Local release of metalloproteinases and their inhibitors after a successful revascularisation procedure.

An altered balance between metalloproteinases (MMPs) and their inhibitor tissue inhibitor of metalloproteinases (TIMPs) may influence the healing process of a minor amputation following a successful vein graft. To speed up this process, negative pressure wound therapy (NPWT) and advanced moist wound dressing have been proposed. We determined the systemic and local release of MMP-1, -2, -3, -9, TIMP-1, and TIMP-2 by enzyme linked immunosorbent assay (ELISA) technique and their influences in the healing process in 26 patients who underwent minor amputation after a successful revascularisation procedure. Twelve patients (group 1) were medicated with NPWT and 14 (group 2) with advanced moist wound dressing. Plasma samples were collected on the morning of surgery and thereafter at 1, 3, and 5 months; exudates were collected 3 days after surgery when amputation was performed and thereafter at 1, 3, and 5 months. Fifteen age-matched healthy male volunteers served as controls. All wounds healed in 5 ± 0.5 months. Follow-up plasma and local release of MMP-1, -2, -3, and -9 were overall significantly lower when compared with the preoperative levels, while those of TIMP-1 and -2 were significantly higher with no differences among the groups. Despite no differences in the healing process being observed among the two types of medications, at 1 month the local release of MMP-2 and -9 was significantly lower (P = .013 and .047, respectively) and that of TIMP-1 was significantly higher (P = .042) in group 1 as compared to group 2. A correct and aggressive local approach to the wound is able to promote the healing of the lesion stimulating the extracellular matrix turnover with local MMP/TIMP adequate balance and favouring the creation of granulation tissue. However, a successful restoration of an adequate blood flow remains the key point of a durable and rapid wound healing.

Different inflammatory cytokines release after open and endovascular reconstructions influences wound healing.

Prodromal signs of a non-healing wound after revascularisation, which might be strictly linked with impending failure of vascular reconstructions, are associated with an inflammatory response mediated by several circulating adhesion molecules, extracellular endopeptidases, and cytokines. The aim of our study was to investigate the role of selected plasma biomarkers in the prediction of both wound healing and failure of infrapopliteal vein graft or percutaneous trans-luminal angioplasty (PTA) with selective stent positioning of the superficial femoral artery (SFA) in a population affected with critical limb ischaemia. A total of 68 patients who underwent either surgical or endovascular revascularisation of the inferior limb with autologous saphenous vein infrapopliteal bypass or PTA and selective stenting of the SFA were enrolled in our study. Patients were divided into two groups according to treatment: 41 patients were included in Group 1 (open surgery) and 27 in Group 2 (endovascular procedure). Plasma and blood samples were collected on the morning of surgery and every 6 months thereafter for up to 2 years of follow-up or until an occlusion occurred of either the vein bypass graft or the vessel treated endovascularly. Fifteen age-matched healthy male volunteers were considered a reference for biological parameters. Vascular cell adhesion molecule 1 [VCAM-1]/CD106, inter-cellular adhesion molecule-1 [ICAM-1]/CD54), interleukin-1 (IL-1), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), and metalloproteinases (MMP)-2 and -9 plasma levels were measured with enzyme-linked immunosorbent assay (ELISA) kits. The mean observed time to heal of 54 wounds was 13 ± 4 months, with no statistically significant differences among the groups. The healing failure of the remaining wounds was strictly related to an unsuccessful open (n = 12) or endovascular (n = 8) treatment. The 2-year primary patency rate was 65% (SE = .09) in Group 1 and 52% (SE = .1) in Group 2. When compared with mean concentration values of Group 1, VCAM-1 and ICAM-1 were always significantly higher during follow-up in patients of Group 2 (P < .05). Furthermore, in the same group, IL-6 and tumour necrosis factor alpha (TNF-α) were found to be significantly higher at 6- and 12-month (P < .05) when compared with surgically treated patients. Cox regression analysis showed that elevated plasma levels of VCAM-1, ICAM-1, IL-6, and TNF-α during follow up were strongly related to impaired wound healing and/or revascularisation failure (P < .05). Elevated plasma levels of inflammatory markers VCAM-1, ICAM-1, IL-6, and TNF-α may be related to the failure of wound healing and revascularisation procedures. Interestingly, we have observed that endovascular treatments cause a higher level of these inflammation biomarkers when compared with a vein graft, although wound-healing and patency and limb salvage rates are not influenced.

