Anionic polymers amplify electrokinetic perfusion through extracellular matrices.

Electrical stimulation (ES) promotes healing of chronic epidermal wounds and delays degeneration of articular cartilage. Despite electrotherapeutic treatment of these non-excitable tissues, the mechanisms by which ES promotes repair are unknown. We hypothesize that a beneficial role of ES is dependent on electrokinetic perfusion in the extracellular space and that it mimics the effects of interstitial flow. In vivo, the extracellular space contains mixtures of extracellular proteins and negatively charged glycosaminoglycans and proteoglycans surrounding cells. While these anionic macromolecules promote water retention and increase mechanical support under compression, in the presence of ES they should also enhance electro-osmotic flow (EOF) to a greater extent than proteins alone. To test this hypothesis, we compare EOF rates between artificial matrices of gelatin (denatured collagen) with matrices of gelatin mixed with anionic polymers to mimic endogenous charged macromolecules. We report that addition of anionic polymers amplifies EOF and that a matrix comprised of 0.5% polyacrylate and 1.5% gelatin generates EOF with similar rates to those reported in cartilage. The enhanced EOF reduces mortality of cells at lower applied voltage compared to gelatin matrices alone. We also use modeling to describe the range of thermal changes that occur during these electrokinetic experiments and during electrokinetic perfusion of soft tissues. We conclude that the negative charge density of native extracellular matrices promotes electrokinetic perfusion during electrical therapies in soft tissues and may promote survival of artificial tissues and organs prior to vascularization and during transplantation.

Magnetic resonance imaging-based finite element stress analysis after linear repair of left ventricular aneurysm.

OBJECTIVE: Linear repair of left ventricular aneurysm has been performed with mixed clinical results. By using finite element analysis, this study evaluated the effect of this procedure on end-systolic stress. METHODS: Nine sheep underwent myocardial infarction and aneurysm repair with a linear repair (13.4 +/- 2.3 weeks postmyocardial infarction). Satisfactory magnetic resonance imaging examinations were obtained in 6 sheep (6.6 +/- 0.5 weeks postrepair). Finite element models were constructed from in vivo magnetic resonance imaging-based cardiac geometry and postmortem measurement of myofiber helix angles using diffusion tensor magnetic resonance imaging. Material properties were iteratively determined by comparing the finite element model output with systolic tagged magnetic resonance imaging strain measurements. RESULTS: At the mid-wall, fiber stress in the border zone decreased by 39% (sham = 32.5 +/- 2.5 kPa, repair = 19.7 +/- 3.6 kPa, P = .001) to the level of remote regions after repair. In the septum, however, border zone fiber stress remained high (sham = 31.3 +/- 5.4 kPa, repair = 23.8 +/- 5.8 kPa, P = .29). Cross-fiber stress at the mid-wall decreased by 41% (sham = 13.0 +/- 1.5 kPa, repair = 7.7 +/- 2.1 kPa, P = .01), but cross-fiber stress in the un-excluded septal infarct was 75% higher in the border zone than remote regions (remote = 5.9 +/- 1.9 kPa, border zone = 10.3 +/- 3.6 kPa, P < .01). However, end-diastolic fiber and cross-fiber stress were not reduced in the remote myocardium after plication. CONCLUSION: With the exception of the retained septal infarct, end-systolic stress is reduced in all areas of the left ventricle after infarct plication. Consequently, we expect the primary positive effect of infarct plication to be in the infarct border zone. However, the amount of stress reduction necessary to halt or reverse nonischemic infarct extension in the infarct border zone and eccentric hypertrophy in the remote myocardium is unknown.

Endoventricular patch plasty for dyskinetic anteroapical left ventricular aneurysm increases systolic circumferential shortening in sheep.

