Intraoperative transit time flow measurement predicts maturation of radiocephalic arteriovenous fistulas.

OBJECTIVE: The arteriovenous fistula (AVF) is the first choice for gaining vascular access for hemodialysis. However, 20% to 50% of AVFs fail within 4 months after creation. Although demographic risk factors have been described, there is little evidence on the intraoperative predictors of AVF maturation failure. The aim of this study was to assess the predictive value of intraoperative transit time flow measurements (TTFMs) on AVF maturation failure. METHODS: In this retrospective cohort study, intraoperative blood flow, measured using TTFM, was compared with AVF maturation after 6 weeks in 55 patients. Owing to its significantly higher prevalence and risk of nonmaturation, the radiocephalic AVF (RCAVF) was the main focus of this study. A recommended cutoff point for high vs low intraoperative blood flow was determined for RCAVFs, using a receiver operating characteristic curve. RESULTS: The average intraoperative blood flow in RCAVFs was 156 mL/min. Patients with an intraoperative blood flow equal or lower than the determined cutoff point of 160 mL/min, showed a 3.03 times increased risk of AVF maturation failure after 6 weeks, compared with patients with a higher intraoperative blood flow (P < .001). CONCLUSIONS: The intraoperative blood flow in RCAVFs measured by TTFM provides an adequate means of predicting AVF nonmaturation 6 weeks after surgery. For RCAVFs, a cutoff point for intraoperative blood flow of 160 mL/min is recommended for maximum sensitivity and specificity to predict AVF maturation failure after 6 weeks.

Perspectives of Patients and Professionals on Patient Education in Complex Endovascular Aortic Repair.

BACKGROUND: Misinterpretation of patient preferences in perioperative education can lead to an undesired treatment decision. This explorative interview study presents differences in perspectives of patients and professionals on patient education in complex endovascular aortic aneurysm management. METHODS: Using convenience sampling, a cross-sectional interview study was performed among patients who were in various stages of the decision-making process for complex endovascular aortic repair. Five physicians were interviewed, representing the main providers of clinical information. Interviews were transcribed verbatim and analyzed inductively. RESULTS: Twelve patients (mean age 76.6 [standard deviation: 6.4], 83% male) were interviewed. Ten (83%) felt like they had no other realistic option besides undergoing surgery, whereas all professionals (5/5) stressed the importance of delicate patient selection. Five patients out of 10 (50%) who commented on their preferred decisional role considered the professional's advice as decisive. All but 1 patient (11/12) reported that the information was easy to understand, whereas 4 out of 5 professionals (80%) doubted whether patients could fully comprehend everything. Patients experienced a lack of information on the recovery process, although professionals stated that this was addressed during consultation. CONCLUSIONS: Several differences were found in the perspectives of patients and professionals on education in complex aortic aneurysm management. In order to optimize patient involvement in decision-making, professionals should be aware of these possible discrepancies and address them during consultation. Future research could focus on these differences in more detail by including more patients depending on their treatment and decision stages.

Increased Aortic Exclusion in Endovascular Treatment of Complex Aortic Aneurysms.

PURPOSE: Perioperative risk assessments for complex aneurysms are based on the anatomical extent of the aneurysm and do not take the length of the aortic exclusion into account, as it was developed for open repair. Nevertheless, in the endovascular repair (ER) of complex aortic aneurysms, additional segments of healthy aorta are excluded compared with open repair (OR). The aim of this study was to assess differences in aortic exclusion between the ER and OR of complex aortic aneurysms, to subsequently assess the current classification for complex aneurysm repair. METHODS: This retrospective observational study included patients that underwent complex endovascular aortic aneurysm repair by means of fenestrated endovascular aneurysm repair (FEVAR), fenestrated and branched EVAR (FBEVAR), or branched EVAR (BEVAR). The length of aortic exclusion and the number of patent segmental arteries were determined and compared per case in ER and hypothetical OR, using a Wilcoxon signed-rank test. RESULTS: A total of 71 patients were included, who were treated with FEVAR (n = 44), FBEVAR (n = 8), or BEVAR (n = 19) for Crawford types I (n = 5), II (n = 7), III (n = 6), IV (n = 7), and V (n = 2) thoracoabdominal or juxtarenal (n = 44) aneurysms. There was a significant increase in the median exclusion of types I, II, III, IV, and juxtarenal aneurysms (p < 0.05) in ER, compared with hypothetical OR. The number of patent segmental arteries in the ER of type I-IV and juxtarenal aneurysms was significantly lower than in hypothetical OR (p < 0.05). CONCLUSION: There are significant differences in the length of aortic exclusion between ER and hypothetical OR, with the increased exclusion in ER resulting in a lower number of patent segmental arteries. The ER and OR of complex aortic aneurysms should be regarded as distinct modalities, and as each approach deserves a particular risk assessment, future efforts should focus on reporting on the extent of exclusion per treatment modality, to allow for appropriate comparison.

