Disease Specific Health Related Quality of Life in Patients With Chronic Limb Threatening Ischaemia Undergoing Revascularisation of Femoropopliteal Lesions.

OBJECTIVE: Patients with chronic limb threatening ischaemia (CLTI) suffer from pain and non-healing ulcers, which impact negatively on both their physical and mental health. While maintaining and improving quality of life is a principal aim with all treatments, little is known about the health related quality of life (HRQoL) of CLTI patients and how revascularisation procedures impact on HRQoL endpoints. The aim of this study was to investigate disease specific HRQoL before and after revascularisation in patients with CLTI undergoing femoropopliteal revascularisation. METHODS: HRQoL was prospectively analysed in 190 CLTI patients with main atherosclerotic target lesions in the femoropopliteal segment, who were planned for endovascular or open revascularisation. The choice of revascularisation method was made by the vascular team, represented by both open and endovascular expertise. The Vascular Quality of Life (VascuQoL) questionnaire was used to assess disease specific HRQoL before revascularisation and one month, one year, and two years after the procedure. Main endpoints were mean VascuQoL score changes, effect sizes of observed changes and the proportion reaching a minimally important difference (half a standard deviation change from baseline) during two years after revascularisation. RESULTS: Patient reported VascuQoL scores were low at baseline (mean 2.68, 95% CI 1.18 - 4.17). After revascularisation, the mean VascuQoL score improved statistically significantly over time, with the largest improvement observed after one year (difference from baseline 2.02, 95% CI 1.75 - 2.29; p < .001). No differences in HRQoL change over time were observed between patients treated with endovascular approaches compared with bypass surgery. Approximately half the patients reached the minimally important threshold at one year (53%), which was largely maintained also at two years (41%). CONCLUSION: While CLTI profoundly affected HRQoL, a large and clinically meaningful HRQoL increase was observed after revascularisation. This confirms the value of CLTI revascularisation on HRQoL and underlines the importance of including patient reported outcomes when evaluating revascularisation procedures in CLTI patients.

Amputation-free survival, limb symptom alleviation, and reintervention rates after open and endovascular revascularization of femoropopliteal lesions in patients with chronic limb-threatening ischemia.

BACKGROUND: The optimal strategy for revascularization in chronic limb-threatening ischemia (CLTI) is not yet completely known and is still under debate. Endovascular treatment methods predominate despite limited evidence for their advantage. In this concurrent, prospective observational cohort study, we investigated outcomes after open and endovascular revascularization in the femoropopliteal segment for CLTI. METHODS: Between March 2011 and January 2015, there were 190 patients presenting with CLTI with the principal target lesion in the superficial femoral or popliteal segment who underwent endovascular intervention (n = 117) or bypass surgery (n = 73) and were observed prospectively. The choice of revascularization technique was based on international and local guidelines. All patients were observed for 2 years. The primary end point was amputation-free survival (AFS) assessed with Kaplan-Meier estimates; secondary end points included CLTI symptom alleviation rates and reintervention rates. A Cox proportional hazards regression model was used to investigate risk factors for amputation and death. RESULTS: AFS at 2 years was 59% in the endovascular group and 76% in the bypass group (P = .020). Kaplan-Meier survival analysis confirmed a significant difference in AFS, with mortality rate as the main driver for the observed intergroup AFS difference. In sequential multivariable regression analysis, the observed difference in AFS between the groups favored bypass surgery and remained significant after controlling for covariates of known prognostic importance (hazard ratio, 2.38; 95% confidence interval, 1.14-4.96). At 2 years, a higher proportion of patients subjected to bypass surgery remained free from ischemic rest pain, wounds, and gangrene (65% vs 45%; P = .009). The proportions of patients who underwent reintervention within 2 years were similar in the two groups (38% vs 39%; P = .90), but repeated reinterventions were more frequent in the bypass group. CONCLUSIONS: At 2 years, bypass surgery was associated with higher AFS than endovascular intervention, a finding that could not be explained only by differences in case mix. More patients who had bypass surgery were free from CLTI symptoms at both 1 year and 2 years after revascularization. Reinterventions to maintain patency were equally common after bypass and endovascular intervention.

Improved quality of life after 1 year with an invasive versus a noninvasive treatment strategy in claudicants: one-year results of the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial.

