Magnetic resonance T1 relaxation time of venous thrombus is determined by iron processing and predicts susceptibility to lysis.

BACKGROUND: The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis. METHODS AND RESULTS: Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T1 relaxation time correlated with thrombus composition. The mean T1 relaxation time of thrombus was shortest at 7 days following thrombus induction and returned to that of blood as the thrombus resolved. T1 relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase (iNOS(-/-))-deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis-derived iron to paramagnetic Fe3+, which causes thrombus T1 relaxation time shortening. Studies using chemokine receptor-2-deficient mice (Ccr2(-/-)) revealed that the return of the T1 signal to that of blood is regulated by removal of Fe3+ by macrophages that accumulate in the thrombus during its resolution. Quantification of T1 relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively. CONCLUSIONS: The source of the T1 signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe3+ form. Quantification of T1 relaxation time appears to be a good predictor of the success of thrombolysis.

TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb.

A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2-expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed to examine the kinetics of TEMs in patients with CLI and whether these cells promote neovascularization of the ischemic limb. Here we show that there are 10-fold more circulating TEMs in CLI patients, and removal of ischemia reduces their numbers to normal levels. TEM numbers in ischemic muscle are two-fold greater than normoxic muscle from the same patient. TEMs from patients with CLI display greater proangiogenic activity than TIE2-negative monocytes in vitro. Using a mouse model of hindlimb ischemia, lentiviral-based Tie2 knockdown in TEMs impaired recovery from ischemia, whereas delivery of mouse macrophages overexpressing TIE2, or human TEMs isolated from CLI patients, rescued limb ischemia. These data suggest that enhancing TEM recruitment to the ischemic muscle may have the potential to improve limb neovascularization in CLI patients.

Hematopoietic progenitor cells and restenosis after carotid endarterectomy.

BACKGROUND AND PURPOSE: Hematopoietic progenitor cells (HPCs) may attenuate the response to vascular injury by maintaining endothelial integrity and function. Our aim was to determine whether circulating HPC number and function correlate with restenosis after carotid endarterectomy. METHODS: HPC number (CD34(+)/CD133(+) cells), early colony-forming units, migratory capacity, and senescence were analyzed in blood collected preoperatively, 1 day, and 6 weeks postoperatively. Mobilizing cytokine levels were also measured. Stenosis was assessed by duplex scanning. RESULTS: HPC numbers (P<0.001) and early colony-forming unit count (P=0.001) fell rapidly 24 hours postoperatively. Restenosis at 6 months correlated negatively with the magnitude of postoperative falls in HPC numbers (R=-0.38, P=0.013) and early colony-forming unit counts (R=-0.42, P=0.008). The migratory capacity of preoperative HPCs correlated negatively with restenosis (R=-0.48, P=0.007). Preoperative SDF1 levels correlated with falls in HPC number (R=0.42, P=0.044) and early colony-forming unit counts (R=0.56, P=0.004). CONCLUSIONS: HPC function appears to be linked to the development of carotid artery restenosis after endarterectomy. These data support the concept that HPCs have a role in regulating remodeling of the injured arterial wall.

A new imaging method for assessment of aortic dissection using four-dimensional phase contrast magnetic resonance imaging.

