Safety and Effectiveness of Smooth Incision Lenticular Keratomileusis (SILKTM) Using the ELITA(TM) Femtosecond Laser System for Correction of Myopic and Astigmatic Refractive Errors.

Purpose: To evaluate visual outcomes following the Smooth Incision Lenticular Keratomileusis (SILKTM) procedure for correction of myopic refractive errors with and without astigmatism, using the ELITATM Femtosecond Laser System. Patients and Methods: A prospective, multicenter, single-arm, open-label clinical study was conducted. Eighty-five myopic subjects (n = 170 eyes), aged 18 years or older, with manifest refractive spherical equivalent (MRSE) up to -12.00 D and astigmatism up to -6.00 D, were treated binocularly using the ELITA femtosecond laser and followed up for 6 months. Intended correction was emmetropia for all eyes. The primary outcome measures included post-operative uncorrected and corrected distance visual acuity (UDVA and CDVA). Secondary outcome measures included surgeon's rating for ease of lenticule extraction, predictability, safety, and stability. Results: A total of 170 eyes of 85 patients underwent SILK. Preoperative mean MRSE was -4.14 D ± 1.32 D (range -1.38 D to -8.88 D) and the mean cylinder was -0.77 D ± 0.62 D. Intraoperative surgeon ease of lenticule dissection was rated as grade 0 or 1 in 85.3% of eyes (no/only mild dissection needed). UDVA at 1 day, 1 week, 1 month, and 6 months was 20/20 or better in 65.9%, 85.4%, 91.5%, and 96% of eyes, respectively. No eyes lost any lines of CDVA at 6 months compared to the preoperative. The postoperative MRSE was stable over time, ranging from -0.34 D ± 0.24 D at 1 month to -0.33 D ± 0.23 D at 6 months. MRSE predictability (± 0.50 D) was 93.5% (129/138) at 3 months and 91.1% (113/124) at 6 months. No serious adverse events were noted. Conclusion: The SILK procedure with the ELITA Femtosecond Laser System is safe and effective for the treatment of myopic refractive errors with and without astigmatism. Fast visual recovery was demonstrated, with stability achieved by 3 months.

Eye-specific 3D modeling of factors influencing oxygen concentration in the lamina cribrosa.

Our goal was to identify the factors with the strongest influence on the minimum lamina cribrosa (LC) oxygen concentration as potentially indicative of conditions increasing hypoxia risk. Because direct measurement of LC hemodynamics and oxygenation is not yet possible, we developed 3D eye-specific LC vasculature models. The vasculature of a normal monkey eye was perfusion-labeled post-mortem. Serial cryosections through the optic nerve head were imaged using fluorescence and polarized light microscopy to visualize the vasculature and collagen, respectively. The vasculature within a 450 µm-thick region containing the LC - identified from the collagen, was segmented, skeletonized, and meshed for simulations. Using Monte Carlo sampling, 200 vascular network models were generated with varying vessel diameter, neural tissue oxygen consumption rate, inflow hematocrit, and blood pressures (arteriole, venule, anterior boundary, and posterior boundary). Factors were varied over ranges of baseline ±20% with uniform probability. For each model we first obtained the blood flow, and from this the neural tissue oxygen concentration. ANOVA was used to identify the factors with the strongest influence on the minimum (10th percentile) oxygen concentration in the LC. The three most influential factors were, in ranked order, vessel diameter, neural tissue oxygen consumption rate, and arteriole pressure. There was a strong interaction between vessel diameter and arteriole pressure whereby the impact of one factor was larger when the other factor was small. Our results show that, for the eye analyzed, conditions that reduce vessel diameter, such as vessel compression due to elevated intraocular pressure or gaze-induced tissue deformation, may particularly contribute to decreased LC oxygen concentration. More eyes must be analyzed before generalizing.

Lamina cribrosa vessel and collagen beam networks are distinct.