Learning Curve Analysis of Complex Endovascular Aortic Repair.

BACKGROUND: When introducing new techniques, attention must be paid to learning curve. Besides quantitative outcomes, qualitative factors of influence should be taken into consideration. This retrospective cohort study describes the quantitative learning curve of complex endovascular aortic repair (EVAR) in a nonhigh-volume academic center and provides qualitative factors that were perceived as contributors to this learning curve. With these factors, we aim to aid in future implementation of new techniques. METHODS: All patients undergoing complex EVAR in the Leiden University Medical Center (LUMC) between July 2013 and April 2021 were included (n = 90). Quantitative outcomes were as follows: operating time, blood loss, volume of contrast, hospital stay, major adverse events (MAE), 30-day mortality, and complexity. Patients were divided into 3 temporal groups (n = 30) for dichotomous outcomes. Regression plots were used for continuous outcomes. In 2017, the treatment team was interviewed by an external researcher. These interviews were reanalyzed for factors that contributed to successful implementation. RESULTS: Length of hospital stay (P = 0.008) and operating time (P = 0.010) decreased significantly over time. Fewer cardiac complications occurred in the third group (3: 0% vs. 2: 17% vs. 1: 17%, P = 0.042). There was a trend of increasing complexity (P = 0.076) and number of fenestrations (P = 0.060). No significant changes occurred in MAE and 30-day mortality. Qualitative factors that, according to the interviewees, positively influenced the learning curve were as follows: communication, mutual trust, a shared sense of responsibility and collective goals, clear authoritative structures, mutual learning, and team capabilities. CONCLUSIONS: In addition to factors previously identified in the literature, new learning curve factors were found (mutual learning and shared goals in the operating room (OR)) that should be taken into account when implementing new techniques.

Aortic and Iliac Involvement in Brucellosis - A Rare but Life Threatening Manifestation: A Review of the Literature.

OBJECTIVE: Brucellosis is the most common zoonosis worldwide. Although cardiovascular complications in human brucellosis comprise only 3% of morbidity, they are the principal cause of death. Endocarditis covers the majority of these cases. Infected aneurysms and ulcerative processes of the aorta are rare but can be life threatening as well. Currently, limited information is available about aortic and iliac involvement in brucellosis. METHODS: A PubMed, Web of Science, and AccessMedicine search (without restriction on language or year of publication) was performed to identify relevant articles on aortic and iliac involvement in brucellosis. Case reports were eligible for inclusion if they reported on thoracic, abdominal, or iliac aortic pathology caused by Brucella. RESULTS: Seventy-one cases were identified over the last 70 years, with an overall mortality rate of 22%. Most of the patients were male (86%) and had a history of Brucella exposure (66%). Approximately one quarter (23%) contracted Brucella while travelling in a (hyper)endemic region. Almost half of the infections were located in the abdominal aorta (49%), followed by the ascending (37%) and descending (13%) thoracic aorta. Infected aneurysms (61%) and ulcerative processes (16%) were seen most frequently. Aortic rupture was present in 31% of cases and occurred mainly in the abdominal (49%) and descending thoracic aorta (44%). The majority of all patients (59%) underwent open surgery combined with long term antibiotics. Over the past 15 years, a trend towards endovascular treatment was observed. CONCLUSION: Although aortic and iliac involvement in brucellosis is rare, it can be a life threatening manifestation. Due to low awareness, this infection may represent an under reported disease. The therapeutic cornerstone in these cases remains open surgery combined with antibiotics. The role of endovascular treatment is yet to be decided, in which the condition of the patient and the risks of long term complications need to be considered.