INTRODUCTION: Medical management of type B aortic dissection can result in progressive dilation of the false lumen and poor long-term outcome. Recent studies using models of aortic dissection have suggested flow characteristics, such as stroke volume, velocity, and helicity, are related to aortic expansion. The aim of this study was to assess whether four-dimensional phase-contrast magnetic resonance imaging (4D PC-MRI) can accurately visualize and quantify flow characteristics in patients with aortic dissection and whether these features are related to the rate of aortic expansion. METHODS: Twelve consecutive patients with medically treated type B thoracic aortic dissection underwent a three-dimensional (3D) MRI anatomy scan using a blood pool contrast agent. Two-dimensional phase contrast MRI data (2D PC-MRI) were acquired in the ascending and descending aorta and 4D PC-MRI data were acquired in the entire thoracic aorta. The 2D PC-MRI measurements were used to assess the quality of the 4D PC-MRI velocity data. Stroke volume, velocity, and the direction of flow were calculated using 4D PC-MRI and related to the rate of aortic expansion measured on contrast-enhanced computed tomography. RESULTS: Comparison of 2D PC-MRI and 4D PC-MRI measurements showed good correlation (Pearson R(2) = 0.98; 95% confidence interval [CI], 0.9818-0.9953; P < .0001) and no proportional bias (bias = 1.0 mL; standard deviation, 4.6). The median aortic growth rate was 6.1 mm/y (interquartile range [IQR], 1.1-15.1 mm/y), and this correlated well with the growth rate of the false lumen (Spearman ρ = 0.62; 95% CI, 0.06-0.89; P = .0347). False lumen thrombosis (FLT) was seen in 7 of 12 patients and was not associated with reduced aortic expansion rate (FLT present: 11.4 mm/y; IQR, 3.6-21.4) vs FLT absent: 9.9 mm/y; IQR, 3.4-24.2; Mann-Whitney P = .8763). False lumen stroke volume and velocity were associated with more rapid aortic expansion (ρ = 0.80 [95% CI, 0.39-0.94; P = .0029] and ρ = 0.59 [95% CI, 0.09-0.87; P = .0480] respectively). The position of the dominant entry tear was associated with rapid expansion, which tended to be higher with distal vs proximal entry tears (distal, 21.4 mm/y [IQR, 11.4-48.9] vs proximal, 5.5 mm/y [IQR, 3.4-16.6]; Mann-Whitney P = .096). Helical flow was seen in the false lumen in 8 of 12 patients and was related to the rate of aortic expansion (ρ = 0.83, P = .0154). CONCLUSIONS: 4D PC-MRI can be accurately applied to visualize and quantify flow characteristics in patients with aortic dissection. Stroke volume, velocity, distal dominant entry tears, and helical flow are related to the rate of aortic expansion. This study demonstrates the potential of this new imaging method. A larger prospective study is now required to measure flow characteristics and determine their predictive value for risk stratification of patients with aortic dissection.

Stent-graft limb deployment in the external iliac artery increases the risk of limb occlusion following endovascular AAA repair.

PURPOSE: To assess whether deployment of an endograft limb in the external iliac artery (EIA) increases the rate of limb occlusion following endovascular aneurysm repair (EVAR). METHODS: Interrogation of a prospectively maintained database identified 661 patients (596 men; median age 73 years, range 37-93) with infrarenal abdominal aortic aneurysm who underwent EVAR between 1996 and 2010 using Zenith stent-grafts predominately. Of these, 567 patients [56 (9.9%) women] had both endograft limbs deployed in the CIA (1203 limbs at risk), while 94 patients [9 (9.6%) women] had at least 1 limb in the EIA (22 bilateral; 116 limbs at risk). An adjunctive bare metal stent was used in 8 (9%) limbs deployed in the EIA. RESULTS: There were 31 limb occlusions, all unilateral: 17 (3%) patients in the CIA group had an occluded limb (1% of limbs at risk) vs. 14 (15%) patients in the EIA group (12% of limbs at risk; p<0.0001). The median time to occlusion was 3 months (0-60) in the CIA group and 1 month (0-36) in the EIA group. The majority of occlusions were treated by extra-anatomical revascularization, most often a femorofemoral crossover bypass. No legs were amputated following occlusion of a limb placed in the CIA, but there were 3 amputations in the EIA group (p=0.003). CONCLUSION: Deployment of endograft limbs into the EIA led to a higher rate of occlusion and leg amputation. Increased tortuosity of the EIA and a smaller caliber vessel are likely to account for the increased risk.

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

A new method for quantification of false lumen thrombosis in aortic dissection using magnetic resonance imaging and a blood pool contrast agent.