OBJECTIVE: Endoventricular patch plasty (Dor procedure) has gained favor as a surgical treatment for heart failure associated with large anteroapical myocardial infarction. We tested the hypotheses that the Dor procedure increases systolic circumferential shortening and longitudinal shortening in noninfarcted left ventricular regions in sheep. METHODS: In 6 male Dorsett sheep, the left anterior descending coronary artery and its second diagonal branch were ligated 40% of the distance from the apex to the base. Sixteen weeks after myocardial infarction, a Dor procedure was performed with a Dacron patch that was 50% of the infarct neck dimension. Two weeks before and 2 and 6 weeks after the Dor procedure, animals underwent magnetic resonance imaging with tissue tagging in multiple short-axis and long-axis slices. Fully three-dimensional strain analyses were performed. All 6 end-systolic strain components were compared in regions 1 cm, 2 cm, 3 cm, and 4 cm below the valves, as well as in the anterior, posterior, and lateral left ventricular walls and the interventricular septum. RESULTS: Circumferential shortening increased from before the Dor procedure to 6 weeks after repair in nearly every left ventricular region (13/16). The greatest regional change in circumferential shortening was found in the equatorial region or 2 cm below the base and in the posterior wall (from 9.0% to 18.4%; P < .0001). Longitudinal shortening increased 2 weeks after the Dor procedure but then returned near baseline by 6 weeks after the Dor procedure. CONCLUSION: The Dor procedure significantly increases systolic circumferential shortening in nearly all noninfarcted left ventricular regions in sheep.

Theoretical impact of the injection of material into the myocardium: a finite element model simulation.

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 (approximately 4.5%) 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.

The effect of anteroapical aneurysm plication on end-systolic three-dimensional strain in the sheep: a magnetic resonance imaging tagging study.

OBJECTIVES: Although repair of left ventricular aneurysm has been extensively studied, its effect on regional ventricular function remains unclear. The primary goal of this study was to quantify the effect of anteroapical aneurysm plication on systolic deformation in noninfarcted adjacent (border zone) and remote left ventricular regions in sheep. METHODS: Eight sheep underwent anteroapical myocardial infarction (25% of left ventricular mass). Ten weeks later, animals underwent aneurysm plication. Two and 6 weeks after this operation, animals underwent magnetic resonance imaging with tissue tagging in multiple short-axis and long-axis slices. Fully 3-dimensional strain analyses were performed. All 6 end-systolic strain components were compared at midwall in the border zone of the aneurysm or repair and in regions 1 cm, 2 cm, and 3 cm below the valves. RESULTS: Circumferential shortening progressively increases from before plication to 2 weeks after plication to 6 weeks after plication toward the border zone. The effect on circumferential shortening is most pronounced in the anterior wall and septum. The biggest change is from 2 to 6 weeks after plication (from 4.3% to 11.3% in anterior wall, P < .0001; from 3.5% to 6.5% in septum, P < .0007). Longitudinal shortening is decreased at 2 weeks after plication but then returns to baseline (with slight improvement in the border zone) at 6 weeks after plication. CONCLUSIONS: Repair of left ventricular aneurysm significantly increases systolic circumferential shortening at the border zone in sheep.

Left ventricular volume and function after endoventricular patch plasty for dyskinetic anteroapical left ventricular aneurysm in sheep.

OBJECTIVE: Endoventricular patch plasty (the Dor procedure) has gained favor as a surgical treatment for heart failure associated with large anteroapical myocardial infarction. We tested the hypothesis that the Dor procedure reduces left ventricular volume, increases end-systolic elastance, decreases diastolic compliance, and maintains left ventricular function. METHODS: In 6 male Dorsett sheep, the left anterior descending coronary artery and its second diagonal branch were ligated 40% of the distance from apex to base. Sixteen weeks after myocardial infarction, a Dor procedure was performed with a Dacron patch that was 50% of the infarct neck dimension. Absolute left ventricular volume was measured with magnetic resonance imaging, and left ventricular pressure and relative left ventricular volume changes during pharmacologic preload reduction were measured with a volume conductance catheter 2 weeks before and 2 and 6 weeks after the Dor procedure. End-systolic elastance, diastolic compliance, and Starling relationships were calculated from the resultant left ventricular pressure/volume loops. RESULTS: Two weeks after the Dor procedure, the left ventricular volume at end systole and end diastole was significantly reduced, and there was no redilation at 6 weeks. Six weeks after the Dor procedure, the ejection fraction was significantly increased. Although stroke volume increased slightly at 6 weeks, the change was not significant. The slopes of end-systolic elastance, diastolic compliance, and Starling relationships were unchanged at 2 and 6 weeks. CONCLUSIONS: The Dor procedure significantly reduces left ventricular volume. Unlike linear repair, left ventricular volume changes seem stable. The ejection fraction is improved, and left ventricular function (stroke volume and the Starling relationship) is maintained.