Ruptured Aneurysm of the Common Iliac Artery Caused by Brucella melitensis: A Case Report.

INTRODUCTION: Brucella is a genus of aerobic Gram negative bacteria that causes the disease brucellosis. It is considered a zoonotic infection transmitted to humans by ingestion of unpasteurised dairy products. Although aortic involvement is rarely seen, it can be a life threatening complication of this disease. This case report describes a ruptured aneurysm of the common iliac artery (CIA) due to secondary infection by Brucella melitensis. REPORT: A 79 year old man with a known isolated aneurysm of the CIA presented with acute abdominal pain. Contrast enhanced computed tomography (CT) revealed rupture of the aneurysm. The patient underwent prompt endovascular repair. Several weeks after an uneventful recovery, the patient presented with spiking fever and abdominal discomfort. CT revealed an abscess anterior to the CIA. Blood and pus cultures grew B. melitensis. In recurrent re-admissions, conservative antibiotic therapy proved to be insufficient. Eventually, neo-aorto-iliac system (NAIS) reconstruction using bilateral femoral veins was performed to provide definitive treatment four months after initial presentation. CONCLUSION: Although Brucella infected aneurysms are rare, they are associated with life threatening disease. Diagnosing this type of brucellar infection can be challenging owing to the long incubation time needed for blood and tissue cultures. Definitive treatment of these aneurysms often needs open surgery and antibiotics for complete treatment. Vigilant surveillance is required to monitor for post-operative complications such as graft infection, recurrent (false) aneurysm, and abscess formation.

Functional Performance After Complex Endovascular Aortic Repair: A Single-Center Retrospective Cohort Study.

PURPOSE: Complex endovascular aortic repair (EVAR) procedures provide a treatment option for patients with aortic aneurysms involving visceral branches. Good technical results and short-term outcomes have been reported. Whether complex EVAR provides acceptable functional outcomes is not clear. The current study aims to describe postoperative functional outcomes in complex EVAR patients-an older and relatively frail patient group. MATERIALS AND METHODS: A single-center retrospective cohort study was performed, using data from a computerized database of consecutive patients who underwent complex EVAR in the Leiden University Medical Center (LUMC, The Netherlands) between July 2013 and September 2020. As of May 2017, patients scheduled for complex EVAR were referred to a geriatric care pathway to determine (Instrumental) Activities of Daily Living ((I)ADL) scores at baseline and, if informed consent was given, after 12 months. For the total patient group, adverse functional performance outcomes were: discharge to a nursing home and 12-month mortality. For the patients included in geriatric follow-up, the additional outcome was the incidence of functional decline (defined by a ≥2 point increase in (I)ADL-score) at 12-month follow-up. RESULTS: Eighty-two patients underwent complex EVAR, of which 68 (82.9%) were male. Mean age was 73.3 years (SD=6.3). Within 30 days postsurgery, 6 patients (7.3%) died. Mortality within 12 months for the total patient group was 14.6% (n=12). After surgery, no patients had to be discharged to a nursing home. Fifteen patients (18.3%) were discharged to a rehabilitation center. Twenty-three patients gave informed consent and were included in geriatric follow-up. Five patients (21.7%) presented functional decline 12 months postsurgery and 4 patients had died (17.4%) by that time. This means that 39.1% of the patients in the care pathway suffered an adverse outcome. CONCLUSION: To our knowledge, this is the only study that examined functional performance after complex EVAR, using a prospectively maintained database. No patients were newly discharged to a nursing home and functional performance results at 12 months are promising. Future multidisciplinary research should focus on determining which patients are most prone to deterioration of function, so that efforts can be directed toward preventing postoperative functional decline.

Risk assessment in aortic aneurysm repair by medical specialists versus the American College of Surgeons National Surgical Quality Improvement Program risk calculator outcomes.

