Rachael Forsythe

Clinical implications of the angiosome model in peripheral vascular disease

Vascular surgery has seen a revolutionary transformation in its approach to peripheral vascular disease over the last 2 decades, fueled by technological innovation and a willingness by the field to adopt these changes. However, the underlying pathology behind critical limb ischemia and the significant rate of unhealed wounds and secondary amputations despite apparently successful revascularization needs to be addressed. In seeking to improve outcomes, it may be beneficial to examine our approach to vascular disease at the fundamental level of anatomy, the angiosome, to better dictate reperfusion strategies beyond a simple determination of open vs endovascular procedure. We performed a systematic review of the current literature concerning the significance of the angiosome concept in the realm of vascular surgery. The dearth of convincing evidence in the form of prospective trials and large patient populations, and the lack of a consistent, comparable vocabulary to contrast study findings, prevent recommendation of the conceptual model at a wider level for guidance of revascularization attempts. Further well-structured, prospective studies are required as well as emerging imaging strategies, such as indocyanine green dye-based fluorescent angiography or hyperspectral imaging, to allow wider adoption of the angiosome model in vascular operations.

MRI using ultrasmall superparamagnetic particles of iron oxide in patients under surveillance for abdominal aortic aneurysms to predict rupture or surgical repair: MRI for abdominal aortic aneurysms to predict rupture or surgery-the MA(3)RS study.

Introduction Population screening for abdominal aortic aneurysms (AAA) halves the associated mortality and has led to the establishment of national screening programmes. Prediction of aneurysm growth and rupture is challenging and currently relies on serial diameter measurements with ultrasound. Recently, a novel MRI-based technique using ultrasmall superparamagnetic particles of iron oxide (USPIO) has demonstrated considerable promise as a method of identifying aneurysm inflammation and expansion. Methods and analysis The MA3RS study is a prospective observational multicentre cohort study of 350 patients with AAA in three centres across Scotland. All participants will undergo MRI with USPIO and aneurysm expansion will be measured over 2 years with CT in addition to standard clinical ultrasound surveillance. The relationship between mural USPIO uptake and subsequent clinical outcomes, including expansion, rupture and repair, will be evaluated and used to determine whether the technique augments standard risk prediction markers. To ensure adequate sensitivity to answer the primary question, we need to observe 130 events (composite of rupture or repair) with an estimated event rate of 41% over 2 years of follow-up. The MA3RS study is currently recruiting and expects to report in 2017. Discussion This is the first study to evaluate the use of USPIO-enhanced MRI to provide additional information to aid risk prediction models in patients with AAA. If successful, this study will lay the foundation for a large randomised controlled trial targeted at applying this technique to determine clinical management. Trial registration number Current Controlled Trials: ISRCTN76413758.

Monitoring the biological activity of abdominal aortic aneurysms Beyond Ultrasound

Abdominal aortic aneurysms (AAAs) are an important cause of morbidity and, when ruptured, are associated with >80% mortality. Current management decisions are based on assessment of aneurysm diameter by abdominal ultrasound. However, AAA growth is non-linear and rupture can occur at small diameters or may never occur in those with large AAAs. There is a need to develop better imaging biomarkers that can identify the potential risk of rupture independent of the aneurysm diameter. Key pathobiological processes of AAA progression and rupture include neovascularisation, necrotic inflammation, microcalcification and proteolytic degradation of the extracellular matrix. These processes represent key targets for emerging imaging techniques and may confer an increased risk of expansion or rupture over and above the known patient-related risk factors. Magnetic resonance imaging, using ultrasmall superparamagnetic particles of iron oxide, can identify and track hotspots of macrophage activity. Positron emission tomography, using a variety of targeted tracers, can detect areas of inflammation, angiogenesis, hypoxia and microcalcification. By going beyond the simple monitoring of diameter expansion using ultrasound, these cellular and molecular imaging techniques may have the potential to allow improved prediction of expansion or rupture and to better guide elective surgical intervention.

18F–Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study

Background Fluorine-18–sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque. Objectives In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes. Methods In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture. Results Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5× more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3× as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043). Conclusions Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758)

Peripheral arterial disease and revascularization of the diabetic foot.

Diabetes is a complex disease with many serious potential sequelae, including large vessel arterial disease and microvascular dysfunction. Peripheral arterial disease is a common large vessel complication of diabetes, implicated in the development of tissue loss in up to half of patients with diabetic foot ulceration. In addition to peripheral arterial disease, functional changes in the microcirculation also contribute to the development of a diabetic foot ulcer, along with other factors such as infection, oedema and abnormal biomechanical loading. Peripheral arterial disease typically affects the distal vessels, resulting in multi‐level occlusions and diffuse disease, which often necessitates challenging distal revascularisation surgery or angioplasty in order to improve blood flow. However, technically successful revascularisation does not always result in wound healing. The confounding effects of microvascular dysfunction must be recognised ‐ treatment of a patient with a diabetic foot ulcer and peripheral arterial disease should address this complex interplay of pathophysiological changes. In the case of non‐revascularisable peripheral arterial disease or poor response to conventional treatment, alternative approaches such as cell‐based treatment, hyperbaric oxygen therapy and the use of vasodilators may appear attractive, however more robust evidence is required to justify these novel approaches.

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study.

Background— Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. Methods and Results— We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. Conclusions— 18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.