BACKGROUND: The quality of evidence for invasive revascularization in intermittent claudication is low or very low. This prospective, randomized, controlled study tested the hypothesis that an invasive treatment strategy versus continued noninvasive treatment improves health-related quality of life after 1 year in unselected patients with intermittent claudication. METHODS AND RESULTS: After clinical and duplex ultrasound assessment, unselected patients with intermittent claudication requesting treatment for claudication were randomly assigned to invasive (n=79) or noninvasive (n=79) treatment groups. Primary end point was health-related quality of life after 1 year, assessed with Medical Outcomes Study Short Form 36 version 1 and Vascular Quality of Life Questionnaire, and secondary end points included walking distances on a graded treadmill. The Medical Outcomes Study Short Form 36 version 1 physical component summary (P<0.001) and 2 Medical Outcomes Study Short Form 36 version 1 physical subscales improved significantly more in the invasive versus the noninvasive treatment group. Overall, Vascular Quality of Life Questionnaire score (P<0.01) and 3 of 5 domain scores improved significantly more in the invasive versus the noninvasive treatment group. Intermittent claudication distance improved significantly in the invasive (+124 m) versus the noninvasive (+50 m) group (P=0.003), whereas the change in maximum walking distance was not significantly different between groups. CONCLUSIONS: An invasive treatment strategy improves health-related quality of life and intermittent claudication distance after 1 year in patients with stable lifestyle-limiting claudication receiving current medical management. Long-term follow-up data and health-economic assessments are warranted to further establish the role for revascularization in intermittent claudication.

Six-minute walk test closely correlates to "real-life" outdoor walking capacity and quality of life in patients with intermittent claudication.

OBJECTIVE: We used outdoor walking distance measured during 40 minutes as "real-life" outdoor walking capacity in 49 patients with intermittent claudication (IC). The outdoor walking distance was measured by a global positioning system application for a smartphone. The relationships of self-reported maximum walking distance (SR-MWD), the MWD on a graded treadmill test, and the 6-minute maximum walk distance (6MWD) vs outdoors walking capacity were investigated. Also studied were the associations of SR-MWD, MWD, and 6MWD with health-related quality of life assessed with the disease-specific instrument the Vascular Quality of Life Questionnaire (VascuQoL). METHODS: In this prospective observational cohort study, 49 IC patients underwent an outdoor walking capacity test for 40 minutes, and MWD and 6MWD were measured. SR-MWD was recorded, and all subjects completed the VascuQoL questionnaire. Associations between the different walk estimates and outdoor walking capacity and health-related quality of life were investigated by correlation analysis (Spearman ρ). RESULTS: Outdoor walking distance during 40 minutes was a median 2495 m (range, 1110-3300 m). SR-MWD correlated moderately and MWD correlated strongly to outdoor walking capacity (r = 0.56 and r = 0.65; P < .001, respectively). The 6MWD test showed the largest correlation to the outdoor walking capacity (r = 0.78; P < .001). The 6MWD was the only test that showed correlations with the VascuQoL sum score (r = 0.53; P < .01) and all of the domain scores, whereas SR-MWD and MWD showed weak correlations to the VascuQoL. CONCLUSIONS: The distance walked during the 6-minute walk test is closely correlated to outdoor walking capacity and health-related quality of life in IC patients. Our data support the use of 6MWD for routine clinical evaluation of walking capacity in IC patients.

National experience with extracranial carotid artery aneurysms: epidemiology, surgical treatment strategy, and treatment outcome.

OBJECTIVE: Extracranial carotid artery aneurysms (CAAs) are rare but confer risk of stroke, rupture, and local symptoms. Few cases have been reported, even from large centers, and therefore knowledge of the disease is limited. The purpose of this study was to review epidemiology, surgical treatment, and outcomes of CAAs in a nationwide setting using the Swedish National Registry for Vascular Surgery (Swedvasc). METHODS: Data on all surgical interventions for CAAs from January 1997 to December 2011 were retrieved from the Swedvasc registry. Additional clinical information was collected from hospital records. RESULTS: A total of 48 cases of CAAs were identified. The cause was atherosclerosis in 34 cases, infection in 2, and pseudoaneurysm in 12. The most common presentation was a pulsatile mass with or without local symptoms. Aneurysms isolated to the internal carotid artery predominated. Resection with end-to-end anastomosis was the most common technique used for treatment. Among true aneurysms, 24% had a known synchronous aneurysm elsewhere. Stroke-free survival (n = 48) was 90% after 30 days and 85% after 1 year. A total of 12.5% patients experienced permanent cranial nerve injury and 33% experienced any complication. CONCLUSIONS: CAAs are rare entities in vascular surgery. In terms of stroke-free survival, the Swedish national results approach reports from large volume centers. The relatively high risk for permanent cranial nerve injury advocates caution when performing surgery on CAAs.