OBJECTIVE: The aim of this online clinical vignette-based survey study was to compare risk assessments by vascular surgeons, anaesthesiologists and interventional radiologists involved in treating patients with aortic aneurysms in the Netherlands with the NSQIP risk calculator outcomes. METHODS: Participants, recruited using purposive sampling, provided their estimation of the likelihood of postoperative complications and events following aortic surgery in five fictional cases. These cases were subsequently scored using the NSQIP calculator. The risk assessments were statistically analysed using the ANOVA and student t-test. RESULTS: All participating specialists i.e. twelve vascular surgeons, ten interventional radiologists and ten anaesthesiologists completed the survey. In the vast majority of outcomes and vignettes, no significant differences were found between various specialists, whereas significant differences were found between the NSQIP risk calculator outcomes and the combined risk assessments of the specialists. Overall, specialist risk assessments differ from the NSQIP, but neither particularly higher nor lower compared to the risk calculator. CONCLUSIONS: Risk assessment by vascular surgeons, anaesthesiologists and interventional radiologists differs significantly with NSQIP risk calculator outcomes, within the framework of both endovascular and open aortic aneurysm repair. Based on these results, implementing the NSQIP risk calculator in preoperative workup could be of added value in both patient planning as well as adequately informing patients for obtaining consent.

A 'Final Destination injury': Penetrating trauma of the neck and a pneumomediastinum by a metal part shot from a lawnmower.

INTRODUCTION: Outside of war regions, penetrating neck injury is rare. Penetrating neck injury due to a lawnmower has never been described, despite the annual 74.000 injuries caused by lawnmowers in the United States. In this report, the case of a 65-year old women, admitted after a penetrating neck injury due to a metal piece shot from a lawnmower, is described. REPORT: A 65-year old women, with no relevant medical history, presented at the Emergency Department after she was hit in the neck by an iron projectile shot from a professional lawnmower. On site, the projectile, a metal part from the lawnmower blade, was removed by her husband. CT scan showed a pneumomediastinum, without signs of vascular injury. Surgical exploration was immediately performed in the operation room (OR). No vascular or esophageal injuries werefound, only lacerated neck muscles. Perioperatively, the ENT surgeon performed an endoscopy, which showed a small injury of the hypopharynx. Postoperatively, the patient was prophylactically treated with antibiotics for 7 days. Patient was discharged in good clinical condition after 7 days, without complications. CONCLUSION: In this report we present a case with a sharp traumatic injury of the neck, caused by a metal projectile shot from a lawnmower. The laceration of the pharynx was explored in the OR by the ENT- and vascular surgeon. The pneumomediastinum was treated with prophylactic antibiotics. Currently the patient is doing fine without any complications of the injury. Traumatic injury of the neck requires direct direct surgical exploration, however, when patients present hemodynamically stable, a neck CTA will add to the diagnosis (e.g. a pneumomediastium).

Antegrade common femoral artery access site closure using the MANTA vascular closure device.

In antegrade peripheral endovascular procedures, the use of covered stents may require a large sheath size, which precludes the use of regular closure devices. The MANTA vascular closure device is a collagen plug-based vascular closure device for large bore percutaneous arterial interventions, which is normally used to close retrograde vascular access sites. We describe successful antegrade common femoral access site closure with the MANTA vascular closure device in 2 patients, a 68-year-old male and an 89-year-old male, both with a popliteal artery aneurysm which was treated by percutaneous endovascular stentgraft placement. Use of the MANTA vascular closure device simplifies large-bore antegrade common femoral artery access and avoids the need for surgical artery cutdown.

Editor's Choice - A Systemic Evaluation of the Costs of Elective EVAR and Open Abdominal Aortic Aneurysm Repair Implies Cost Equivalence.