Assessment of foot perfusion in patients with a diabetic foot ulcer

Assessment of foot perfusion is a vital step in the management of patients with diabetic foot ulceration, in order to understand the risk of amputation and likelihood of wound healing. Underlying peripheral artery disease is a common finding in patients with foot ulceration and is associated with poor outcomes. Assessment of foot perfusion should therefore focus on identifying the presence of peripheral artery disease and to subsequently estimate the effect this may have on wound healing. Assessment of perfusion can be difficult because of the often complex, diffuse and distal nature of peripheral artery disease in patients with diabetes, as well as poor collateralisation and heavy vascular calcification. Conventional methods of assessing tissue perfusion in the peripheral circulation may be unreliable in patients with diabetes, and it may therefore be difficult to determine the extent to which poor perfusion contributes to foot ulceration. Anatomical data obtained on cross‐sectional imaging is important but must be combined with measurements of tissue perfusion (such as transcutaneous oxygen tension) in order to understand the global and regional perfusion deficit present in a patient with diabetic foot ulceration. Ankle‐brachial pressure index is routinely used to screen for peripheral artery disease, but its use in patients with diabetes is limited in the presence of neuropathy and medial arterial calcification. Toe pressure index may be more useful because of the relative sparing of pedal arteries from medial calcification but may not always be possible in patients with ulceration. Fluorescence angiography is a non‐invasive technique that can provide rapid quantitative information about regional tissue perfusion; capillaroscopy, iontophoresis and hyperspectral imaging may also be useful in assessing physiological perfusion but are not widely available.

Distal Bypasses in Patients With Diabetes and Infrapopliteal Disease: Technical Considerations to Achieve Success

The combination of diabetes and peripheral arterial disease (PAD) is challenging in many ways. The characteristic and complex distal distribution of PAD often encountered in patients with diabetes means that bypass surgery in this context is technically challenging. In addition, many of these patients have a burden of serious comorbidities that must be optimized and managed concurrently. While the authors acknowledge that “achieving success” in distal bypass relies on much more than technical expertise, there are some technical aspects that should be considered when planning surgery on these patients. This article outlines some important issues in the treatment pathway of a patient with diabetes and PAD requiring distal bypass surgery—from selection and optimization of the patient (in the context of a multidisciplinary team) and preoperative workup, to the operative strategy planning, technical tips, and nonoperative adjuncts. These considerations, as well as sound knowledge of the underlying disease process, confounding medical factors and awareness of the difficulty in predicting treatment outcomes, should help maximize the chances of success.

Commentary on “Angiosome-targeted Lower Limb Revascularization for Ischaemic Foot Wounds: Systematic Review and Meta-analysis”

Angiosome-directed revascularisation of ischaemic limbs is a source of growing debate. In contrast to other recent systematic reviews, the current review suggests that, when feasible, direct revascularisation (DR) using the angiosome concept, may improve outcomes such as leg salvage and wound healing. There are many limitations of the evidence for this novel concept, including small study numbers, predominantly retrospective data, use of historical controls, and lack of angiographic data. The heterogeneity of data, patient characteristics, and lack of standardised definitions are further confounders. One fundamental issue that Professor Biancari does not address separately is the concept of indirect revascularisation through collaterals (IRc) and its effect on outcomes. The “angiosome” was originally described as a three-dimensional network of vessels, with a unit of tissue supplied by direct source arteries, but reinforced by arterialearterial connections between angiosomes. These collateral connections allow compensatory blood flow from a neighbouring angiosome in the event that the direct artery to the given angiosome is compromised. Therefore, the concept of IRc is important to consider, given that outcomes may be similar to those achieved with DR. However, the usefulness of IRc in a population of patients with diabetes has potential limitations. It follows that the obliteration of collaterals typical of a patient with diabetes would likely render IRc less useful than DR. The angiosome concept was developed in healthy patients. Very little consideration has been given to the distribution of angiosomes in patients with critical limb ischaemia or diabetes. Recent evidence suggests that the traditional angiosome model may not accurately predict the distribution of blood flow in an unselected group of patients with critical ischaemia, whose pattern of perfusion is distorted by abnormalities of the vascular bed, development of collaterals (especially in patients with diabetes) and atrophy of existing microvasculature. Therefore, the topographical location of an ulcer may not actually correlate accurately with the source artery supplying that area of tissue. With standard angiography, it is impossible to ascertain the functional perfusion of a

BioPARR: A software system for estimating the rupture potential index for abdominal aortic aneurysms

An abdominal aortic aneurysm (AAA) is a permanent and irreversible dilation of the lower region of the aorta. It is a symptomless condition that, if left untreated, can expand until rupture. Despite ongoing efforts, an efficient tool for accurate estimation of AAA rupture risk is still not available. Furthermore, a lack of standardisation across current approaches and specific obstacles within computational workflows limit the translation of existing methods to the clinic. This paper presents BioPARR (Biomechanics based Prediction of Aneurysm Rupture Risk), a software system to facilitate the analysis of AAA using a finite element analysis based approach. Except semi-automatic segmentation of the AAA and intraluminal thrombus (ILT) from medical images, the entire analysis is performed automatically. The system is modular and easily expandable, allows the extraction of information from images of different modalities (e.g. CT and MRI) and the simulation of different modelling scenarios (e.g. with/without thrombus). The software uses contemporary methods that eliminate the need for patient-specific material properties, overcoming perhaps the key limitation to all previous patient-specific analysis methods. The software system is robust, free, and will allow researchers to perform comparative evaluation of AAA using a standardised approach. We report preliminary data from 48 cases.