External Iliac Artery to Tibial Arteries Vein Graft for Inaccessible Femoral Artery.

BACKGROUND: An endovascular-first approach to limb salvage and relief from lifestyle-limiting claudication is widely accepted. Stenosis or short occlusion of common, superficial femoral, and popliteal arteries can be corrected with percutaneous transluminal angioplasty (PTA) with stent positioning. Patency rates of these procedures are limited. We report our experience with external iliac artery to the infrapopliteal vessels vein grafts when the endovascular treatment fails. METHODS: Between January 2013 and January 2019, 16 patients (16 limbs) were operated on for limb-threatening ischemia after the occlusion of PTA with stent positioning of the common, superficial femoral, and popliteal arteries. Three patients were treated at our hospital by interventional radiologists; the remaining were operated on elsewhere. An external iliac artery to the infrapopliteal vessels vein bypass graft was anatomically interposed to restore blood flow. End points of the study were death-related events, vein graft failure, and major (above- or below-knee amputation) or minor (foot or toe amputation) limb loss. RESULTS: There were 12 men and 4 women. Mean age of patients was 68 years. Indication for the initial PTA with stent positioning of the common and superficial femoral artery was according to the Rutherford classification Grade I: Category 1, 11 patients (69%) and Category 2, 5 (31%) patients (Stage IIa and IIb according to Fontaine classification, respectively). Great saphenous vein was used in 14 (87%) cases and in 2 (13%) cases a composite graft with a segment of cephalic vein was required. The distal anastomoses were performed on the posterior tibial artery in 6 (37%) cases, anterior tibial artery in 4 (26%), and peroneal artery in 6 (37%). Four-year survival and primary patency rates were 71% (standard error [SE] = 0.15) and 73% (SE = 0.14), respectively. One graft occlusion required an above-knee amputation. Four-year limb salvage rate was 86% (SE = 0.13). DISCUSSION: We recommend the external iliac artery as source of inflow in patients in whom the vein bypass cannot originate from the common femoral or from a more distal inflow source because of previous PTA with stent positioning or it is deemed hazardous.

Inflammatory biomarkers, vascular procedures of lower limbs, and wound healing.

Abnormal, persistent inflammation after bypass surgery could prevent healing of an ischaemic foot lesion. In 37 patients with peripheral arterial disease (PAD) (Rutherford Grade III Category 5) who underwent infrapopliteal vein graft and midfoot amputation, plasma levels of fibrinogen, C-reactive protein (CRP), interleukin-1 (IL-1), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) were determined preoperatively and during the follow up. Nine patients without clinical and Doppler evidence of arterial disease, who underwent post-traumatic midfoot primary amputation, were included in the experiment group, and 15 age-matched healthy volunteers served as control. In patients who had midfoot amputation for trauma, all wounds healed. Seven (19%) wounds in patients with an occluded graft healed, and five (13%) required major amputation because of a non-healing wound. Time required for complete healing of the lesion was similar between trauma and PAD patients (8 ± 2 months vs 11 ± 6, respectively, P = NS). Univariate analysis demonstrated that, in PAD patients, the postoperative high levels of TNF-α, IL-6, and MMP-2 and -9 were predictive for wound healing failure at 3, 6, and 9 months (P < 0.05), respectively. Furthermore, the subgroup of patients who experienced occlusion of the vein graft during follow up had a significant increase of MMP-2, -9, IL-6, and TNF-α at 3, 6, and 9 months (P < 0.05), respectively. Monitoring inflammatory markers allows the determination of patients at risk of healing failure of midfoot amputation after distal revascularisation and might predict the fate of the vein graft.

Infection of Prosthetic Patches after Femoral Endarterectomy: An Unreported Complication.