OBJECTIVE: The suggested high costs of endovascular aneurysm repair (EVAR) hamper the choice of insurance companies and financial regulators for EVAR as the primary option for elective abdominal aortic aneurysm (AAA) repair. However, arguments used in this debate are impeded by time related aspects such as effect modification and the introduction of confounding by indication, and by asymmetric evaluation of outcomes. Therefore, a re-evaluation minimising the impact of these interferences was considered. METHODS: A comparative analysis was performed evaluating a period of exclusive open repair (OR; 1998-2000) and a period of established EVAR (2010-2012). Data from four hospitals in The Netherlands were collected to estimate resource use. Actual costs were estimated by benchmark cost prices and a literature review. Costs are reported at 2019 prices. A break even approach, defining the costs for an endovascular device at which cost equivalence for EVAR and OR is achieved, was applied to cope with the large variation in endovascular device costs. RESULTS: One hundred and eighty-six patients who underwent elective AAA repair between 1998 and 2000 (OR period) and 195 patients between 2010 and 2012 (EVAR period) were compared. Cost equivalence for OR and EVAR was reached at a break even price for an endovascular device of €13 190. The main cost difference reflected the longer duration of hospital stay (ward and Intensive Care Unit) of OR (€11 644). Re-intervention rates were similar for OR (24.2%) and EVAR (24.6%) (p = .92). CONCLUSION: Cost equivalence for EVAR and OR occurs at a device cost of €13 000 for EVAR. Hence, for most routine repairs, EVAR is not costlier than OR until at least the five year follow up.

Supervised preoperative forearm exercise to increase blood vessel diameter in patients requiring an arteriovenous access for hemodialysis: rationale and design of the PINCH trial.

BACKGROUND: Failure of maturation occurs in 30%-60% of arteriovenous fistula (AVF) creation for hemodialysis, with highest rates in distal radiocephalic fistulas. This is partly due to initial small blood vessel size with limited blood flow capacity. Forearm exercise has shown potential as stimulus for increasing blood vessel size in patients with end-stage renal disease (ESRD) and may promote maturation of AVFs in the upper limb when applied postoperatively. However, it is unknown if forearm exercise increases blood vessel size pre-operatively, which may contribute to more distal AVF creation and raise success rates of AVF surgery. This study will investigate these issues. METHODS AND RESULTS: The PINCH trial (refers to 'pinching') is an investigator-initiated, multicenter, single-blinded, randomized controlled trial with 1:1 randomization to perform supervised forearm exercises compared to no exercise 6 weeks pre-operatively before creation of an AVF. Forty patients receiving an AVF will be included. The main study endpoints are blood vessel diameter (cephalic or basilic vein and radial and ulnar artery), AVF surgical plan (radiocephalic or brachiobasilic/cephalic), and three-month (assisted) maturation rate. The burden of the performed forearm exercises will be evaluated using Kidney Disease Quality of Life (KDQOL-SF Dutch version 1.2) and exercise specific questionnaires. The PINCH trial is planned to start in November 2017. Enrollment is expected to be completed at the end of 2019. CONCLUSIONS: The PINCH study is the first trial to evaluate the effect of pre-operative, supervised forearm exercises on vein diameter and fistula maturation in hemodialysis patients. TRIAL REGISTRATION: NTR6382.

Aortic Aneurysm Rupture After Urokinase Treatment for Acute Limb Ischemia in Two Patients After EVAR.

Endovascular aneurysm repair (EVAR) is first-choice treatment for many patients with abdominal aortic aneurysms. Complications unique to endovascular treatment include endoleak and endotension, which can eventually lead to rupture. We present two cases of late aortic rupture after EVAR, where both patients had recent preceding catheter-directed thrombolysis with urokinase for acute limb ischemia. These cases suggest a relation between thrombolytic therapy and aortic rupture after EVAR, and we should therefore be aware of this possible complication.

Improvement of radiocephalic fistula maturation: rationale and design of the Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study - a randomized controlled trial.

BACKGROUND: Non-maturation is a frequent complication of radiocephalic arteriovenous fistulas (RCAVF). In an animal model, liposomal prednisolone improved maturation of experimental fistulas. The Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study investigates if liposomal prednisolone improves RCAVF maturation. METHODS AND RESULTS: The LIPMAT study is an investigator-initiated, multicenter, double-blinded, placebo-controlled randomized controlled trial with 1:1 randomization to liposomal prednisolone or placebo. Eighty patients receiving an RCAVF will be included. The primary outcome is the cephalic vein diameter six weeks after surgery, measured by ultrasound. The LIPMAT study started in May 2016. Enrollment is expected to be completed by the end of 2017. CONCLUSIONS: The LIPMAT study is the first to evaluate the efficacy of liposomal prednisolone to enhance RCAVF maturation.

Experience with the GORE EXCLUDER iliac branch endoprosthesis for common iliac artery aneurysms.

