infarct modification by way of material-induced infarct stiffening and thickening limits infarct expansion and LV remodeling. We used a biocompatible, calcium hydroxyapatite–based soft-tissue filler to modify the infarct in an ovine anteroapical infarction model [14].

	Material and Methods

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All animals in this study were treated and cared for in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Research Council, Washington, DC, 1996).

Animal Model
Myocardial infarction was surgically induced in 21 adult male sheep (weight, 35 to 40 kg) using a well-described method [19]. Briefly, the animals were anesthetized and underwent left thoracotomy. An anteroapical infarction was produced by ligating the left anterior descending artery and its diagonal branches, resulting in an infarction of approximately 20% of the LV mass. This technique reproducibly creates infarctions of a very consistent size.

The sheep were randomized in a 1:2 fashion to receive 2.6 mL of saline or tissue filler within 3 hours of infarction. The injectate was delivered in 20 equally sized boluses spaced evenly over the accessible region of the infarct on the anteroapical region of the LV (Fig 1 ). The septal component of the infarct was not treated. Six additional animals that did not have an infarction were used in the study to act as referent controls for dobutamine stress echocardiographic testing, regional blood flow assessments, and postmortem morphometric measurements.

View larger version (69K): [in this window] [in a new window]   Fig 1. A sheep heart as seen through a left thoracotomy (A) immediately after coronary ligation (note the discolored apical region in the area of the infarct) and (B) immediately after dermal filler injection.

Echocardiographic Protocol
Transapical epicardial 3-dimensional (3D) echocardiography was performed through a left thoracotomy immediately before MI, 30 minutes after MI, and 15 minutes after injection in all animals. Transdiaphragmatic echocardiography was performed at 8 weeks after MI at resting conditions and after dobutamine (5 µg/kg/min) was administered. All echocardiograms were recorded using a Philips iE 33 platform with a 7-MHz ultrasound probe (Philips, Bothell, WA). Full volume 3D data were acquired and exported for offline analysis using QLAB software (Philips, Bothell, WA).

The 3D images were manipulated to display two orthogonally related long-axis views, bisecting each other on the central long axis of the LV. End diastole (ED) was defined as the frame before closure of the mitral valve and end systole (ES) as the frame before closure of the aortic valve. For each of these two points, the ED volume, (EDV), the ES volume (ESV), and ejection fraction (EF) were obtained, according to the software manufacturer's recommended method. Myocardial infarct length (wall motion abnormality length in long axis) was also measured. All image analysis was performed by a blinded analyst.

Hemodynamic Measurements
A pulmonary artery catheter was placed to allow for the measurement of cardiac output (CO) by means of thermodilution as well as central venous pressure (CVP). A high-fidelity pressure transducer was placed in the LV to assess LVED pressure. Hemodynamic data were recorded immediately before the echocardiographic studies.

Regional Blood Flow Measurements
In all infarcted animals as well as in 6 uninfarcted animals, 15 million color-coded, 15.5 µm diameter NuFlow Fluorescent microspheres (IMT Laboratories, Irvine, CA) were injected during the terminal study under resting conditions and after dobutamine was administered. Reference blood samples were taken at both points. IMT Laboratories used flow cytometry to analyze the reference blood samples and myocardial specimens from the infarct, adjacent border zone, and remote regions for microsphere content. Regional perfusion was calculated using the formula: [Q_m = (C_m x Q_r)/Cr], where Q _m is myocardial blood flow per gram (mL/min/g) of sample, C _m is microsphere count per gram of tissue in the sample, Q _r is the withdrawal rate of the reference blood sample (mL/min), and C _r is microsphere count in the reference blood sample.

Postmortem Morphometric Assessment
Animals were sacrificed after the final microsphere injection. The heart was excised, the LV was opened through the septum, and a standardized digital photo was taken (Casio EX-Z850, Tokyo Japan). Photographs were imported into the Image Pro Plus image analysis program (Media Cybernetics, Silver Spring, MD), and the size of the infarct was assessed with computerized planimetry [15]. The infarct area was expressed as a percentage of the LV area. The right and left ventricles were weighed individually.

A 15-mm² section of infarct tissue was excised from the center of the infarct for biaxial mechanical testing. A digital micrometer was used to measure myocardial thickness in the most apical portion of the infarct, the most basilar portion of the infarct, the borderzone, and the remote region. The infarct tissue was fixed and stained with Masson trichrome.

Mechanical Testing of Infarct Tissue
Mechanical testing was performed using a biaxial tensile mechanical testing device [24]. Custom software permitted the precise control of the applied load to both axes and tracked fiducial markers. Specimens were preconditioned to a 10-kPa peak equi-biaxial stress for 15 cycles with a 15-second half-cycle time. A 1-gram tare was used as the testing reference state, although free-floating reference states after preconditioning were obtained for postprocessing analyses. Equi-biaxial mechanical testing to a 10-kPa peak stress was performed on all specimens for 10 cycles at a 15-second half-cycle time.

