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Objectives To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu's arteritis (TAK) and giant cell arteritis (GCA). Methods Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification. Results Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA. Conclusions Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

As a sequel of brain ischemia, selective neuronal loss (SNL)—as opposed to pannecrosis (i.e. infarction)—is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and 11C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary ‘exofocal’ phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences—including the impact on neurological recovery and contribution to vascular cognitive impairment—association with possible causal processes such as microglial activation, and preventability of SNL.

Key Points Visual loss is the most feared manifestation of giant cell arteritis (GCA) and occurs in up to 20% of patients before glucocorticoid therapy is commenced Anterior ischaemic optic neuropathy (AION) owing to arteritis of the posterior ciliary arteries is the most common cause of visual loss in GCA and must be differentiated from non-arteritic AION Cerebrovascular accidents — stroke and transient ischaemic attack — occur in 1.5–7% of patients with GCA and are caused by stenosis or occlusion of the extradural vertebral or carotid arteries A previous ischaemic event in GCA is the strongest predictor for a subsequent event; patients with traditional cardiovascular risk factors and a lower inflammatory response are more likely to develop ischaemic manifestations Adequate doses of glucocorticoids in GCA largely prevent further cranial ischaemic events, but are scarcely effective at improving established visual loss Fast-track clinics for the diagnosis of GCA might substantially reduce the occurrence of permanent sight loss by reducing diagnostic delay. Visual loss is a major concern for patients with giant cell arteritis (GCA). In this Review, the authors discuss visual loss and other ischaemic events in GCA, its epidemiology, associated risk factors, clinical presentation and current therapeutic approaches. Giant cell arteritis (GCA) is the most common form of vasculitis in individuals aged 50 years and over. GCA typically affects large and medium-sized arteries, with a predilection for the extracranial branches of the carotid artery. Patients with GCA usually present with symptoms and signs that are directly related to the artery that is affected, with or without constitutional manifestations. The most dreaded complication of GCA is visual loss, which affects about one in six patients and is typically caused by arteritis of the ophthalmic branches of the internal carotid artery. Before the advent of glucocorticoid treatment, the prevalence of visual complications was high. Increasing awareness by physicians of the symptoms of GCA and advances in diagnostic techniques over the past twenty years have also contributed to a substantial decline in the frequency of permanent visual loss. Ischaemic brain lesions are less common than visual lesions, and mostly result from vasculitis of the extradural vertebral or carotid arteries. In the case of both the eye and the brain, ischaemic damage is thought to result from arterial stenosis or occlusion that occurs secondary to the inflammatory process. The inflammatory response at the onset of arteritis, its role as a predictor of complications and the role of traditional cardiovascular risk factors have been extensively investigated in the past decade. In this Review, the epidemiology, risk factors, clinical presentation and current therapeutic approach of GCA-related ischaemic events are discussed, with a particular emphasis on visual loss.

In this observational study involving 5720 Japanese adults who had saccular aneurysms that were 3 mm or larger, the annual risk of rupture was 0.95%. The risk of rupture varied according to the size, location, and shape of the aneurysm. Although incidentally discovered cerebral aneurysms are common, 1 the management of these lesions has been controversial, 2 – 6 and the number of patients undergoing repair has been increasing. 7 Previous studies have shown that aneurysms smaller than 5 or 7 mm in the largest dimension rarely rupture and that aneurysms in the posterior circulation have a greater tendency to rupture than do those in the anterior circulation. 5 , 8 To determine the most appropriate treatment for individual patients, we need to have a better understanding of the risk of rupture of cerebral aneurysms. We conducted a large, prospective cohort study of unruptured cerebral aneurysms . . .

Background Positron emission tomography (PET) scan is emerging as a promising imaging technique to detect large-vessel inflammation in giant cell arteritis (GCA). However, the lack of a standardised definition of arteritis based on 18fluorodeoxyglucose (FDG) uptake is an important limitation to the use of PET scan for diagnostic purposes. Objective To prospectively assess the intensity and distribution of FDG uptake at different vascular territories in patients with newly diagnosed GCA compared with controls. Methods 32 consecutive, biopsy-proven, GCA patients treated with glucocorticoids for ≤3 days were included. The control group consisted of 20 individuals, who underwent PET/CT for cancer staging. Maximal standardised uptake value (SUVm) was calculated at four aortic segments, supraaortic branches and iliac-femoral territory. Sensitivity and specificity was calculated by receiver–operator characteristic curves (ROC) analysis. Results Mean SUVm was significantly higher in patients than in controls in all vessels explored and correlated with acute-phase reactants and serum IL-6. Mean of the SUVm at all the vascular territories had an area under the curve (AUC) of 0.830, and a cut-off of 1.89 yielded a sensitivity of 80% and a specificity of 79% for GCA diagnosis. There were no significant differences in AUC among the vascular beds examined. Conclusions FDG uptake by large vessels has a substantial sensitivity and specificity for GCA diagnosis.