OBJECTIVE: In this study, we analyzed the procedural success and early outcome of endovascular treatment of a multicenter cohort of patients with common iliac artery (CIA) aneurysms treated with the new GORE EXCLUDER (W. L. Gore & Associates, Flagstaff, Ariz) iliac branch endoprosthesis (IBE). METHODS: A retrospective cohort analysis was performed in 13 sites in The Netherlands. Anatomic, demographic, procedural, and follow-up data were assessed from hospital records. RESULTS: From November 2013 to December 2014, 51 CIA aneurysms were treated with an IBE in 46 patients. The median diameter of the treated aneurysm was 40.5 (range, 25.0-90.0) mm. The mean procedural time was 198 ± 56 minutes. All but one implantation were successful; two type Ib endoleaks were noticed, resulting in a procedural success rate of 93.5%. The two type Ib endoleaks spontaneously disappeared at 30 days. There was no 30-day mortality. Ipsilateral buttock claudication was present in only two cases at 30 days and disappeared during follow-up. The incidence of reported erectile dysfunction was low and severe ischemic complications were absent. After a mean follow-up of 6 months, data on 17 treated aneurysms were available. Two showed a stable diameter, whereas 15 showed a mean decrease of 3.9 ± 2.2 mm (P < .001). Reinterventions were performed in two patients (7.1%). The 6-month primary patency of the internal component of the IBE device was 94%. CONCLUSIONS: The use of the GORE EXCLUDER IBE device for CIA aneurysms is related to high procedural success, high patency rates, and low reintervention rates at short-term follow-up. Prospective data with longer follow-up are awaited to establish the role of the device in the treatment algorithm of CIA aneurysms.

A novel urokinase receptor-targeted inhibitor for plasmin and matrix metalloproteinases suppresses vein graft disease.

AIMS: Matrix metalloproteinases (MMP) and plasminogen activator (PA)/plasmin-mediated proteolysis, especially at the cell surface, play important roles in matrix degeneration and smooth muscle cell migration, which largely contributes to vein graft failure. In this study, a novel hybrid protein was designed to inhibit both protease systems simultaneously. MMP and plasmin activity were inhibited at the cell surface by this hybrid protein, consisting of the receptor-binding amino-terminal fragment (ATF) of urokinase-type PA, linked to both the tissue inhibitor of metalloproteinases (TIMP-1) and bovine pancreas trypsin inhibitor (BPTI), a potent protease inhibitor. The effect of overexpression of this protein on vein graft disease was studied. METHODS AND RESULTS: A non-viral expression vector encoding the hybrid protein TIMP-1.ATF.BPTI was constructed and validated. Next, cultured segments of human veins were transfected with this vector. Expressing TIMP-1.ATF.BPTI in vein segments resulted in a mean 36 ± 14% reduction in neointima formation after 4 weeks. In vivo inhibition of vein graft disease by TIMP-1.ATF.BPTI is demonstrated in venous interpositions placed into carotid arteries of hypercholesterolaemic APOE*3Leiden mice. After 4 weeks, vein graft thickening was significantly inhibited in mice treated with the domains TIMP-1, ATF, or BPTI (36-49% reduction). In the TIMP-1.ATF.BPTI-treated mice, vein graft thickening was reduced by 67±4%, which was also significantly stronger when compared with the individual components. CONCLUSION: These data provide evidence that cell surface-bound inhibition of the PA and MMP system by the hybrid protein TIMP-1.ATF.BPTI, overexpressed in distant tissues after electroporation-mediated non-viral gene transfer, is a powerful approach to prevent vein graft disease.

In vivo suppression of vein graft disease by nonviral, electroporation-mediated, gene transfer of tissue inhibitor of metalloproteinase-1 linked to the amino terminal fragment of urokinase (TIMP-1.ATF), a cell-surface directed matrix metalloproteinase inhibitor.