A finite-element-based surface interpolation technique was used to determine the 2D in-surface Eulerian strain tensor "e" at each time point [25]. A single four-node linear Lagrangian element was used. To reference the deformed state configuration and calculate "e," a convective, in-surface coordinate system was used in which the axes were aligned to the local longitudinal and circumferential directions of the myocardium. In this analysis, the Eulerian strain tensor components were computed at each load iteration. In addition, the second Piola-Kirchhoff stress was computed using the deformation gradient tensor. Strain energy was computed by using the trapezoidal rule for circumferential and radial directions.

Statistical Analysis
Measurements are reported as means ± standard errors of the mean. Between-group differences for the echocardiographic and hemodynamic data were compared by analysis of variance for repeated measures. If analysis of variance revealed significant differences, the Student t test with the Bonferroni correction was used to assess differences between groups at specific times after infarction. Data were analyzed using SPSS software (SPSS Inc, Chicago, IL).

For mechanical testing of the infarct tissue for each group, raw data were compiled, consisting of peak directional strains and direction and total strain energies. Statistically significant differences were assessed using a one-way analysis of variance test. Significance was assumed at p < 0.05.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Animal Survival
One animal in the control group and 2 animals in the treatment group died of intractable ventricular arrhythmias within an hour of coronary occlusion, before injection of the tissue filler or saline. One treatment animal died approximately 24 hours after infarction of a presumed arrhythmia. Six control animals and 11 treatment animals completed the study without further complications.

LV Remodeling
Echocardiographic data are presented in Table 1. None of the baseline echocardiographic variables were statistically different between the groups. LV dilatation occurred in both groups immediately after infarction. ESV and EDV were similar in both groups and increased significantly relative to preinfarction. The initial length of the apical wall motion abnormality was 7.2 ± 0.3 cm in the control group and 7.1 ± 0.3 cm in the treatment group, confirming that the initial infarct size was comparable in both groups. Significant LV dilatation occurred in both groups during the 8-week study period; however, ESV (60.8 ± 4.3 vs 80.3 ± 6.9 mL) and EDV (87.2 ± 4.0 vs 110.6 ± 8.4 mL) were significantly smaller in the treatment group. Although EF also decreased significantly in both groups, it was significantly higher in the treatment group at 8 weeks after infarction (0.310 ± 0.026 vs 0.276 ± 0.013). ESV and EDV decreased significantly and EF increased significantly in both groups after the administration of dobutamine; however, the differences between groups persisted. Infarct length was significantly smaller in the treatment group at 8 weeks after MI, consistent with reduced infarct expansion (8.0 ± 0.2 vs 9.3 ± 0.6 cm). In addition to experiencing less LV dilatation, the treatments animals also demonstrated a trend toward preservation of the normal elliptical shape of the ovine heart (Fig 2 ).

View larger version (63K): [in this window] [in a new window]   Fig 2. Representative 2-dimensional long-axis echocardiograms are shown in (A) diastole and (B) systole in representative (C) treatment and (D) control hearts 8 weeks after infarction. Note the preservation of the normal elliptical left ventricular (LV) shape in the treated heart and the nearly spherical shape of the control heart. The white arrows identify the radiopaque filler material in the apical region of the treated heart. (LA = left atrium.)

Regional Myocardial Blood Flow
Regional myocardial blood flow data are reported in Table 2. Blood flow in the infarct region was significantly reduced in the infarct zone relative to the borderzone and remote zone at 8 weeks after infarction in both groups; however, infarct blood flow was significantly higher in the treatment group (0.22 ± 0.04 vs 0.11 ± 0.03 mL/min/g). This difference became more pronounced under pharmacologic stress with dobutamine (0.43 ± 0.11 vs 0.14 ± 0.03 mL/min/g). Borderzone and remote blood flow in the unstressed state was significantly higher in the control group (0.78 ± 0.11 and 0.75 ± 0.14 mL/min/g) than in the treatment group (0.51 ± 0.05 and 0.48 ± 0.04 mL/min/g) or in the normal animals without infarcts (0.52 ± 0.07 and 0.47 ± 0.04 mL/min/g). In response to dobutamine-induced stress, regional blood flow in uninfarcted myocardial segments did not increase in the control group or the therapy group to levels achieved in normal animals.

View larger version (39K): [in this window] [in a new window]   Fig 3. Representative examples are shown of long-axis sections taken from sheep left ventricles to assess regional myocardial thickness. (A) A normal uninfarcted heart. (B) A treated heart 8 weeks after injection of the tissue filler materia. The black arrow indicates where thickness measurements were made. (C) Section from an untreated control heart 8 weeks after infarction. Note the preservation in thickness of the apical region in the treated heart and the profound thinning experienced in the untreated heart.