BACKGROUND: False lumen thrombosis after aortic dissection is a major predictor of prognosis. First pass computed tomography (CT) and magnetic resonance (MR) imaging are used routinely, where the image acquisition is timed to the arrival of contrast in the proximal unaffected aorta. Delayed phase imaging is difficult to refine because flow rates in the false lumen are often very slow and highly variable between patients. Blood pool contrast agents bind to albumin and become homogenously distributed in the intravascular circulation, allowing accurate imaging of areas where flow is low. We compared first pass MR and CT with a delayed phase MR acquisition using a blood pool agent to assess whether this more accurately quantified false lumen thrombosis. METHODS: Patients with medically treated chronic type B aortic dissection and evidence of false lumen thrombosis on previous CT imaging underwent first pass CT, first pass MR, and delayed phase MR with blood pool agent. Absence of false lumen contrast enhancement was quantified to assess the apparent differences in thrombosis. Phase-contrast MR data were also obtained to assess the affect of flow velocity on false lumen contrast enhancement, and direct thrombus MR images were used to confirm the presence of thrombus. RESULTS: Twelve patients were recruited. No difference was seen in apparent thrombus volume between first pass CT and first pass MR imaging (146.9 cm(3) [SD, 88.6] vs 187.6 cm(3) [SD, 136.1], P = .1119; R(2) = .67 [95% confidence interval (CI), r = .46-.95], P = .0012). In all patients, the volume of thrombus derived from first pass acquisitions was greater than the volume derived from delayed phase MR imaging with blood pool agent: first pass CT (paired t test, P = .0007; mean difference = 83.4 cm(3) [95% CI, 44.1-122.6]) and first pass MR (paired t test, P = .0009; mean difference = 124.0 cm(3) [95% CI, 63.2-184.9]). The difference in thrombus volume between first pass and delayed phase MR imaging with blood pool agent correlated significantly with the mean velocity of flow in the false lumen, with lower flow related to a greater difference (R(2) = .61, P = .0028 [95% CI, r = -.94--.37]). Direct thrombus MR images were able to correctly discriminate between thrombus and blood and matched the area of contrast absence on delayed phase MR with blood pool agent images. CONCLUSION: First pass techniques to assess false lumen thrombosis in aortic dissection consistently overestimate the apparent thrombus volume by five to six times. This has implications for interpretation of cohort studies and clinical trials that use false lumen thrombosis as an outcome measure. We recommend delayed phase MR imaging with a blood pool agent when accurate assessment of false lumen thrombosis is required.

Endovascular treatment of acute aortic syndrome.

BACKGROUND: The term acute aortic syndrome (AAS) encompasses a range of conditions that have a risk of imminent aortic rupture and where delays in treatment result in increased mortality. Endovascular treatment offers an attractive alternative to open surgery but little is known about the durability of the repair and the factors that predict mortality. METHODS: Prospective data were collected for a cohort of 110 consecutive patients with endovascular treatment for AAS. Patient and procedural characteristics were related to short- and midterm outcome using multivariate logistic regression analysis. RESULTS: There were 75 men and 35 women with a median age of 68 (range 57-76) years. The pathologies treated were acute dissection (35), symptomatic aneurysm (32), infected aneurysm (18), transection (12), chronic dissection (9), penetrating ulcer (3), and intramural hematoma (1). Thirty-day mortality was 12.7% and this was associated with hypotension (odds ratio [OR], 5.25), use of general anesthetic (OR, 5.23), long procedure duration (OR, 2.03), and increasing age (OR, 1.07). The causes of death were aortic rupture (4), myocardial infarction (4), stroke (3), and multisystem organ failure (3). The stroke and paraplegia rates were 7.3% and 6.4%, respectively. The 1-year survival was 81% and the 5-year survival 63%. Secondary procedures were required in 13 (11.8%) patients. Factors associated with death at 1 year were presence of an aortic fistula (OR, 9.78), perioperative stroke (OR, 5.87), and use of general anesthetic (OR, 3.76); and at 5 years were aortic fistula (OR, 12.31) and increasing age (OR, 1.06). CONCLUSIONS: Acute aortic syndrome carries significant early and late mortality. Emergency endovascular repair offers a minimally invasive treatment option associated with acceptable short and midterm results. Continued surveillance is important as secondary procedures and aortic-related deaths continue to occur throughout the follow-up period.

Upregulation of hypoxia-inducible factor 1 alpha in local vein wall is associated with enhanced venous thrombus resolution.

