Baseline local hemodynamics as predictor of lumen remodeling at 1-year follow-up in stented superficial femoral arteries

In-stent restenosis (ISR) is the major drawback of superficial femoral artery (SFA) stenting. Abnormal hemodynamics after stent implantation seems to promote the development of ISR. Accordingly, this study aims to investigate the impact of local hemodynamics on lumen remodeling in human stented SFA lesions. Ten SFA models were reconstructed at 1-week and 1-year follow-up from computed tomography images. Patient-specific computational fluid dynamics simulations were performed to relate the local hemodynamics at 1-week, expressed in terms of time-averaged wall shear stress (TAWSS), oscillatory shear index and relative residence time, with the lumen remodeling at 1-year, quantified as the change of lumen area between 1-week and 1-year. The TAWSS was negatively associated with the lumen area change (ρ = − 0.75, p = 0.013). The surface area exposed to low TAWSS was positively correlated with the lumen area change (ρ = 0.69, p = 0.026). No significant correlations were present between the other hemodynamic descriptors and lumen area change. The low TAWSS was the best predictive marker of lumen remodeling (positive predictive value of 44.8%). Moreover, stent length and overlapping were predictor of ISR at follow-up. Despite the limited number of analyzed lesions, the overall findings suggest an association between abnormal patterns of WSS after stenting and lumen remodeling

Cellular Therapy With Ixmyelocel-T to Treat Critical Limb Ischemia: The Randomized, Double-blind, Placebo-controlled RESTORE-CLI Trial

Ixmyelocel-T is a patient-specific, expanded, multicellular therapy evaluated in patients with lower extremity critical limb ischemia (CLI) with no options for revascularization. This randomized, double-blind, placebo-controlled, phase 2 trial (RESTORE-CLI) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo. Patients received one-time injections over 20 locations in a single leg and were followed for 12 months. Safety assessments included occurrence of adverse events. Efficacy assessments included time to first occurrence of treatment failure (TTF; major amputation of injected leg; all-cause mortality; doubling of total wound surface area from baseline; de novo gangrene) and amputation-free survival (AFS; major amputation of injected leg; all-cause mortality). A total of 77 patients underwent bone marrow or sham aspiration; 72 patients received ixmyelocel-T (48 patients) or placebo (24 patients). Adverse event rates were similar. Ixmyelocel-T treatment led to a significantly prolonged TTF (P = 0.0032, logrank test). AFS had a clinically meaningful 32% reduction in event rate that was not statistically significant (P = 0.3880, logrank test). Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced (TTF: P < 0.0001, AFS: P = 0.0802, logrank test). Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option

Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia

Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia (CLI) of the lower extremities and no other established treatment options. This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells (TRCs).A prospective, randomized double-blinded, placebo controlled, multicenter study (RESTORE-CLI) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization. Enrollment of 86 patients began in April 2007 and ended in February 2010. For the prospectively planned interim analysis, conducted in February 2010, 33 patients had the opportunity to complete the trial (12 months of follow-up), and 46 patients had completed at least 6 months of follow-up. The interim analysis included analysis of both patient populations. An independent physician performed the bone marrow or sham control aspiration. The aspirate was processed in a closed, automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells. An average of 136 ± 41 × 10 total viable cells or electrolyte (control) solution were injected into 20 sites in the ischemic lower extremity. The primary end point was safety as evaluated by adverse events, and serious adverse events as assessed at multiple follow-up time points. Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure (defined as any of the following: major amputation, death, de novo gangrene, or doubling of wound size), as well as major amputation rate and measures of wound healing.There was no difference in adverse or serious adverse events between the two groups. Statistical analysis revealed a significant increase in time to treatment failure (log-rank test, = .0053) and amputation-free survival in patients receiving TRC treatment, (log-rank test, = .038). Major amputation occurred in 19% of TRC-treated patients compared to 43% of controls ( = .14, Fisher exact test). There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months.Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options

In-Stent Restenosis Progression in Human Superficial Femoral Arteries: Dynamics of Lumen Remodeling and Impact of Local Hemodynamics