Our goal was to analyze the spatial interrelation between vascular and collagen networks in the lamina cribrosa (LC). Specifically, we quantified the percentages of collagen beams with/without vessels and of vessels inside/outside of collagen beams. To do this, the vasculature of six normal monkey eyes was labeled by perfusion post-mortem. After enucleation, coronal cryosections through the LC were imaged using fluorescence and polarized light microscopy to visualize the blood vessels and collagen beams, respectively. The images were registered to form 3D volumes. Beams and vessels were segmented, and their spatial interrelationship was quantified in 3D. We found that 22% of the beams contained a vessel (range 14%-32%), and 21% of vessels were outside beams (13%-36%). Stated differently, 78% of beams did not contain a vessel (68%-86%), and 79% of vessels were inside a beam (64%-87%). Individual monkeys differed significantly in the fraction of vessels outside beams (p < 0.01 by linear mixed effect analysis), but not in the fraction of beams with vessels (p > 0.05). There were no significant differences between contralateral eyes in the percent of beams with vessels and of vessels outside beams (p > 0.05). Our results show that the vascular and collagenous networks of the LC in monkey are clearly distinct, and the historical notions that each LC beam contains a vessel and all vessels are within beams are inaccurate. We postulate that vessels outside beams may be relatively more vulnerable to mechanical compression by elevated IOP than are vessels shielded inside of beams.

So-Called Lamina Cribrosa Defects May Mitigate IOP-Induced Neural Tissue Insult.

Purpose: The prevailing theory about the function of lamina cribrosa (LC) connective tissues is that they provide structural support to adjacent neural tissues. Missing connective tissues would compromise this support and therefore are regarded as "LC defects", despite scarce actual evidence of their role. We examined how so-called LC defects alter IOP-related mechanical insult to the LC neural tissues. Methods: We built numerical models incorporating LC microstructure from polarized light microscopy images. To simulate LC defects of varying sizes, individual beams were progressively removed. We then compared intraocular pressure (IOP)-induced neural tissue deformations between models with and without defects. To better understand the consequences of defect development, we also compared neural tissue deformations between models with partial and complete loss of a beam. Results: The maximum stretch of neural tissues decreased non-monotonically with defect size. Maximum stretch in the model with the largest defect decreased by 40% in comparison to the model with no defects. Partial loss of a beam increased the maximum stretch of neural tissues in its adjacent pores by 162%, compared with 63% in the model with complete loss of a beam. Conclusions: Missing LC connective tissues can mitigate IOP-induced neural tissue insult, suggesting that the role of the LC connective tissues is more complex than simply fortifying against IOP. The numerical models further predict that partial loss of a beam is biomechanically considerably worse than complete loss of a beam, perhaps explaining why defects have been reported clinically but partial beams have not.

Lamina Cribrosa Capillaries Straighten as Intraocular Pressure Increases.

Purpose: The purpose of this study was to visualize the lamina cribrosa (LC) capillaries and collagenous beams, measure capillary tortuosity (path length over straight end-to-end length), and determine if capillary tortuosity changes when intraocular pressure (IOP) increases. Methods: Within 8 hours of sacrifice, 3 pig heads were cannulated via the external ophthalmic artery, perfused with PBS to remove blood, and then perfused with a fluorescent dye to label the capillaries. The posterior pole of each eye was mounted in a custom-made inflation chamber for control of IOP with simultaneous imaging. Capillaries and collagen beams were visualized with structured light illumination enhanced imaging at IOPs from 5 to 50 mm Hg at each 5 mm Hg increment. Capillary tortuosity was measured from the images and paired two-sample t-tests were used to assess for significant changes in relation to changes in IOP. Results: Capillaries were highly tortuous at 15 mm Hg (up to 1.45). In all but one eye, tortuosity decreased significantly as IOP increased from 15 to 25 mm Hg (P < 0.01), and tortuosity decreased significantly in every eye as IOP increased from 15 to 40 mm Hg (P < 0.01). In only 16% of capillaries, tortuosity increased with elevated IOP. Capillaries had a surprisingly different topology from the collagen beams. Conclusions: Although high capillary tortuosity is sometimes regarded as potentially problematic because it can reduce blood flow, LC capillary tortuosity may provide slack that mitigates against reduced flow and structural damage caused by excessive stretch under elevated IOP. We speculate that low capillary tortuosity could be a risk factor for damage under high IOP.