During development of myointimal hyperplasia in human arteries, smooth muscle cells have hyperpolarized mitochondrial membrane potential (ΔΨm), high proliferation and apoptosis resistance; PDK2 is a key regulatory protein whose activation is necessary for myointima formation, and its blockade with dichloroacetate prevents Δψm hyperpolarization, facilitates apoptosis and reduces myointima formation in injured arteries, without preventing vessel re-endothelialization, possibly representing a novel strategy to prevent proliferative vascular diseases. Possible drug treatment of in-stent restenosis In-stent restenosis, a narrowing of a blood vessel or heart valve, is a frequent complication of the use of cardiac stents (metal or plastic tubes) to treat coronary artery disease. The condition is characterized by smooth muscle cell proliferation and the proliferation of cells of the myointima or innermost blood-vessel wall. Sonja Schrepfer and colleagues characterize the metabolic features of these proliferating cells during formation and find transient mitochondrial reprogramming and altered metabolism. They find that the drug dichloroacetate, which is known to suppress tumour growth, prevents some of these metabolic alterations and reduces myointimal hyperplasia in a number of preclinical models, at least in part by inhibiting pyruvate dehydrogenase kinase 2. Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States 1 . In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation 2 , 3 and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

Moyamoya disease is a cerebrovascular condition predisposing affected patients to stroke in association with progressive stenosis of the intracranial internal carotid arteries and their proximal branches. Patients with characteristic moyamoya vasculopathy plus associated conditions are categorized as having moyamoya syndrome. This review describes the demographic characteristics, pathogenesis, evaluation, and treatment of moyamoya disease and syndrome. Moyamoya Moyamoya disease is a cerebrovascular condition predisposing affected patients to stroke in association with progressive stenosis of the intracranial internal carotid arteries and their proximal branches. This review describes the demographic characteristics, pathogenesis, evaluation, and treatment of moyamoya disease and syndrome. The moyamoya syndrome is a cerebrovascular condition that predisposes affected patients to stroke in association with progressive stenosis of the intracranial internal carotid arteries and their proximal branches. Reduced blood flow in the major vessels of the anterior circulation of the brain leads to compensatory development of collateral vasculature by small vessels near the apex of the carotid, on the cortical surface, leptomeninges, and branches of the external carotid artery supplying the dura and the base of the skull. In rare cases, this process also involves the posterior circulation, including the basilar and posterior cerebral arteries. First described in 1957 . . .

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow.

Background Locally advanced cancers of the pancreatic body can abut or involve the celiac axis, hepatic artery, or superior mesenteric artery. Recent evidence suggests that these tumors are amenable to surgery after neoadjuvant chemotherapy (Hackert et al., Locally advanced pancreatic cancer: neoadjuvant therapy with FOLFIRINOX results in resectability in 60 % of the patients. Ann Surg 264:457–463, 2016; Rangelova et al., Surgery improves survival after neoadjuvant therapy for borderline and locally advanced pancreatic cancer: a single-institution experience. Ann Surg 273:579–86, 2021). An arterial divestment technique can be used for these cancers to get an R0 clearance, thereby avoiding morbid arterial resections (Miao et al., Arterial divestment instead of resection for locally advanced pancreatic cancer (LAPC). Pancreatology 16:S59, 2016; Habib et al., Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: surgical planning with the “halo sign” and “string sign.” Surgery 169(5):1026–1031, 2021; Diener et al., Periarterial divestment in pancreatic cancer surgery. Surgery 169(5):1026–31, 2020). Two techniques are described for arterial divestment. In the periarterial divestment technique, the plane of the dissection is between the tumor and the adventitia (Habib et al., Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: surgical planning with the “halo sign” and “string sign.” Surgery 169(5):1026–1031, 2021; Diener et al., Periarterial divestment in pancreatic cancer surgery. Surgery 169(5):1026–31, 2020). In sub-adventitial dissection, the plane of dissection is between the tunica adventitia and the external elastic lamina (Gao et al., Sub-adventitial divestment technique for resecting artery-involved pancreatic cancer: a retrospective cohort study. Langenbecks Arch Surg 406:691–701, 2021). The TRIANGLE operation also is one of the surgical techniques to achieve R0 resection in locally advanced pancreatic cancer (Hackert et al., The TRIANGLE operation: radical surgery after neoadjuvant treatment for advanced pancreatic cancer: a single-arm observational study. HPB Oxford 19:1001–1007, 2017). This multimedia article aims to demonstrate peri-arterial and sub-adventitial divestment techniques as well as the TRIANGLE operation for a locally advanced cancer of the body of the pancreas. The video also highlights the technique of posterior radical antegrade modular pancreato-splenectomy (RAMPS) together with lymph node clearance. Patient and Methods A 57-year-old women was detected to have pancreatic body adenocarcinoma with tumor contact of the artery and superior mesenteric artery. After neoadjuvant chemotherapy, she was planned to undergo surgical resection. Results The surgical technique consisted of peri-arterial and sub-adventitial divestment, the TRIANGLE operation and RAMPS (Fig. 1). The procedure was performed within 240 min and involved blood loss of 250 mL. After the procedure, pancreatic leak (POPF-B), chyle leak and diarrhea developed, which were managed conservatively. The final histopathology showed residual, viable, moderately differentiated adenocarcinoma (ypT2N1M0) with all resection margins free. Conclusion The surgical technique consisting of peri-arterial and sub-adventitial divestment, the TRIANGLE operation and RAMPS helps in R0 resection of locally advanced pancreatic body cancer without any compromise in oncologic outcomes and offers an alternative surgical approach to morbid arterial resection.