BACKGROUND: The femoral prosthetic patch is a surgical procedure frequently used to treat atherosclerotic lesions involving femoral artery bifurcation. Even though it is an easy to perform procedure, surgical management of complications, first of all graft infection, may be challenging, with a high morbidity and mortality risk for patients. We report our experience on surgical treatment of femoral patch infections. MATERIALS AND METHODS: Between April 2012 and April 2018, 26 patients (26 limbs) were referred to the emergency department at our institution for the treatment of femoral prosthetic patch infections. None of the patients had been previously treated at our institution. All patients underwent a wide debridement of the infection site. Blood flow was restored through a vein interposition graft anastomosed at least 4-5 cm from the site of infection. End points of the study were death-related events, major or minor limb loss (major loss for above or below the knee amputation and minor for foot or toe), vein interposition graft failures, recurrent graft infections, or surgical wound healing. RESULTS: A total of 26 patients (21 male and 5 female patients) underwent surgical treatment. The mean age of patients was 69 years. The majority of our patients (54%) had been previously treated with an isolated femoral artery prosthetic patch. Three (11%) patients had been treated with a bilateral prosthetic femoral patch, but only one side was infected. After debridement of the infection site, we used the great saphenous vein to revascularize the lower limb in 22 (85%) cases, whereas the cephalic vein was used in only 4 cases (15%). The 5-year survival rate was 81% (standard error [SE] = 0.12). The 5-year primary patency rate was 70% (SE = 0.14). During follow-up, 4 graft occlusions occurred, and in 2 cases, a major amputation was required. The limb salvage rate at 5 years was 81% (SE = 0.13). CONCLUSIONS: An infection can complicate the femoral prosthetic patch carrying a high rate of morbidity, mortality, and limb loss. Surgical indication for a primary procedure must be restricted to critical limb ischemia, and it must be associated to a multilevel correction of the atherosclerotic disease.

Is the Endovascular Treatment of Mild Iliac Stenoses Worthwhile to Improve Wound Healing in Patients Undergoing Femorotibial Bypass?

BACKGROUND: After an infrapopliteal reconstruction, minor amputations are frequently required, but even in the case of successful revascularization, wound healing is a major concern. We studied the role of iliac artery inflow correction in patients undergoing infrapopliteal vein grafts to improve the heal of midfoot amputation. METHODS: Thirty-eight patients affected with Rutherford grade III category 5 peripheral arterial disease, who underwent successful simultaneous iliac endovascular procedure, infrapopliteal reversed vein bypass graft, and minor amputation, were enrolled in this retrospective study. The population was divided in group 1 (20 patients) with inflow vessels Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease (TASC) II type B atherosclerotic lesions and group 2 (18 patients) with TASC II type A atherosclerotic lesions determining an invasive pressure drop greater than 15 mm Hg. Fifteen patients (group 3) undergoing infrapopliteal reversed vein bypass graft without associated inflow procedures (TASC II type A and invasive pressure drop greater than 15 mm Hg) were matched with group 2 based on propensity score. Healing was calculated by subtracting the final ulcer area from the initial ulcer area and dividing by the number of follow-up months to obtain the total area healed per month (cm2/month). Stepwise logistic regression analysis adjusted for demographics and medical comorbid conditions was used to test the association between wound healing and treatment modalities. RESULTS: Forty-three patients were available for further analysis. Ten patients were excluded because of graft occlusion with consequent impairment of wound healing. After midfoot amputations, mean wound diameter was 20 ± 8 cm2, and mean healing time was 10 ± 4 months (range 3-20 months; median 9 months). Wounds of groups 1 and 2 healed faster than those of group 3 at 4 and 8 months (P < 0.02 and P < 0.001, respectively; P < 0.04 and P < 0.001, respectively). Multivariate analysis demonstrated the association between wound healing and inflow correction (P < 0.001). CONCLUSIONS: An aggressive treatment is necessary to obtain the heal of the ischemic wounds. The most important predictive factor for nonhealing wounds is the absence of inflow correction. We demonstrated that the inflow should be also corrected in the presence of subclinical lesions.