Arterial Blood Flow and Effects on Limb Tissue Perfusion During Endoshunting of the Common Iliac Artery in an Experimental Porcine Model.

Objective: Temporary arterial shunting is an established method to prevent tissue ischaemia. Although less well established, shunting might also be achieved through endovascular and hybrid techniques, known as endoshunting. Endoshunting offers advantages, for example, enabling minimally invasive access and avoiding complete occlusion of the donor artery. In an ex vivo bench test, volume flow in various interconnected endoshunt systems has been tested previously. This study aimed to investigate the capacity of the best performing endoshunt system in vivo. Methods: Six anaesthetised pigs had their common iliac arteries (CIAs) explored, with the left CIA serving as the experimental and the right CIA as the control. Mean arterial pressure, regional blood flow, endoshunt flow, and regional oxygen extraction and lactate production were recorded. Distal muscle perfusion was monitored using near infrared spectroscopy (NIRS). Each experiment involved baseline registration, cross clamping of the left CIA, a 120 minute endoshunt session, and restoration of native flow. Results: During cross clamping, NIRS values on the experimental side reached the lowest measurable value. Following endoshunt activation, there were no NIRS value differences between the experimental and control extremities whereas the average arterial flow decreased in both the experimental (270-140 mL/min, p = .028) and control extremities (245-190 mL/min, p = .25), with a greater drop on the endoshunted side (48% vs. 22%, respectively). Lactate levels temporarily increased by 42% in the endoshunted limb on endoshunt activation but were normalised within an hour. Oxygen extraction remained constant at 55% on the control side but increased to 70% on the endoshunted side (p = .068). Conclusion: In this animal model, a flow optimised endoshunt system appeared to provide sufficient blood flow and restored stable tissue perfusion. Although arterial flow was slightly lower and oxygen extraction slightly higher on the endoshunted side, the endoshunt seemed to deliver adequate perfusion to prevent significant ischaemia.

Optimisation of Volume Flow Rates when Using Endovascular Shunting Techniques: An Experimental Study in Different Bench Flow Circuits.

Objective: Acute tissue ischaemia may arise due to arterial emergencies or during more complex vascular procedures and may be mitigated by temporary shunting techniques.Endovascular shunting (ES) techniques enable percutaneous access and shunting from the donor artery without the need to completely interrupt the arterial flow in the donor artery. An endoshunt system may also cover longer distances than most conventional shunts. The aim was to investigate and optimise the flow rates in different endovascular shunt systems. Methods: Step 1: The flow capacity of different ES configurations was compared with the flow capacity of a 9 Fr Pruitt-Inahara shunt (PIS). An intravenous bag with 0.9% NaCl, pressurised to 90 mmHg, was connected simultaneously to a PIS and to one of the tested ES configurations. The two shunt systems were then opened at the same time.The delivered fluid volumes from the shunt systems were collected and measured. The volume flow rate was subsequently calculated.Steps 2 and 3: Within a heart lung machine circuit, pressure-flow charts were constructed for the individual ES components and for the fully connected optimised endoshunt systems. The flow rate was increased in steps of 40-50 mL/min while monitoring the driving pressure, enabling the creation and comparison of the pressure-flow charts for the individually tested components. In total, seven individual inflow and outflow potential ES components were investigated with inflow and outflow diameters ranging from 6 to 15 Fr. Results: ES systems based on standard donor introducers led to substantially lower volume flow than the corresponding PIS volume flow, whereas ES systems based on dedicated 6 or 8 Fr dialysis access introducers (Prelude Short Sheet, Merit Medical) matched PIS flow rates. The introduction of 30 cm long »'' perfusion tubing within the ES system did not affect volume flow for any of the tested ES configurations. Conclusion: Endoshunting techniques can match PIS volume flow rates over short and long distances. The achieved ES flow rate is highly dependent on the components used within the ES system.

Corrigendum to "Optimization of Volume Flow Rates when Using Endovascular Shunting Techniques - An Experimental Study in Different Bench Flow Circuits. [EJVES Vascular Forum Volume 58, 2023, Pages 5-10]".

[This corrects the article DOI: 10.1016/j.ejvsvf.2022.11.002.][This corrects the article DOI: 10.1016/j.ejvsvf.2023.03.001.].

Personalized tissue-engineered veins - long term safety, functionality and cellular transcriptome analysis in large animals.