INTRODUCTION: Venous thrombus resolution may be regulated by an angiogenic process that involves the surrounding vein wall. The aims of this study were to determine whether: (i) thrombosis stimulates activation of the angiogenic transcription factor, hypoxia-inducible factor (HIF) 1α, and downstream expression of growth factors in vein wall; and (ii) upregulation of HIF1α in vein wall leads to increased growth factor expression and enhanced thrombus resolution. MATERIALS AND METHODS: HIF1α, vascular endothelial growth factor (VEGF), and placental growth factor (PLGF) were quantified in mouse inferior vena cava (IVC) at days 1, 3, 7, and 14 after thrombus formation (n = 10-13 per group). An additional group of thrombosed mice were treated with the prolyl-hydroxylase domain (PHD) inhibitor, L-mimosine (L-mim) or vehicle control. HIF1α, VEGF, and PLGF in IVC were measured at days 1 and 7; and vein recanalisation and thrombus resolution were measured at days 7 and 10 (n = 6-7 per group). RESULTS: HIF1α was expressed in thrombosed IVC and its levels remained relatively constant throughout natural resolution. The levels of VEGF in thrombosed IVC were elevated at days 1 (P < 0.0001) and 3 (P < 0.05); and PLGF at days 1 (P < 0.0001), 3 (P < 0.0001), and 7 (P < 0.0001). Treatment with L-mim led to: increased HIF1α (P<0.05), VEGF (P < 0.005), and PLGF (P < 0.001) levels in the IVC; decreased thrombus size (P < 0.01); and increased vein recanalisation (P < 0.001). CONCLUSIONS: HIF1α levels in vein wall are not affected by thrombosis and it appears that the angiogenic drive in the vein surrounding resolving thrombus is regulated independently of HIF1α. Stimulating HIF1α levels in the vein wall leads to an increased angiogenic drive and promotes vein recanalisation and thrombus resolution.

Hypoxia and upregulation of hypoxia-inducible factor 1{alpha} stimulate venous thrombus recanalization.

OBJECTIVE: Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1α enhances thrombus resolution and vein recanalization. METHODS AND RESULTS: Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS] = -0.77, P<0.0001), whereas HIF1α levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R] = 0.85, P<0.0005), during resolution in a murine model. HIF1α (P<0.005), VEGF (P<0.005), and VEGF receptor 1 (VEGFR1) (P<0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor L-mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight (P<0.001) and volume (P<0.05) were reduced by a third in l-mimosine-treated mice compared with controls, whereas vein recanalization (P<0.005) and thrombus neovascularization (P<0.001) were 2-fold greater, and this was associated with increased inflammatory cell content. CONCLUSIONS: Hypoxia and HIF1α are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1α enhances thrombus resolution and vein recanalization. HIF1α may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome.

Emergency endovascular aneurysm repair for ruptured abdominal aortic aneurysm: the way forward?

We present the early results of a policy of treating all anatomically suitable ruptured abdominal aortic aneurysms (rAAAs) by emergency endovascular aneurysm repair (eEVAR), regardless of hemodynamic instability. Data were retrospectively collected from prospectively maintained databases identifying patients with rAAA from 2006 to 2007. Forty-seven patients with true rAAA were identified (87% men; median age 76 years [range 63-97 years]), of whom 18 (38%) were treated with eEVAR, 19 (40%) received open aneurysm repair (OAR), and 10 (21%) were managed nonoperatively. Fifteen of 18 (83%) eEVAR patients received an aortouni-iliac device + femorofemoral crossover, 2 patients (11%) had bifurcated devices, and 1 patient (6%) had a new iliac limb. Thirty-day mortality was 11% (2 of 18) for eEVAR and 32% (6 of 19) for OAR (p = not significant). At the 6-month follow-up, mortality was 22% (4 of 18) for eEVAR and 37% (7 of 19) for OAR (p = not significant). A clinically significant early survival advantage is suggested for eEVAR in patients presenting with rAAA.

The monocyte/macrophage as a therapeutic target in atherosclerosis.

It is now clear that the monocyte/macrophage has a crucial role in the development of atherosclerosis. This cell appears to be involved in all stages of atherosclerotic plaque development and is increasingly seen as a candidate for therapeutic intervention and as a potential biomarker of disease progression and response to therapy. The main mechanisms related to the activity of the monocyte/macrophage that have been targeted for therapy are those that facilitate recruitment, cholesterol metabolism, inflammatory activity and oxidative stress. There is also increasing evidence that there is heterogeneity within the monocyte/macrophage population, which may have important implications for plaque development and regression. A better insight into how specific phenotypes may influence plaque progression should facilitate the development of novel methods of imaging and more refined treatments.

Systemic administration of heparin intraoperatively in patients undergoing open repair of leaking abdominal aortic aneurysm may be beneficial and does not cause problems.