View larger version (91K): [in this window] [in a new window]   Fig 4. Masson trichrome staining in representative (A and C) control animals and (B and D) treatment animals 8 weeks after infarction. Panels A and B are at original magnification x1; panels B and D are at original magnification x1.2. Notice the exuberant collagen production (blue) and lack of fat infiltration in the treated animal relative to control. The increase in collagen was responsible for most of the increased infarct thickness. At 8 weeks after infarction, the carrier gel of the tissue filler had been completely absorbed and a cellular (red) infiltrate was left surrounding the calcium hydroxyapatite microspheres.

View larger version (14K): [in this window] [in a new window]   Fig 5. Results are shown of the mechanical testing of the infarct tissue. (A) Representative stress-strain plots are presented of specimens from both groups. (B) Peak strain and (C) peak strain energy are shown for all groups. Longitudinal peak strain (E11) and total strain energy were significantly less in the treatment group than in the controls. As with the mean peak strain data, the directional strain energies were isotropic in the treatment group and anisotropic in the control group. *p < 0.05 between group difference. (E22= circumferential strain; E12= longitudinal-circumferential shear strain.)

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

This work builds on our previous study in which we demonstrated that the same tissue filler material limited infarct dyskinetic movement immediately after injection [14]. One unique aspect of the current study is that we used a state-of-the-art tensile mechanical testing device to directly compare infarct material properties in treated and untreated infarct tissue. Our data confirm the hypotheses proposed in previously published theoretic and experimental studies that have suggested that stiffening of the infarct region should have beneficial effects on LV remodeling and function [26–28]. Specifically, infarct thickening and stiffening should result in reduced mechanical stresses not only in the infarct region but also in the perfused myocardial segments outside the infarct. This has important implications, because increased myocardial stress has been identified as stimulus for inherent biologic changes in remodeled myocardium [29–31].

This study adds to a growing body of literature that supports the efficacy of using injectable materials to limit infarct expansion in the early post-MI period [14–18, 32]. The significance of pursuing this therapeutic concept is potentially profound, because it raises the distinct possibility of a percutaneous catheter-based direct treatment of the infarct to modify its material properties in the early post-MI period with the intent of limiting or preventing long-term adverse LV remodeling and loss of global contractile function.

As the potential for such a therapeutic paradigm has become apparent, so have the limitations of our current knowledge. The injectable biomaterials that have been studied include biologic materials, such as alginate [16], fibrin [33], and derivatives of the extracellular matrix [34], as well as synthetic materials such as self-assembling peptides [18] and thermoresponsive N-isopropyl acrylamide gels [35]. These materials, as used and delivered with various injection techniques and activation processes (eg, alginate gels are activated in the presence of divalent cations, whereas N-isopropyl acrylamide gels transition based on temperature), present a very wide range of mechanical, resorptive, and tissue reaction properties. In addition most materials tested to date have used common formulations developed for other applications, and in many of these materials, there is little control over their physical properties. Thus, there is a need for a material system that can be engineered to optimize stiffness, durability, and ease of delivery.

The tissue filler used in this experiment demonstrated efficacy in limiting adverse LV remodeling, but it is likely suboptimal for clinical use. Remodeling was attenuated but was not prevented: LV dilatation did progress during the 8-week follow-up period. Theoretically, an optimally engineered material would prevent progressive infarct expansion and LV dilatation beyond the point where the ventricle has compensated for the loss of contractile myocardium and normalized stroke volume. The high viscosity of this particulate containing filler would also make catheter delivery difficult.

The infarcts in the treatment group were stiffer than in the control group, and the mechanism by which stiffening occurred as well as its time course was likely complex. These are important issues that the current study did not directly address. Immediately after injection, the bulk material properties of the injectate likely imparted an increased to stiffness to the infarct region. Over time there was the expected tissue response to the filler in which macrophages cleared the carrier gel and responded to the microspheres to induce an exuberant production of collagen that contributed to the anisotropic infarct stiffening documented by the biaxial mechanical testing.

The material used in this experiment has no known inherent angiogenic properties; therefore, it is likely that the increased blood flow observed in the infarcts of the treated animals was the result of a reactive inflammatory response to the material. This is an important finding, because the injection of various cells, genes, and gene products into infarcts has been touted as a technique to increase infarct blood flow based on the in vitro determinations of the material's angiogenic potential [36, 37]. This study documents that nonspecific responses to injected materials can produce increased infarct blood flow.

In summary, durable infarct thickening and stiffening can be achieved by biomaterial injection into the infarct, resulting in the anticipated amelioration in infarct expansion and in global LV remodeling. Although much work remains to be accomplished, the requisite catheter technology, imaging modalities, and material science expertise exist to make this novel preventative approach to infarction-induced heart failure a clinical reality in the not-too-distant future.

	Acknowledgments

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This research project was supported by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health (HL63954 and HL73021), Bethesda, Maryland. R. Gorman and J. Gorman are supported by individual Established Investigator Awards from the American Heart Association, Dallas, Texas.

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Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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