MRI-based finite-element analysis of left ventricular aneurysm.

Tagged MRI and finite-element (FE) analysis are valuable tools in analyzing cardiac mechanics. To determine systolic material parameters in three-dimensional stress-strain relationships, we used tagged MRI to validate FE models of left ventricular (LV) aneurysm. Five sheep underwent anteroapical myocardial infarction (25% of LV mass) and 22 wk later underwent tagged MRI. Asymmetric FE models of the LV were formed to in vivo geometry from MRI and included aneurysm material properties measured with biaxial stretching, LV pressure measurements, and myofiber helix angles measured with diffusion tensor MRI. Systolic material parameters were determined that enabled FE models to reproduce midwall, systolic myocardial strains from tagged MRI (630 +/- 187 strain comparisons/animal). When contractile stress equal to 40% of the myofiber stress was added transverse to the muscle fiber, myocardial strain agreement improved by 27% between FE model predictions and experimental measurements (RMS error decreased from 0.074 +/- 0.016 to 0.054 +/- 0.011, P < 0.05). In infarct border zone (BZ), end-systolic midwall stress was elevated in both fiber (24.2 +/- 2.7 to 29.9 +/- 2.4 kPa, P < 0.01) and cross-fiber (5.5 +/- 0.7 to 11.7 +/- 1.3 kPa, P = 0.02) directions relative to noninfarct regions. Contrary to previous hypotheses but consistent with biaxial stretching experiments, active cross-fiber stress development is an integral part of LV systole; FE analysis with only uniaxial contracting stress is insufficient. Stress calculations from these validated models show 24% increase in fiber stress and 115% increase in cross-fiber stress at the BZ relative to remote regions, which may contribute to LV remodeling.

Helical myofiber orientation after myocardial infarction and left ventricular surgical restoration in sheep.

OBJECTIVES: It has been proposed that successful left ventricular surgical restoration should restore normal helical myofiber orientation. A magnetic resonance imaging technique, magnetic resonance diffusion tensor imaging, has been developed to measure myocyte orientation. By using magnetic resonance diffusion tensor imaging, this study tested the hypothesis that (1) myocyte orientation is altered after anteroapical myocardial infarction and (2) left ventricular surgical restoration restores normal helix angles. METHODS: Thirteen sheep underwent anteroapical myocardial infarction (25% of left ventricular mass). Ten weeks later, animals underwent either aneurysm plication (n = 8) or sham operations (n = 5). Six weeks after this operation, hearts were excised, perfusion fixed in diastole, and underwent magnetic resonance diffusion tensor imaging. Hearts from normal sheep (n = 5) were also harvested and imaged. Primary eigenvectors of the diffusion tensors from magnetic resonance diffusion tensor imaging were resolved into helix angles relative to a local wall coordinate system. Transmural samples of the helix angles were compared at the border zone of the aneurysm or repair (or a comparable distance from the base in normal sheep), 1 cm below the valves, and halfway between. RESULTS: The helical myofiber orientation did not change after myocardial infarction. However, aneurysm plication caused myofibers in the anterior border zone to rotate counterclockwise (-35.6 +/- 10.5 degrees , P = .028) and those in the lateral border zone to rotate clockwise (34.4 +/- 8.1 degrees , P = .031). CONCLUSIONS: Surgical restoration alters myocyte orientation adjacent to the surgical repair. However, myofiber orientation is not abnormal after myocardial infarction, and thus surgical restoration techniques intent on restoring normal helix angles might not be warranted.