Role of radially aligned scleral collagen fibers in optic nerve head biomechanics.

Collagen fibers organized circumferentially around the canal in the peripapillary sclera are thought to provide biomechanical support to the sensitive tissues within the optic nerve head (ONH). Recent studies have demonstrated the existence of a family of fibers in the innermost sclera organized radially from the scleral canal. Our goal was to determine the role of these radial fibers in the sensitivity of scleral canal biomechanics to acute increases in intraocular pressure (IOP). Following the same general approach of previous parametric sensitivity studies, we created nonlinear generic finite element models of a posterior pole with various combinations of radial and circumferential fibers at an IOP of 0 mmHg. We then simulated the effects of normal and elevated IOP levels (15 and 30 mmHg). We monitored four IOP-induced geometric changes: peripapillary sclera stretch, scleral canal displacement, lamina cribrosa displacement, and scleral canal expansion. In addition, we examined the radial (maximum tension) and through-thickness (maximum compression) strains within the ONH tissues. Our models predicted that: 1) radial fibers reduced the posterior displacement of the lamina, especially at elevated IOP; 2) radial fibers reduced IOP-induced radial strain within the peripapillary sclera and retinal tissue; and 3) a combination of radial and circumferential fibers maintained strains within the ONH at a level similar to those conferred by circumferential fibers alone. In conclusion, radial fibers provide support for the posterior globe, additional to that provided by circumferential fibers. Most importantly, a combination of both fiber families can better protect ONH tissues from excessive IOP-induced deformation than either alone.

Peripapillary sclera architecture revisited: A tangential fiber model and its biomechanical implications.

The collagen fiber architecture of the peripapillary sclera (PPS), which surrounds the scleral canal, is a critical factor in determining the mechanical response of the optic nerve head (ONH) to variations in intraocular pressure (IOP). Experimental and clinical evidence point to IOP-induced deformations within the scleral canal as important contributing factors of glaucomatous neural tissue damage and consequent vision loss. Hence, it is imperative to understand PPS architecture and biomechanics. Current consensus is that the fibers of the PPS form a closed ring around the canal to support the delicate neural tissues within. We propose an alternative fiber architecture for the PPS, in which the scleral canal is supported primarily by long-running fibers oriented tangentially to the canal. We present evidence that this tangential model is consistent with histological observations in multiple species, and with quantitative measurements of fiber orientation obtained from small angle light scattering and wide-angle X-ray scattering. Using finite element models, we investigated the biomechanical implications of a tangential fiber PPS architecture. We found that the tangential arrangement of fibers afforded better mechanical support to the tissues within the scleral canal as compared to a simple circumferential ring of fibers or a combination of fibers oriented radially and circumferentially. We also found that subtle variations from a tangential orientation could reproduce clinically observed ONH behavior which has yet to be explained using current theories of PPS architecture and simulation, namely, the contraction of the scleral canal under elevated IOP. STATEMENT OF SIGNIFICANCE: It is hypothesized that vision loss in glaucoma is due to excessive mechanical deformation within the neural tissue inside the scleral canal. This study proposes a new model for how the collagen of the peripapillary sclera surrounding the canal is organized to support the delicate neural tissue inside. Previous low-resolution studies of the peripapillary sclera suggested that the collagen fibers are arranged in a ring around the canal. Instead, we provide microscopic evidence suggesting that the canal is also supported by long-running interwoven fibers oriented tangentially to the canal. We demonstrate that this arrangement has multiple biomechanical advantages over a circular collagen arrangement and can explain previously unexplained experimental findings including contraction of the scleral canal under elevated intraocular pressure.

Seeing the Hidden Lamina: Effects of Exsanguination on the Optic Nerve Head.