Tissue engineering is a promising methodology to produce advanced therapy medicinal products (ATMPs). We have developed personalized tissue engineered veins (P-TEV) as an alternative to autologous or synthetic vascular grafts utilized in reconstructive vein surgery. Our hypothesis is that individualization through reconditioning of a decellularized allogenic graft with autologous blood will prime the tissue for efficient recellularization, protect the graft from thrombosis, and decrease the risk of rejection. In this study, P-TEVs were transplanted to vena cava in pig, and the analysis of three veins after six months, six veins after 12 months and one vein after 14 months showed that all P-TEVs were fully patent, and the tissue was well recellularized and revascularized. To confirm that the ATMP product had the expected characteristics one year after transplantation, gene expression profiling of cells from P-TEV and native vena cava were analyzed and compared by qPCR and sequencing. The qPCR and bioinformatics analysis confirmed that the cells from the P-TEV were highly similar to the native cells, and we therefore conclude that P-TEV is functional and safe in large animals and have high potential for use as a clinical transplant graft.

Very urgent carotid endarterectomy confers increased procedural risk.

BACKGROUND AND PURPOSE: Current Swedish guidelines recommend that carotid endarterectomy should be performed within 14 days of a qualifying neurological event, but it is not clear if very urgent surgery after an event is associated with increased perioperative risk. The aim of this study was to determine how the time between the event and carotid endarterectomy affects the procedural risk of mortality and stroke. METHODS: We prospectively analyzed data on all patients who underwent carotid endarterectomies for symptomatic carotid stenosis between May 12, 2008, and May 31, 2011, with records in the Swedish Vascular Registry (Swedvasc). Patients were divided according to time between the qualifying event and surgery (0-2 days, 3-7 days, 8-14 days, 15-180 days). Stroke rate and mortality at 30 days postsurgery were determined. RESULTS: We analyzed data for 2596 patients and found that the combined mortality and stroke rate for patients treated 0 to 2 days after qualifying event was 11.5% (17 of 148) versus 3.6% (29 of 804), 4.0% (27 of 677), and 5.4% (52 of 967) for the groups treated at 3 to 7 days, 8 to 14 days, and 15 to 180 days, respectively. In a multivariate analysis, time was an independent risk factor for perioperative complications: patients treated at 0 to 2 days had a relative OR of 4.24 (CI, 2.07-8.70; P<0.001) compared with the reference 3- to 7-day group. CONCLUSIONS: In this study of patients treated for symptomatic carotid disease, it was safe to perform surgery as early as Day 3 after a qualifying neurological event in contrast to patients treated within 0 to 2 days, which has a significantly increased perioperative risk.

Personalized tissue-engineered arteries as vascular graft transplants: A safety study in sheep.

Patients with cardiovascular disease often need replacement or bypass of a diseased blood vessel. With disadvantages of both autologous blood vessels and synthetic grafts, tissue engineering is emerging as a promising alternative of advanced therapy medicinal products for individualized blood vessels. By reconditioning of a decellularized blood vessel with the recipient's own peripheral blood, we have been able to prevent rejection without using immunosuppressants and prime grafts for efficient recellularization in vivo. Recently, decellularized veins reconditioned with autologous peripheral blood were shown to be safe and functional in a porcine in vivo study as a potential alternative for vein grafting. In this study, personalized tissue engineered arteries (P-TEA) were developed using the same methodology and evaluated for safety in a sheep in vivo model of carotid artery transplantation. Five personalized arteries were transplanted to carotid arteries and analyzed for safety and patency as well as with histology after four months in vivo. All grafts were fully patent without any occlusion or stenosis. The tissue was well cellularized with a continuous endothelial cell layer covering the luminal surface, revascularized adventitia with capillaries and no sign of rejection or infection. In summary, the results indicate that P-TEA is safe to use and has potential as clinical grafts.

Individualized tissue-engineered veins as vascular grafts: A proof of concept study in pig.

Personalized tissue engineered vascular grafts are a promising advanced therapy medicinal product alternative to autologous or synthetic vascular grafts utilized in blood vessel bypass or replacement surgery. We hypothesized that an individualized tissue engineered vein (P-TEV) would make the body recognize the transplanted blood vessel as autologous, decrease the risk of rejection and thereby avoid lifelong treatment with immune suppressant medication as is standard with allogenic organ transplantation. To individualize blood vessels, we decellularized vena cava from six deceased donor pigs and tested them for cellular removal and histological integrity. A solution with peripheral blood from the recipient pigs was used for individualized reconditioning in a perfusion bioreactor for seven days prior to transplantation. To evaluate safety and functionality of the individualized vascular graft in vivo, we transplanted reconditioned porcine vena cava into six pigs and analyzed histology and patency of the graft at different time points, with three pigs at the final endpoint 4-5 weeks after surgery. Our results showed that the P-TEV was fully patent in all animals, did not induce any occlusion or stenosis formation and we did not find any signs of rejection. The P-TEV showed rapid recellularization in vivo with the luminal surface covered with endothelial cells. In summary, the results indicate that P-TEV is functional and have potential for use as clinical transplant grafts.

