Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury

Carbon monoxide (CO) has emerged as a vascular homeostatic molecule that prevents balloon angioplasty-induced stenosis via antiproliferative effects on vascular smooth muscle cells. The effects of CO on reendothelialization have not been evaluated

Does hostile neck anatomy preclude successful endovascular aortic aneurysm repair?

AbstractObjectivesPoor outcomes have been reported with endovascular aneurysm repair (EVAR) in patients with hostile neck anatomy. Unsupported endografts with active fixation may offer certain advantages in this situation. We compared EVAR results using the Ancure (Guidant) endograft in patients with and without hostile neck anatomy.MethodsRecords of EVAR patients from October 1999 to July 2002 at a tertiary care hospital were retrospectively reviewed from a division database. Patients with elective open abdominal aortic aneurysm (AAA) repair during the same period were reviewed to determine those unsuitable for EVAR. Hostile neck anatomy, assessed by computer tomography (CT) scans and angiograms, was defined as one or more of the following: (1) neck length ≤10 mm, (2) focal bulge in the neck >3 mm, (3) >2-mm reverse taper within 1 cm below the renal arteries, (4) neck thrombus ≥50% of circumference, and (5) angulation ≥60 degrees within 3 cm below renals.ResultsThree hundred and twenty-two patients underwent EVAR with an average follow-up of 18 months. Patients in Phase II trials (n = 41), repaired with other graft types (n = 48), or without complete anatomic records (n = 27) were excluded. Demographics and co-morbidities were similar in the 115 good-neck (GN) and 91 bad-neck (BN) patients except for age (mean, 72.9 years GN vs 75.7 BN; P = 0.13), gender (11% female GN vs 22% BN; P =.04); neck length (mean, 21.8 mm GN vs 14.4 mm BN: P < .001), and angulation (mean, 22 degrees GN vs 40 degrees BN; (P < .001). Perioperative mortality (0 GN vs 1.1% BN), late mortality (5.2% GN vs 4.4% BN), all endoleaks (19.1% GN vs 17.6% BN), proximal endoleaks (0.8% GN vs 2.1% BN), and graft migration (0 for both groups) did not reach statistical significance. Neck anatomy precluded EVAR in 106 of 165 (64%) patients with open AAA.ConclusionsUnsupported endografts with active fixation can yield excellent results in treating many medically compromised patients with hostile neck anatomy. Nonetheless, an unsuitable neck remains the most frequent cause for open abdominal AAA

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

A modified rat model of hindlimb ischemia for augmentation and functional measurement of arteriogenesis

Arteriogenesis (collateral artery development) is an adaptive pathway critical for salvage of tissue in the setting of arterial occlusion. Rodent models of arteriogenesis typically involve an experimental occlusion (ligation) of a hindlimb artery and then rely on indirect measures such as laser Doppler perfusion imaging to assess blood flow recovery. Unfortunately, the more commonly utilized measures of distal tissue perfusion at rest are unable to account for hemodynamic and vasoactive variables and thus provide an incomplete assessment of collateral network capacity. We provide a detailed description of modifications to the commonly used model of femoral artery ligation. These serve to alter and then directly assess collateral network’s hemodynamic capacity. By incorporating an arteriovenous fistula distal to the arterial ligation, arterial growth is maximized. Hindlimb perfusion may be isolated to measure minimum resistance of flow around the arterial occlusion, which provides a direct measure of collateral network capacity. Our results reinforce that arteriogenesis is driven by hemodynamic variables, and it can be reliably augmented and measured in absolute terms. Using these modifications to a widely used model, functional arteriogenesis may be more directly studied

TLR2 and TLR4 mediate differential responses to limb ischemia through MyD88-dependent and independent pathways.

The danger signal HMGB1 is released from ischemic myocytes, and mediates angiogenesis in the setting of hindlimb ischemia. HMGB1 is a ligand for innate immune receptors TLR2 and TLR4. While both TLR2 and TLR4 signal through myeloid differentiation factor 88 (MyD88), TLR4 also uniquely signals through TIR-domain-containing adapter-inducing interferon-β (TRIF). We hypothesize that TLR2 and TLR4 mediate ischemic myocyte regeneration and angiogenesis in a manner that is dependent on MyD88 signaling.Mice deficient in TLR2, TLR4, MyD88 and TRIF underwent femoral artery ligation in the right hindlimb. Laser Doppler perfusion imaging was used to assess the initial degree of ischemia and the extent of perfusion recovery. Muscle regeneration, necrosis and fat replacement at 2 weeks post-ligation were assessed histologically and vascular density was quantified by immunostaining. In vitro, endothelial tube formation was evaluated in matrigel in the setting of TLR2 and TLR4 antagonism.While control and TLR4 KO mice demonstrated prominent muscle regeneration, both TLR2 KO and TRIF KO mice exhibited marked necrosis with significant inflammatory cell infiltrate. However, MyD88 KO mice had a minimal response to the ischemic insult with little evidence of injury. This observation could not be explained by differences in perfusion recovery which was similar at two weeks in all the strains of mice. TLR2 KO mice demonstrated abnormal vessel morphology compared to other strains and impaired tube formation in vitro.TLR2 and TRIF signaling are necessary for muscle regeneration after ischemia while MyD88 may instead mediate muscle injury. The absence of TLR4 did not affect muscle responses to ischemia. TLR4 may mediate inflammatory responses through MyD88 that are exaggerated in the absence of TLR2. Additionally, the actions of TLR4 through TRIF may promote regenerative responses that are required for recovery from muscle ischemia