A multidisciplinary approach to a complex case of lower limb trauma.

INTRODUCTION: Blunt trauma of the popliteal fossa is an uncommon cause of lower limb ischemia and it is associated with a high risk for limb loss. REPORT: The case of a young man with anterior dislocation of the right knee joint causing post-traumatic popliteal artery occlusion and severe lower limb ischemia is reported. DISCUSSION: To our knowledge we first report a multidisciplinary approach involving the vascular and plastic surgical teams to treat a wide soft tissue damage after a blunt injury to the popliteal artery.

Adductor canal compression syndrome: a forgotten disease.

Superficial femoral vessels entrapped at the level of the adductor canal are rarely described. We first report the case of a young patient who practices professional soccer, affected with superficial femoral vein and artery occlusion due to a hypertrophied vastus medialis and adductor magnus at the Hunter's canal outlet. A careful literature search through MedLine was performed to elucidate the fascinating aspect of this occurrence.

Long-term outcomes of direct and indirect below-the-knee open revascularization based on the angiosome concept in diabetic patients with critical limb ischemia.

BACKGROUND: We compared long-term outcomes of isolated below-the-knee (BTK) bypass revascularization in diabetic patients presenting with critical limb ischemia (CLI) with and without achieving the bypass on the artery corresponding to the territory of the lesion based on the angiosome concept. MATERIALS: We analyzed outcomes of 58 consecutive CLI limbs of 54 diabetic patients presenting with tissue loss who underwent isolated BTK bypasses from 2003 to 2009 for crural occlusive arterial disease. Bypasses were classified into direct and indirect groups based on the angiosome concept, whether feeding artery flow to the site of ischemic tissue loss was achieved or not. We compared median ulcer-healing time, survival, primary patency, and limb salvage rates between both groups by Kaplan-Meier analysis and log-rank test. Independent factors of major amputations were explored by univariate analysis. Variables with P < 0.2 in univariate analysis were submitted to multivariable analysis. RESULTS: Median ulcer-healing time was 56 ± 18 days in direct group (n = 36) and 112 ± 45 days in indirect group (n = 22, P = 0.01). There was no difference between both groups in terms of survival or primary patency. Limb salvage rate was significantly higher in direct group than in indirect group: 91% vs. 66% at 1 year, 65% vs. 24% at 3 years, and 58% vs. 18% at 5 years, respectively (P = 0.03). After multivariable Cox proportional analysis, independent factors associated with major amputation were end-stage renal disease (P = 0.030) and C-reactive protein level (P = 0.025). CONCLUSIONS: Achieving a direct arterial flow based on angiosome concept in CLI diabetic patients presenting with tissue loss appears to be important for ulcer healing and limb salvage.

Dose-dependent effect of rosuvastatin in the regulation of metalloproteinase expression.

BACKGROUND: The importance of rosuvastatin at therapeutic dosage in regulating the release, activity, protein level, and expression of matrix metalloproteinases (MMP)-2 and MMP-9 was investigated. METHODS: Human umbilical artery smooth muscle cells were stimulated, in vitro, in a serum-free medium with rosuvastatin at various concentrations (2, 4, 7, and 10 ng/mL, which correspond to the maximal plasma concentration observed in healthy men after a daily oral intake of 5, 10, 20, and 40 mg, respectively). The release of MMP-2 and MMP-9 in the conditioned medium was assessed by enzyme-linked immunosorbent assay and confirmed by Western blot, the activity and expression were determined by zymography and polymerase chain reaction, respectively. RESULTS: Human umbilical artery smooth muscle cells stimulated with rosuvastatin at 7 and 10 ng/mL had a significant lower release, activity, protein level, and expression of MMP-2 and MMP-9, when compared with those stimulated at 2 and 4 ng/mL (MMP-2 =p < 0.0001 and p < 0.0001, respectively; MMP-9 =p < 0.0001 and p < 0.0001, respectively). CONCLUSION: The effects of rosuvastatin in reducing MMP-2 and MMP-9, which might stabilize the atherosclerotic plaques, are dose-dependent.