In-stent restenosis (ISR) represents a major drawback of stented superficial femoral arteries (SFAs). Motivated by the high incidence and limited knowledge of ISR onset and development in human SFAs, this study aims to (i) analyze the lumen remodeling trajectory over 1-year follow-up period in human stented SFAs and (ii) investigate the impact of altered hemodynamics on ISR initiation and progression. Ten SFA lesions were reconstructed at four follow-ups from computed tomography to quantify the lumen area change occurring within 1-year post-intervention. Patient-specific computational fluid dynamics simulations were performed at each follow-up to relate wall shear stress (WSS) based descriptors with lumen remodeling. The largest lumen remodeling was found in the first post-operative month, with slight regional-specific differences (larger inward remodeling in the fringe segments, p&nbsp;&lt;&nbsp;0.05). Focal re-narrowing frequently occurred after 6&nbsp;months. Slight differences in the lumen area change emerged between long and short stents, and between segments upstream and downstream from stent overlapping portions, at specific time intervals. Abnormal patterns of multidirectional WSS were associated with lumen remodeling within 1-year post-intervention. This longitudinal study gave important insights into the dynamics of ISR and the impact of hemodynamics on ISR progression in human SFAs

Flow-induced neointimal regression in baboon polytetrafluoroethylene grafts is associated with decreased cell proliferation and increased apoptosis

AbstractObjective: We have previously shown that baboon grafts subjected to elevated shear stress exhibit an increase in luminal area through atrophy of the neointimal layer. This study was designed to investigate the smooth muscle cell (SMC) growth kinetics during early regression and evaluate the influence of nitric oxide (NO) in the regulation of this process. Methods: Sixteen baboons underwent bilateral polytetrafluorethylene aortoiliac graft placement. After development of a neointima over an 8-week period, blood flow through one graft was increased with placement of a downstream arteriovenous fistula. Grafts were harvested at 4 (n = 6), 7 (n = 5), and 14 (n = 5) days and assessed for neointimal cross-sectional area, SMC proliferation and apoptosis, and macrophage infiltration. High-flow grafts were compared with contralateral normal-flow controls. Eleven baboons underwent an identical experimental preparation to evaluate the effect of NO inhibition. Eight weeks after graft implantation, the animals were treated with an initial bolus (100 mg/kg) followed by continuous infusion (60 mg/kg/d) of either NG-nitro-L-arginine methyl ester (L-NAME; n = 6) or the inactive stereoisomer NG-nitro-D-arginine methyl ester (n = 5). Grafts were harvested at 7 days and evaluated with the experimental endpoints detailed previously. Results: Distal fistula placement resulted in a 3.8-fold increase in mean centerline velocity and wall shear stress. Grafts harvested during the initial 14 days after flow manipulation showed a progressive reduction in neointimal cross-sectional area. This change was associated with a decrease in subendothelial SMC proliferation and an increase in neointimal SMC apoptosis, the latter being in the region adjacent to the graft. Animals treated with L-NAME showed a 20% reduction in platelet cyclic guanosine monophosphate and a 17% reduction in serum nitrate/nitrite concentrations. Despite this inhibition of NO production, no effect on the flow-dependent changes in neointimal area, cell proliferation, or apoptosis was observed in the L-NAME-treated baboons. Conclusion: The local hemodynamic environment within healing prosthetic grafts modulates neointimal SMC proliferation and apoptosis. An increase in graft flow leads to atrophy of the neointima. (J Vasc Surg 2002;36:1248-55.

Superficial femoral artery stenting: Impact of stent design and overlapping on the local hemodynamics

Background: Superficial femoral arteries (SFAs) treated with self-expanding stents are widely affected by in-stent restenosis (ISR), especially in case of long lesions and multiple overlapping devices. The altered hemodynamics provoked by the stent is considered as a promoting factor of ISR. In this context, this work aims to analyze the impact of stent design and stent overlapping on patient-specific SFA hemodynamics. Methods: Through a morphing technique, single or multiple stents were virtually implanted within two patient-specific, post-operative SFA models reconstructed from computed tomography. The stented domains were used to perform computational fluid dynamics simulations, quantifying wall shear stress (WSS) based descriptors including time-averaged WSS (TAWSS), oscillatory shear index (OSI), transverse WSS (transWSS), and WSS ratio (WSSRATIO). Four stent designs (three laser-cut – EverFlex, Zilver and S.M.A.R.T. – and one prototype braided stent), and three typical clinical scenarios accounting for different order of stent implantation and overlapping length were compared. Results: The main hemodynamic differences were found between the two types of stent designs (i.e. laser-cut vs. braided stents). The braided stent presented lower median transWSS and higher median WSSRATIO than the laser-cut stents (p &lt; 0.0001). The laser-cut stents presented comparable WSS-based descriptor values, except for the Zilver, exhibiting a median TAWSS ∼30% higher than the other stents. Stent overlapping provoked an abrupt alteration of the WSS-based descriptors. The overlapping length, rather than the order of stent implantation, highly and negatively impacted the hemodynamics. Conclusion: The proposed computational workflow compared different SFA stent designs and stent overlapping configurations, highlighting those providing the most favorable hemodynamic conditions