The aim of this study was to investigate whether intravenous heparin administration was associated with a reduction in perioperative mortality and late distal thrombectomy in patients with ruptured abdominal aortic aneurysms (AAAs). One hundred thirty-one patients had repair of ruptured AAA between January 1999 and January 2004. Sixty-three received heparin according to the consultant's preference at the time of the operation. Data were prospectively collected, and multivariate analysis was performed for independent predictive factors. Thirty-day mortality was 29%. Patients receiving heparin had lower perioperative mortality (16% vs 42%; p= .001). Heparin administration was not associated with increased hemorrhage or transfusion. Multivariate analysis confirmed that heparin administration was independently predictive of survival (p= .036). Other factors found to reduce survival were age (p= .023), smoking (p= .042), and systolic blood pressure (<100 mmHg) at presentation (p= .045). Fewer patients had thrombectomy after heparin (8% vs 12%), but this was not statistically significant. Perioperative complications were similar in both groups. The administration of systemic heparin before the clamp is applied to leaking aneurysms does not appear to increase hemorrhage and subsequent mortality and may reduce the need for early thrombectomy.

Cysteine protease activity in the wall of abdominal aortic aneurysms.

BACKGROUND: Cysteine proteases are potent elastolytic enzymes and together with their inhibitor, cystatin C, have been linked with the growth of abdominal aortic aneurysms (AAAs). These enzymes and their inhibitors have previously been studied in AAAs, but comparisons have always been made with wall from normal aorta. Atherosclerosis is a feature of aneurysmal disease and may therefore confound comparisons with normal wall. This study compared the expression and activity of cysteine proteases and their inhibitors in aneurysm wall with their expression in the aortic wall of patients with aortic occlusive disease (AOD). METHODS: Aortic wall was obtained from 82 patients with AAA and 13 with AOD. Protein expression and activity of cathepsin B, H, K, L and S, and cystatins A, B, and C were measured by enzyme-linked immunosorbent assay and specific fluorogenic substrate assays. Matrix metalloproteinase 9 (MMP-9) activity was measured by quantitative bioimmunoassay in the same extracts. RESULTS: AAA wall had 330% more cathepsin H protein (P = .007) and >30% less cystatin C (P = .03) than the aortic wall from patients with AOD. The activity of cathepsins B, H, L, and S was significantly greater in AAA than AOD (376%, [P < .0001], 191%, [P = 0.019], 223%, P = 0.002, and approximately 20% [P = 0.045] respectively). MMP-9 activity was also increased in AAA compared with AOD (P<0.0001) and levels in the wall of AAA correlated positively with cathepsin L activity (r = 0.42, P<.0001) and negatively with cystatin C (r = -0.75, P<.0001). CONCLUSIONS: The activity of four cathepsins B, H, L, and S was higher in the aneurysm wall than in aortic wall of patients with occlusive disease. This was associated with a reduced level of cystatin C in the aneurysmal wall. Cathepsin H was the only protein in which there was a correlation between protein level and activity, which suggests that post-translational modifications were responsible for activation of the other cathepsins. Increased cathepsin activity may influence the activity of MMP-9, which is thought to have an important role in aneurysm development.

Endovascular grafting of the thoracic aorta, an evolving therapy: ten-year experience in a single centre.

BACKGROUND: Surgical therapy for the thoracic aorta carries a high morbidity and mortality. Endovascular therapy for aneurysms and its adaptation to the thoracic aorta over the past 10 years is an exciting advance. This is a retrospective review of endovascular grafting of the thoracic aorta during the past decade at Royal Prince Alfred Hospital and the outcomes achieved over this period. METHODS: A retrospective review of all patients at our institution who underwent endovascular grafting of the thoracic aorta between March 1995 and March 2005 was carried out. Data were analysed using Stata version 8.0 (Stata corporation, College Station, TX, USA). RESULTS: Sixty-five patients underwent endovascular stent grafting of the thoracic aorta. The indications were degenerative aneurysm (31), Stanford type B dissection (23) both acute (12) and chronic (11), traumatic transection (9) and penetrating ulcer (2). There were no conversions to open repair. Twenty-two patients required additional procedures, six of which were unplanned. The median age was 65 (range 18-85), 68% of patients were men. The median procedure time was 115 min (range 55-240 min). Mean hospital stay was 9.8+/-7.3 days and high dependency/intensive care unit stay 1.5+/-3.2 days. Thirty-day mortality was 0 in 41 for elective cases (one patient (2.5%) died 37 days post-procedure) and 12% (3 of 25) for emergency cases. Complications occurred in 20 of 41 (49%) elective cases and 14 of 24 (58%) emergency cases within the first 30 days. The most frequent major complications were neurological including paraplegia (transient 2 of 65, permanent (2 of 65)) and stroke (4 of 65). Other complications included endoleak (12 of 65), acute renal failure (1 of 65), and brachial artery false aneurysm (1 of 65). The mean length of follow up was 22.5 months (range, 1-97 months). Six patients required further endovascular procedures for persistent endoleak or ongoing perfusion of chronic dissection. Late deaths (>30 days) related to the endovascular treatment occurred in two patients (3%). CONCLUSION: Endovascular grafting of the thoracic aorta is an evolution in the treatment of thoracic aortic pathology. The results of elective endovascular grafts were acceptable. Emergency procedures had a higher incidence of complications and death. Improvement in graft technology, design and deployment are required.