Purpose: To introduce an experimental approach for direct comparison of the primate optic nerve head (ONH) before and after death by exsanguination. Method: The ONHs of four eyes from three monkeys were imaged with spectral-domain optical coherence tomography (OCT) before and after exsanguination under controlled IOP. ONH structures, including the Bruch membrane (BM), BM opening, inner limiting membrane (ILM), and anterior lamina cribrosa (ALC) were delineated on 18 virtual radial sections per OCT scan. Thirteen parameters were analyzed: scleral canal at BM opening (area, planarity, and aspect ratio), ILM depth, BM depth; ALC (depth, shape index, and curvedness), and ALC visibility (globally, superior, inferior, nasal, and temporal quadrants). Results: All four ALC quadrants had a statistically significant improvement in visibility after exsanguination (overall P < 0.001). ALC visibility increased by 35% globally and by 36%, 37%, 14%, and 4% in the superior, inferior, nasal, and temporal quadrants, respectively. ALC increased 4.1%, 1.9%, and 0.1% in curvedness, shape index, and depth, respectively. Scleral canals increased 7.2%, 25.2%, and 1.1% in area, planarity, and aspect ratio, respectively. ILM and BM depths averaged -7.5% and -55.2% decreases in depth, respectively. Most, but not all, changes were beyond the repeatability range. Conclusions: Exsanguination allows for improved lamina characterization, especially in regions typically blocked by shadowing in OCT. The results also demonstrate changes in ONH morphology due to the loss of blood pressure. Future research will be needed to determine whether there are differences in ONH biomechanics before and after exsanguination and what those differences would imply.

Cerebrospinal Fluid Pressure: Revisiting Factors Influencing Optic Nerve Head Biomechanics.

Purpose: To model the sensitivity of the optic nerve head (ONH) biomechanical environment to acute variations in IOP, cerebrospinal fluid pressure (CSFP), and central retinal artery blood pressure (BP). Methods: We extended a previously published numerical model of the ONH to include 24 factors representing tissue anatomy and mechanical properties, all three pressures, and constraints on the optic nerve (CON). A total of 8340 models were studied to predict factor influences on 98 responses in a two-step process: a fractional factorial screening analysis to identify the 16 most influential factors, followed by a response surface methodology to predict factor effects in detail. Results: The six most influential factors were, in order: IOP, CON, moduli of the sclera, lamina cribrosa (LC) and dura, and CSFP. IOP and CSFP affected different aspects of ONH biomechanics. The strongest influence of CSFP, more than twice that of IOP, was on the rotation of the peripapillary sclera. CSFP had similar influence on LC stretch and compression to moduli of sclera and LC. On some ONHs, CSFP caused large retrolamina deformations and subarachnoid expansion. CON had a strong influence on LC displacement. BP overall influence was 633 times smaller than that of IOP. Conclusions: Models predict that IOP and CSFP are the top and sixth most influential factors on ONH biomechanics. Different IOP and CSFP effects suggest that translaminar pressure difference may not be a good parameter to predict biomechanics-related glaucomatous neuropathy. CON may drastically affect the responses relating to gross ONH geometry and should be determined experimentally.

Lamina Cribrosa Pore Shape and Size as Predictors of Neural Tissue Mechanical Insult.

Purpose: The purpose of this study was to determine how the architecture of the lamina cribrosa (LC) microstructure, including the shape and size of the lamina pores, influences the IOP-induced deformation of the neural tissues within the LC pores using computational modeling. Methods: We built seven specimen-specific finite element models of LC microstructure with distinct nonlinear anisotropic properties for LC beams and neural tissues based on histological sections from three sheep eyes. Changes in shape (aspect ratio and convexity) and size (area and perimeter length) due to IOP-induced hoop stress were calculated for 128 LC pores. Multivariate linear regression was used to determine if pore shape and size were correlated with the strain in the pores. We also compared the microstructure models to a homogenized model built following previous approaches. Results: The LC microstructure resulted in focal tensile, compressive, and shear strains in the neural tissues of the LC that were not predicted by homogenized models. IOP-induced hoop stress caused pores to become larger and more convex; however, pore aspect ratio did not change consistently. Peak tensile strains within the pores were well predicted by a linear regression model considering the initial convexity (negative correlation, P < 0.001), aspect ratio (positive correlation, P < 0.01), and area (negative correlation, P < 0.01). Significant correlations were also found when considering the deformed shape and size of the LC pores. Conclusions: The deformation of the LC neural tissues was largely dependent on the collagenous LC beams. Simple measures of LC pore shape and area provided good estimates of neural tissue biomechanical insult.

