Matthew Waltham

Management of Abdominal Aortic Aneurysms Clinical Practice Guidelines of the European Society for Vascular Surgery

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands b Imperial College, London, UK University Hospital Innsbruck, Austria Azienda Ospedaliera di Perugia, Italy Hopital Cardiologique, CHRU de Lille, Lille, France f St Thomas’ Hospital, London, UK g St George’s Vascular Institute, London, UK Yale University School of Medicine, New Haven, Connecticut, USA University of Siena, Siena, Italy University of Poitiers, Poitiers, France

Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions

Observational studies have shown that inflammatory cells accumulate within the thrombus and surrounding vein wall during the natural history of venous thrombosis. More recent studies have begun to unravel the mechanisms that regulate this interaction and have confirmed that thrombosis and inflammation are intimately linked. This review outlines our current knowledge of the complex relationship between inflammatory cell activity and venous thrombosis and highlights new areas of research in this field. A better understanding of this relationship could lead to the development of novel therapeutic targets that inhibit thrombus formation or promote its resolution.

Is endovascular repair of mycotic aortic aneurysms a durable treatment option

OBJECTIVE Endovascular repair for degenerative aortic aneurysms is well established, but its role in those with infective pathology remains controversial. This study aims to assess the durability of endovascular repair with a review of our midterm results. METHOD A retrospective analysis of a prospectively maintained endovascular database (1998-2008) was conducted, which identified 673 consecutive patients with aortic aneurysms. RESULTS Nineteen patients (2.8%) were identified with infected aortic aneurysms, in which there were a total of 23 separate aneurysms (16 thoracic and seven abdominal). Six patients (32%) presented with rupture. Eleven patients (58%) had received antibiotics preoperatively for a median duration of 11 days (1-54 days). Fifteen of the 19 (79%) had positive blood cultures, with Staphylococcus aureus being the most common organism. All 19 patients underwent endovascular repair. There were three Type I endoleaks (one requiring conversion to open repair) and two Type II endoleaks. One patient developed transient paraplegia, resolved by cerebrovascular fluid (CSF) drainage, and one patient had a stroke. The 30-day mortality was 11%, and survival at median follow-up of 20 months (0-83 months) was 73%. All eight deaths in the series were related to aneurysm. CONCLUSION Endovascular treatment of infective aortic pathology provides an early survival benefit; however, concerns over on-going graft infection remain.

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.

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.

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.

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.

Role of miR-195 in aortic aneurysmal disease.

Rationale: Abdominal aortic aneurysms constitute a degenerative process in the aortic wall. Both the miR-29 and miR-15 families have been implicated in regulating the vascular extracellular matrix. Objective: Our aim was to assess the effect of the miR-15 family on aortic aneurysm development. Methods and Results: Among the miR-15 family members, miR-195 was differentially expressed in aortas of apolipoprotein E–deficient mice on angiotensin II infusion. Proteomics analysis of the secretome of murine aortic smooth muscle cells, after miR-195 manipulation, revealed that miR-195 targets a cadre of extracellular matrix proteins, including collagens, proteoglycans, elastin, and proteins associated with elastic microfibrils, albeit miR-29b showed a stronger effect, particularly in regulating collagens. Systemic and local administration of cholesterol-conjugated antagomiRs revealed better inhibition of miR-195 compared with miR-29b in the uninjured aorta. However, in apolipoprotein E–deficient mice receiving angiotensin II, silencing of miR-29b, but not miR-195, led to an attenuation of aortic dilation. Higher aortic elastin expression was accompanied by an increase of matrix metalloproteinases 2 and 9 in mice treated with antagomiR-195. In human plasma, an inverse correlation of miR-195 was observed with the presence of abdominal aortic aneurysms and aortic diameter. Conclusions: We provide the first evidence that miR-195 may contribute to the pathogenesis of aortic aneurysmal disease. Although inhibition of miR-29b proved more effective in preventing aneurysm formation in a preclinical model, miR-195 represents a potent regulator of the aortic extracellular matrix. Notably, plasma levels of miR-195 were reduced in patients with abdominal aortic aneurysms suggesting that microRNAs might serve as a noninvasive biomarker of abdominal aortic aneurysms.

Effect of statins on proteolytic activity in the wall of abdominal aortic aneurysms

The aim of this study was to examine the effect of statin treatment on the activity of proteases in the wall of abdominal aortic aneurysms (AAAs).

A variant in LDLR is associated with abdominal aortic aneurysm

Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance. Methods and Results—A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10−4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83; P=2.08×10−10). Conclusions—LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.