Vascular endothelial growth factor naked DNA gene transfer enhances thrombus recanalization and resolution.

OBJECTIVES: Enhancing thrombus resolution may reduce the long-term complications of venous thrombosis. The aim of this study was to examine whether a sustained release of vascular endothelial growth factor (VEGF) would further improve thrombus recanalization. METHODS: Inferior caval vein thrombosis was induced in a cohort of 21 male Wistar rats. A plasmid encoding the human VEGF gene (phVEGF) was injected directly into thrombus (30 to 50 microg) and the muscle adjacent to the inferior vena cava (300 to 400 microg). A plasmid containing the gene encoding beta-galactosidase (pCMVbeta) was injected into the same sites of a separate cohort of rats to act as a control. Tissues were harvested after 1 and 2 weeks, and beta-galactosidase activity was measured to estimate transfection efficiency. Muscle and serum VEGF were measured by enzyme-inked immunosorbent assay. Thrombus size, recanalization, and organization were determined by computer-assisted image analysis. RESULTS: The efficiency of control plasmid transfection into muscle was about 1%. No serum hVEGF was detected in phVEGF- or pCMVbeta-treated animals. Significantly raised levels of hVEGF (P < .01) were detected in the muscle injected with phVEGF after 2 weeks compared with control muscle. There was a significant reduction in thrombus size of 23% (P < .05) and 48% (P < .001) in phVEGF-treated animals compared with pCMVbeta-treated controls after 1 and 2 weeks, respectively. Thrombus recanalization was a significantly greater in the phVEGF-treated group after 2 weeks (mean 19% +/- 2% [SEM]) compared with controls (mean 13% +/- 2%, P < .01). There were no differences in the thrombus organization score. CONCLUSION: VEGF gene therapy of venous thrombus resulted in smaller thrombi with greater recanalization. Angiogenic gene therapy may form the basis of a novel treatment that may improve the resolution of venous thrombi. CLINICAL RELEVANCE: Deep vein thrombosis may lead to residual venous obstruction or reflux and result in post-thrombotic complications that are debilitating and have a substantial socioeconomic impact. Enhancing the resolution of venous thrombi may reduce post thrombotic complications.

The role of neovascularisation in the resolution of venous thrombus.

Deep vein thrombosis (DVT) can give rise to chronic debilitating complications, which are expensive to treat. Anticoagulation, the standard therapy for DVT, prevents propagation, but does not remove the existing thrombus, which undergoes slow natural resolution. Alternative forms of treatment that accelerate resolution may arise from a better understanding of the cellular and molecular pathways that regulate the natural resolution of thrombi. This review will outline our current understanding of the mechanisms of thrombus resolution and the role of neovascularisation in this process. Novel experimental treatments that may one day find clinical use are also discussed. The process of thrombus resolution resembles wound healing. The mainly monocytic inflammatory infiltrate, which develops, is associated with the appearance of vascular channels. These cells may drive resolution by encouraging angiogenesis, which contributes to restoration of the vein lumen. Significant numbers of bone marrow-derived progenitor cells have also been found in naturally resolving thrombi, but their precise phenotype and their role in thrombus recanalisation is unclear. Enhanced thrombus neovascularisation and rapid vein recanalisation have been achieved in experimental models with proangiogenic agents. Recent reports of the role of bone marrow-derived progenitor cells in the revascularisation of ischaemic tissues suggest that it may be possible to obtain the same effect by delivering pluripotent or lineage specific stem cells into thrombus. These cells could contribute to thrombus recanalisation by expressing a variety of proangiogenic cytokines or by lining the new vessels that appear within the thrombus.