Microstructural Crimp of the Lamina Cribrosa and Peripapillary Sclera Collagen Fibers.

Purpose: Although collagen microstructural crimp is a major determinant of ocular biomechanics, no direct measurements of optic nerve head (ONH) crimp have been reported. Our goal was to characterize the crimp period of the lamina cribrosa (LC) and peripapillary sclera (PPS) at low and normal IOPs. Methods: ONHs from 11 sheep eyes were fixed at 10-, 5-, or 0-mm Hg IOP and crimp periods measured manually from coronal cryosections imaged with polarized light microscopy (PLM). Using linear mixed-effect models, we characterized the LC and PPS periods, and how they varied with distance from the scleral canal edge. Results: A total of 17,374 manual collagen crimp period measurements were obtained with high repeatability (1.9 µm) and reproducibility (4.7 µm). The periods were smaller (P < 0.001) and less variable in the LC than in the PPS: average (SD) of 13.8 (3.1) µm in the LC, and 31.0 (10.4) µm in the PPS. LC crimp period did not vary with distance from the scleral canal wall (P > 0.1). PPS period increased with the square root of the distance to the canal (P < 0.0001). Conclusions: Small, uniform crimp periods within the sheep LC and immediately adjacent PPS may indicate that these tissues are setup to prevent large or heterogeneous deformations that insult the neural tissues within the canal. An increasing more variable period with distance from the canal provides a smooth transition of mechanical properties that minimizes stress and strain concentrations.

Whole-globe biomechanics using high-field MRI.

The eye is a complex structure composed of several interconnected tissues acting together, across the whole globe, to resist deformation due to intraocular pressure (IOP). However, most work in the ocular biomechanics field only examines the response to IOP over smaller regions of the eye. We used high-field MRI to measure IOP induced ocular displacements and deformations over the whole globe. Seven sheep eyes were obtained from a local abattoir and imaged within 48 h using MRI at multiple levels of IOP. IOP was controlled with a gravity perfusion system and a cannula inserted into the anterior chamber. T2-weighted imaging was performed to the eyes serially at 0 mmHg, 10 mmHg, 20 mmHg and 40 mmHg of IOP using a 9.4 T MRI scanner. Manual morphometry was conducted using 3D visualization software to quantify IOP-induced effects at the globe scale (e.g. axial length and equatorial diameters) or optic nerve head scale (e.g. canal diameter, peripapillary sclera bowing). Measurement sensitivity analysis was conducted to determine measurement precision. High-field MRI revealed an outward bowing of the posterior sclera and anterior bulging of the cornea due to IOP elevation. Increments in IOP from 10 to 40 mmHg caused measurable increases in axial length in 6 of 7 eyes of 7.9 ± 5.7% (mean ± SD). Changes in equatorial diameter were minimal, 0.4 ± 1.2% between 10 and 40 mmHg, and in all cases less than the measurement sensitivity. The effects were nonlinear, with larger deformations at normal IOPs (10-20 mmHg) than at elevated IOPs (20-40 mmHg). IOP also caused measurable increases in the nasal-temporal scleral canal diameter of 13.4 ± 9.7% between 0 and 20 mmHg, but not in the superior-inferior diameter. This study demonstrates that high-field MRI can be used to visualize and measure simultaneously the effects of IOP over the whole globe, including the effects on axial length and equatorial diameter, posterior sclera displacement and bowing, and even changes in scleral canal diameter. The fact that the equatorial diameter did not change with IOP, in agreement with previous studies, indicates that a fixed boundary condition is a reasonable assumption for half globe inflation tests and computational models. Our results demonstrate the potential of high-field MRI to contribute to understanding ocular biomechanics, and specifically of the effects of IOP in large animal models.