Reduced neointima in vein grafts following a blockage of cell recruitment from the vein and the surrounding tissue.

OBJECTIVE: Accumulation of intimal smooth muscle cells (SMC) is an important event in vein graft-stenosis. Different SMC sources have been reported, but their interrelations have been poorly studied. In a mouse vein graft model we investigated whether recipient-derived intimal SMCs are recruited from the surrounding tissue and whether blockage of SMC recruitment from the surrounding tissue and/or the donor vein will reduce neointimal formation. METHODS: To detect recipient-derived cells, wild-type veins were implanted into ROSA26 transgenic mice. To block cell recruitment from the surrounding tissue, implanted veins were isolated with a tube-shaped plastic film. To exclude vein-derived cells in the neointimal formation, acellular veins were implanted. RESULTS: In vein grafts isolated from the surrounding tissue the recipient contribution became minimal, but the total number of SMCs was not decreased. Acellular grafts contained an equal number of intimal SMCs as cellular controls after 4 weeks. Isolation of acellular grafts from the surrounding tissue decreased the number of intimal SMCs by 90%. CONCLUSIONS: Recipient-derived SMCs are mainly recruited from the surrounding tissue. Cell recruitment from either the vein or the surrounding tissue is enough to form a neointima. Therefore, a simultaneous inhibition of both these sources is needed to reduce accumulation of intimal SMCs.

Cadmium exposure as measured in blood in relation to macrophage density in symptomatic atherosclerotic plaques from human carotid artery.

BACKGROUND AND AIMS: The general population is exposed to cadmium through diet and smoking. Cadmium is pro-atherogenic and pro-inflammatory in experimental and observational studies. Cadmium levels in blood and carotid plaque endarterectomies correlate. Cadmium concentrations are much higher in plaque-areas that most frequently rupture. Here we investigated if blood cadmium concentrations are associated with macrophage density and the accumulation of CD14 as indicator of macrophage activation by lipopolysaccharide (LPS) in endarterectomies from patients with symptomatic carotid plaques. METHODS: Endarterectomies from ninety nine patients were fixed in formalin, embedded in paraffin, serially sectioned and stained for assessment of morphology. As predefined, the two section levels with most prevalent plaque rupture were used for further analyses. Macrophages were assessed as area of staining for CD68 (%). Blood cadmium was measured with ICP-MS. RESULTS: The CD68 median [25,75 percentiles] from the average of both sections were higher in cadmium tertile 3 than in tertile 1 (9.8 [4.9,16.1] % and 3.8 (0.6,12.4) %, p = 0.017). This difference remained in a multiple linear regression analysis with (10)log meanCD68 as dependent variable and adjustment for sex, age, smoking, statin treatment, index event, time between event and surgery (beta coefficient 0.44 [95% CI 0.05-0.87]. CD14 was not associated with blood cadmium. CONCLUSIONS: The results showed that blood cadmium was associated with proinflammatory macrophage density in the sections of carotid plaques with most frequent rupture, previously shown to contain most cadmium. No association between cadmium and LPS-mediated macrophage-activation was found. Cadmium exposure may promote plaque inflammation.

Intimal hyperplasia in mouse vein grafts is regulated by flow.

Altered flow conditions are presumed to cause stenosis in vein grafts due to exaggerated neointimal formation. The aim of this study was to establish a mouse model of flow-regulated intimal hyperplasia (IH) in vein grafts. The caval vein was grafted into the common carotid artery of 38 mice, followed by modulation of the blood flow, resulting in vein grafts with high (HF) and low flow (LF). The vessel wall thickening was evaluated after 3, 14 and 42 days by morphometric analyses and immunohistochemistry. There was an immediate significant change in flow, which was persistent throughout the time of observation. After 42 days, flow was increased 2.7 times in HF animals compared to LF animals. The vessel wall was composed of two layers where the inner layer was positive for alpha-actin and considered as IH. The area of neointimal formation was 74% larger in the LF group compared to the HF group. The present study demonstrates that flow regulates IH in vein grafts in mice. This model gives the potential to study the effect of shear stress on vascular biology in genetically modified animals.