BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.
Successful engineering of load-bearing tissues requires recapitulation of their complex mechanical functions. Given the intimate relationship between function and form, biomimetic materials that replicate anatomic form are of great interest for tissue engineering applications. However, for complex tissues such as the annulus fibrosus, scaffolds have failed to capture their multi-scale structural hierarchy. Consequently, engineered tissues have yet to reach functional equivalence with their native counterparts. Here we present a novel strategy for annulus fibrosus tissue engineering that replicates this hierarchy with anisotropic nanofibrous laminates seeded with mesenchymal stem cells. These scaffolds directed the deposition of organized, collagen-rich extracellular matrix that mimicked the angle-ply, multi-lamellar architecture and achieved mechanical parity with native tissue after 10 weeks of in vitro culture. Further, we identified a novel role for inter-lamellar shearing in reinforcing the tensile response of biologic laminates, a mechanism that has not previously been considered for these tissues.
Study Design Develop construction algorithm in which electrospun nanofibrous scaffolds are coupled with a biocompatible hydrogel to engineer a mesenchymal stem cell (MSC)-based disc replacement. Objective Engineer a disc-like angle-ply structure (DAPS) that replicates the multi-scale architecture of the intervertebral disc. Summary of Background Data Successful engineering of a replacement for the intervertebral disc requires replication of its mechanical function and anatomic form. Despite many attempts to engineer a replacement for ailing and degenerated discs, no prior study has replicated the multi-scale hierarchical architecture of the native disc, and very few have assessed the mechanical function of formed neo-tissues. Methods A new algorithm for the construction of a disc analogue was developed, using agarose to form a central nucleus pulposus and electrospun nanofibrous scaffolds to form the annulus fibrosus region (AF, based on oriented nanofibrous scaffolds). Bovine MSCs were seeded into both regions and biochemical, histological, and mechanical maturation were observed with in vitro culture. Results We show that mechanical testing in compression and torsion, two loading modalities commonly used to assess disc mechanics, reveal equilibrium and time-dependent behaviors that are qualitatively similar to native tissue, although lesser in magnitude. Further, we demonstrate that cells seeded into the two regions adopt distinct morphologies that mirror those seen in native tissue, and that, in the AF region, this ordered community of cells deposited matrix that is organized in an angle-ply configuration. Finally, constructs demonstrated functional development with long-term in vitro culture. Conclusion These findings provide a new approach for disc tissue engineering that replicates multi-scale form and function of the intervertebral disc, providing a foundation from which to build a multi-scale, biologic, anatomically and hierarchically relevant composite disc analogue for eventual disc replacement.
The intervertebral disc maintains a balance between externally applied loads and internal osmotic pressure. Fluid flow plays a key role in this process, causing fluctuations in disc hydration and height. The objectives of this study were to quantify and model the axial creep and recovery responses of nondegenerate and degenerate human lumbar discs. Two experiments were performed. First, a slow compressive ramp was applied to 2000 N, unloaded to allow recovery for up to 24 hours, and re-applied. The linear-region stiffness and disc height were within 5% of the initial condition for recovery times greater than 8 hours. In the second experiment, a 1000 N creep load was applied for four hours, unloaded recovery monitored for 24 hours, and the creep load repeated. A viscoelastic model comprised of a "fast" and "slow" exponential response was used to describe the creep and recovery, where the fast response is associated with flow in the nucleus pulposus (NP) and endplate, while the slow response is associated with the annulus fibrosus (AF). The study demonstrated that recovery is 3-4X slower than loading. The fast response was correlated with degeneration, suggesting larger changes in the NP with degeneration compared to the AF. However, the fast response comprised only 10-15% of the total equilibrium displacement, with the AF-dominated slow response comprising 40-70%. Finally, the physiological loads and deformations and their associated long equilibrium times confirm that diurnal loading does not represent "equilibrium" in the disc, but that over time the disc is in steady-state.
The annulus fibrosus (AF) of the intervertebral disc undergoes large and multidirectional stresses and strains. Uniaxial tensile tests are limited for measuring AF material properties, because freely contracting edges can prevent fiber stretch and are not representative of in situ boundary conditions. The objectives of this study were to measure human AF biaxial tensile mechanics and to apply and validate a constitutive model to determine material properties. Biaxial tensile tests were performed on samples oriented along the circumferential-axial and the radial-axial directions. Data were fit to a structurally-motivated anisotropic hyperelastic model composed of isotropic extrafibrillar matrix, nonlinear fibers, and fiber-matrix interactions (FMI) normal to the fibers. The validated model was used to simulate shear and uniaxial tensile behavior, to investigate AF structure-function, and to quantify the effect of degeneration. The biaxial stress-strain response was described well by the model (R2>0.9). The model showed that the parameters for fiber nonlinearity and the normal FMI correlated with degeneration, resulting in an elongated toe region and lower stiffness with degeneration. The model simulations in shear and uniaxial tension successfully matched previously published circumferential direction Young’s modulus, provided an explanation for the low values in previously published axial direction Young’s modulus, and was able to simulate shear mechanics. The normal FMI were important contributors to stress and changed with degeneration, therefore, their microstructural and compositional source should be investigated. Finally, the biaxial mechanical data and constitutive model can be incorporated into a disc finite element model to provide improved quantification of disc mechanics.
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