Myocardial Infarction Superimposed on Aging: MMP-9 Deletion Promotes M2 Macrophage Polarization.

In this study, we examined the combined effect of aging and myocardial infarction on left ventricular remodeling, focusing on matrix metalloproteinase (MMP)-9-dependent mechanisms. We enrolled 55 C57BL/6J wild type (WT) and 85 MMP-9 Null (Null) mice of both sexes at 11-36 months of age and evaluated their response at Day 7 post-myocardial infarction. Plasma MMP-9 levels positively linked to age in WT mice (r = .46, p = .001). MMP-9 deletion improved survival (76% for WT vs 88% for Null, p = .021). Post-myocardial infarction, there was a progressive increase in left ventricular dilation with age in WT but not in Null mice. By inflammatory gene array analysis, WT mice showed linear age-dependent increases in three different proinflammatory genes (C3, CCl4, and CX3CL1; all p < .05), whereas Null mice showed increases in three proinflammatory genes (CCL5, CCL9, and CXCL4; all p < .05) and seven anti-inflammatory genes (CCL1, CCL6, CCR1, IL11, IL1r2, IL8rb, and Mif; all p < .05). Compared with WT, macrophages isolated from Null left ventricle infarct demonstrated enhanced expression of anti-inflammatory M2 markers CD163, MRC1, TGF-ß1, and YM1 (all p < .05), without affecting proinflammatory M1 markers. In conclusion, MMP-9 deletion stimulated anti-inflammatory polarization of macrophages to attenuate left ventricle dysfunction in the aging post-myocardial infarction.

Biomechanics of Cardiac Function.

The heart pumps blood to maintain circulation and ensure the delivery of oxygenated blood to all the organs of the body. Mechanics play a critical role in governing and regulating heart function under both normal and pathological conditions. Biological processes and mechanical stress are coupled together in regulating myocyte function and extracellular matrix structure thus controlling heart function. Here, we offer a brief introduction to the biomechanics of left ventricular function and then summarize recent progress in the study of the effects of mechanical stress on ventricular wall remodeling and cardiac function as well as the effects of wall mechanical properties on cardiac function in normal and dysfunctional hearts. Various mechanical models to determine wall stress and cardiac function in normal and diseased hearts with both systolic and diastolic dysfunction are discussed. The results of these studies have enhanced our understanding of the biomechanical mechanism in the development and remodeling of normal and dysfunctional hearts. Biomechanics provide a tool to understand the mechanism of left ventricular remodeling in diastolic and systolic dysfunction and guidance in designing and developing new treatments.

Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction.

Matrix metalloproteinase-9 (MMP-9) deletion attenuates collagen accumulation and dilation of the left ventricle (LV) post-myocardial infarction (MI); however the biomechanical mechanisms underlying the improved outcome are poorly understood. The aim of this study was to determine the mechanisms whereby MMP-9 deletion alters collagen network composition and assembly in the LV post-MI to modulate the mechanical properties of myocardial scar tissue. Adult C57BL/6J wild-type (WT; n=88) and MMP-9 null (MMP-9(-/-); n=92) mice of both sexes underwent permanent coronary artery ligation and were compared to day 0 controls (n=42). At day 7 post-MI, WT LVs displayed a 3-fold increase in end-diastolic volume, while MMP-9(-/-) showed only a 2-fold increase (p<0.05). Biaxial mechanical testing revealed that MMP-9(-/-) infarcts were stiffer than WT infarcts, as indicated by a 1.3-fold reduction in predicted in vivo circumferential stretch (p<0.05). Paradoxically, MMP-9(-/-) infarcts had a 1.8-fold reduction in collagen deposition (p<0.05). This apparent contradiction was explained by a 3.1-fold increase in lysyl oxidase (p<0.05) in MMP-9(-/-) infarcts, indicating that MMP-9 deletion increased collagen cross-linking activity. Furthermore, MMP-9 deletion led to a 3.0-fold increase in bone morphogenetic protein-1, the metalloproteinase that cleaves pro-collagen and pro-lysyl oxidase (p<0.05) and reduced fibronectin fragmentation by 49% (p<0.05) to enhance lysyl oxidase activity. We conclude that MMP-9 deletion increases infarct stiffness and prevents LV dilation by reducing collagen degradation and facilitating collagen assembly and cross-linking through preservation of the fibronectin network and activation of lysyl oxidase.