BACKGROUND: Smooth muscle cell (SMC) migration and proliferation are important in the development of intimal hyperplasia, the major cause of vein graft failure. Proteases of the plasminogen activator (PA) system and of the matrix metalloproteinase (MMP) system are pivotal in extracellular matrix degradation and, by that, SMC migration. Previously, we demonstrated that inhibition of both protease systems simultaneously with viral gene delivery of the hybrid protein TIMP-1.ATF, consisting of the tissue inhibitor of metalloproteinase-1 (TIMP-1) and the receptor-binding amino terminal fragment (ATF) of urokinase, reduces SMC migration and neointima formation in an in vitro restenosis model using human saphenous vein cultures more efficiently than both protease systems separately. Because use of viral gene delivery is difficult in clinical application, this study used nonviral delivery of TIMP-1.ATF plasmid to reduce vein graft disease in a murine bypass model. Nonviral gene transfer by electroporation was used to avert major disadvantages of viral gene delivery, such as immune responses and short-term expression. METHODS: Plasmids encoding ATF, TIMP-1, TIMP-1.ATF, or luciferase, as a control, were injected and electroporated in both calf muscles of hypercholesterolemic apolipoprotein E3-Leiden (APOE*3Leiden) mice (n = 8). One day after electroporation, a venous interposition of a donor mouse was placed into the carotid artery of a recipient mouse. In this model, vein graft thickening develops with features of accelerated atherosclerosis. Vein grafts were harvested 4 weeks after electroporation and surgery, and histologic analysis of the vessel wall was performed. RESULTS: Electroporation-mediated overexpression of the plasmid vectors resulted in a prolonged expression of the transgenes and resulted in a significant reduction of vein graft thickening (ATF: 36% +/- 9%, TIMP-1: 49% +/- 5%, TIMP-1.ATF: 58% +/- 5%; P < .025). Although all constructs reduced vein graft thickening compared with the controls, the luminal area was best preserved in the TIMP-1.ATF-treated mice. CONCLUSION: Intramuscular electroporation of TIMP-1.ATF inhibits vein graft thickening in vein grafts in carotid arteries of hypercholesterolemic mice. Binding of TIMP-1.ATF hybrid protein to the u-PA receptor at the cell surface enhances the inhibitory effect of TIMP-1 on vein graft remodeling in vitro as well as in vivo and may be an effective strategy to prevent vein graft disease.

Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice.

OBJECTIVE: Inflammatory responses to vascular injury are key events in vein graft disease and accelerated atherosclerosis, which may result in bypass failure. The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor (CCR)-2 pathway is hypothesized to play a central role. A murine model for vein graft disease was used to study the effect of local application of lentiviral short hairpin RNA (shRNA) targeted against CCR2. METHODS: A venous interposition was placed into the carotid artery of hypercholesterolemic apolipoprotein E3-Leiden (APOE*3-Leiden) mice to induce vein graft thickening with features of accelerated atherosclerosis. To demonstrate the efficacy of the lentiviral shRNA targeting murine CCR2 (shCCR2) in blocking vein graft disease in vivo, lentiviral shCCR2 or a control lentivirus was used to infect the vein graft locally (n = 8). RESULTS: Vascular CCR2 and MCP-1 messenger RNA expression levels were significantly upregulated during lesion progression in the vein graft. Infection of smooth muscle cells (SMCs) with a lentiviral shRNA targeting shCCR2 completely abolished MCP-1-induced SMC migration and inhibited SMC proliferation in vitro (n = 3 per group). Morphometric analysis of sections of grafts showed a significant 38% reduction in vein graft thickening in the shCCR2-treated mice 4 weeks after surgery (control, 0.42 +/- 0.05 mm(2); shCCR2, 0.26 +/- 0.03 mm(2); P = .007). CONCLUSION: Vascular CCR2 contributes to vein graft disease, and local application of shRNA against CCR2 to the vessel wall prevents vein graft thickening in hypercholesterolemic mice, suggesting that local overexpressing of shRNA using organ-targeted lentiviral gene delivery may be a promising therapeutic tool to improve vein graft disease in bypassed patients. CLINICAL RELEVANCE: Vein graft disease is an important clinical issue that results from an inflammatory response. The monocyte chemoattractant protein (MCP)-1/CC-chemokine receptor (CCR)-2 pathway plays a key role in the initiation and development of vein graft disease. This study demonstrates that perivascular overexpression of short hairpin RNA, targeted against CCR2, inhibits vein graft thickening. These data show that organ-targeted gene therapy against CCR2 in the vessel wall could be a promising therapeutic tool to improve vein graft patency in bypassed patients.