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction.

Aging is linked to increased matrix metalloproteinase-9 (MMP-9) expression and extracellular matrix turnover, as well as a decline in function of the left ventricle (LV). Previously, we demonstrated that C57BL/6J wild-type (WT) mice > 18 mo of age show impaired diastolic function, which was attenuated by MMP-9 deletion. To evaluate mechanisms that initiate the development of cardiac dysfunction, we compared the LVs of 6-9- and 15-18-mo-old WT and MMP-9 null (Null) mice. All groups showed similar LV function by echocardiography, indicating that dysfunction had not yet developed in the older group. Myocyte nuclei numbers and cross-sectional areas increased in both WT and Null 15-18-mo mice compared with young controls, indicating myocyte hypertrophy. Myocyte hypertrophy leads to an increased oxygen demand, and both WT and Null 15-18-mo mice showed an increase in angiogenic signaling. Plasma proteomic profiling and LV analysis revealed a threefold increase in von Willebrand factor and fivefold increase in vascular endothelial growth factor in WT 15-18-mo mice, which were further elevated in Null mice. In contrast to the upregulation of angiogenic stimulating factors, actual LV vessel numbers increased only in the 15-18-mo Null LV. The 15-18-mo WT showed amplified expression of inflammatory genes related to angiogenesis, including C-C chemokine receptor (CCR)7, CCR10, interleukin (IL)-1f8, IL-13, and IL-20 (all, P < 0.05), and these increases were blunted by MMP-9 deletion (all, P < 0.05). To measure vascular permeability as an index of endothelial function, we injected mice with FITC-labeled dextran. The 15-18-mo WT LV showed increased vascular permeability compared with young WT controls and 15-18-mo Null mice. Combined, our findings revealed that MMP-9 deletion improves angiogenesis, attenuates inflammation, and prevents vascular leakiness in the setting of cardiac aging.

A model to determine the effect of collagen fiber alignment on heart function post myocardial infarction.

BACKGROUND: Adverse remodeling of the left ventricle (LV) following myocardial infarction (MI) leads to heart failure. Recent studies have shown that scar anisotropy is a determinant of cardiac function post-MI, however it remains unclear how changes in extracellular matrix (ECM) organization and structure contribute to changes in LV function. The objective of this study is to develop a model to identify potential mechanisms by which collagen structure and organization affect LV function post-MI. METHODS: A four-region, multi-scale, cylindrical model of the post-MI LV was developed. The mechanical properties of the infarct region are governed by a constitutive equation based on the uncrimping of collagen fibers. The parameters of this constitutive equation include collagen orientation, angular dispersion, fiber stiffness, crimp angle, and density. Parametric variation of these parameters was used to elucidate the relationship between collagen properties and LV function. RESULTS: The mathematical model of the LV revealed several factors that influenced cardiac function post-MI. LV function was maximized when collagen fibers were aligned longitudinally. Increased collagen density was also found to improve stroke volume for longitudinal alignments while increased fiber stiffness decreased stroke volume for circumferential alignments. CONCLUSIONS: The results suggest that cardiac function post-MI is best preserved through increased circumferential compliance. Further, this study identifies several collagen fiber-level mechanisms that could potentially regulate both infarct level and organ level mechanics. Improved understanding of the multi-scale relationships between the ECM and LV function will be beneficial in the design of new diagnostic and therapeutic technologies.