Ian J. Franklin

Inhibition of Prostaglandin E2 Synthesis in Abdominal Aortic Aneurysms : Implications for Smooth Muscle Cell Viability, Inflammatory Processes, and the Expansion of Abdominal Aortic Aneurysms

BACKGROUND There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin. METHODS AND RESULTS Aneurysm biopsies were used for explant cultures, the preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E2 (PGE2) concentrations in aneurysm tissue homogenates, conditioned medium from explants, and isolated macrophages were 49+/-22 ng/g, 319+/-38 ng/mL, and 22+/-21 ng/mL, respectively. PGE2 inhibited DNA synthesis and proliferation in normal aortic smooth muscle cells (IC50, 23.2+/-3.8 and 23.6+/-4.5 ng/mL, respectively). In smooth muscle cells derived from aneurysmal aorta, PGE2 also caused cell death, with generation of oligonucleosomes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fractionation of this medium showed that the growth-inhibitory molecule(s) coeluted with PGE2. In explants, indomethacin 10 micromol/L or mefenamic acid 10 micromol/L abolished PGE2 secretion and significantly reduced IL-1beta and IL-6 secretion. In a separate case-control study, the expansion of abdominal aortic aneurysms was compared in 15 patients taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P=0.001. CONCLUSIONS The adverse effects of PGE2 on aortic smooth muscle cell viability and cytokine secretion in vitro and the apparent effect of anti-inflammatory drugs to lower aneurysm growth rates suggest that selective inhibition of PGE2 synthesis could be an effective treatment to curtail aneurysm expansion.

Early Results of Fenestrated Endovascular Repair of Juxtarenal Aortic Aneurysms in the United Kingdom

Background— Fenestrated endovascular repair of abdominal aortic aneurysms has been proposed as an alternative to open surgery for juxtarenal and pararenal abdominal aortic aneurysms. At present, the evidence base for this procedure is predominantly limited to single-center or single-operator series. The aim of this study was to present nationwide early results of fenestrated endovascular repair in the United Kingdom. Methods and Results— All patients who underwent fenestrated endovascular repair between January 2007 and December 2010 at experienced institutions in the United Kingdom(>10 procedures) were retrospectively studied by use of the GLOBALSTAR database. Site-reported data relating to patient demographics, aneurysm morphology, procedural details, and outcome were recorded. Data from 318 patients were obtained from 14 centers. Primary procedural success was achieved in 99% (316/318); perioperative mortality was 4.1%, and intraoperative target vessel loss was observed in 5 of 889 target vessels (0.6%). The early reintervention (<30 days) rate was 7% (22/318). There were 11 deaths during follow-up; none were aneurysm-related. Survival by Kaplan–Meier analysis was 94% (SE 0.01), 91% (0.02), and 89% (0.02) at 1, 2, and 3 years, respectively. Freedom from target vessel loss was 93% (0.02), 91% (0.02), and 85% (0.06), and freedom from late secondary intervention (>30 days) was 90% (0.02), 86% (0.03), and 70% (0.08) at 1, 2, and 3 years. Conclusions— In this national sample, fenestrated endovascular repair has been performed with a high degree of technical and clinical success. Late survival and target vessel patency are satisfactory. These results support continued use and evaluation of this technique for juxtarenal aneurysms, but illustrate the need for a more robust evidence base.

Hypertension and the post-carotid endarterectomy cerebral hyperperfusion syndrome.

OBJECTIVE Cerebral hyperperfusion syndrome is a preventable cause of stroke after carotid endarterectomy (CEA). It manifests as headache, seizures, hemiparesis or coma due to raised intracranial pressure or intracerebral haemorrhage (ICH). There is currently no consensus on whether to control blood pressure, blood pressure thresholds associated with cerebral hyperperfusion syndrome, choice of anti-hypertensive agent(s) or duration of treatment. METHOD A systematic review of the PubMed database (1963-2010) was performed using appropriate search terms according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS A total of 36 studies were identified as fitting a priori inclusion criteria. Following CEA, the incidence of severe hypertension was 19%, that of cerebral hyperperfusion 1% and ICH 0.5%. The postoperative mean systolic blood pressure of patients, who went on to develop cerebral hyperperfusion syndrome, was 164 mmHg (95% confidence interval (CI) 150-178 mmHg) and the cumulative incidence of cases rose appreciably above a postoperative systolic blood pressure of 150 mmHg. The mean systolic blood pressure of cerebral hyperperfusion cases was 189 mmHg (95% CI 183-196 mmHg) at presentation. The incidence of cerebral hyperperfusion in the first week was 92% with a median time to presentation of 5 days (interquartile range (IQR) 3-6 days). 36% of patients presented with seizures 31% with hemiparesis and 33% with both. The proportion of patients with severe hypertension was significantly higher in cases than in post-CEA controls (p < 0.0001, Odds ratio 19 (95% CI 9-41)). Three large case-control studies identify postoperative hypertension as a risk factor for ICH. CONCLUSION There is currently level-3 evidence for the prevention of ICH through control of postoperative blood pressure. From the available data, we suggest a definition for cerebral hyperperfusion syndrome, blood pressure thresholds, duration of monitoring and a postoperative blood pressure control strategy for validation in a prospective study. The implications of this are that one in five patients would need intravenous anti-hypertensives and home blood pressure monitoring for 1 week.

Open repair versus fenestrated endovascular aneurysm repair of juxtarenal aneurysms.

BACKGROUND Open repair is the gold standard management for juxtarenal aneurysms. Fenestrated endovascular aneurysm repair (FEVAR) is indicated for high-risk patients. The long-term outcomes of FEVAR are largely unknown, and there is no Level I comparative evidence. This systematic review and meta-analysis of case series compares elective juxtarenal aneurysm surgery by open repair and FEVAR. METHODS A systematic literature search was conducted for all published studies on elective repair of juxtarenal aneurysms by FEVAR and open repair. The MEDLINE, EMBASE, and Cochrane databases were searched from 1947 to April 2013. The exclusion criteria were case series of <10 patients or ruptured aneurysms. The primary outcomes were perioperative mortality and postoperative renal insufficiency. The secondary outcomes were secondary reinterventions and long-term survival. RESULTS We identified 35 case series with data on 2326 patients. Perioperative mortality was 4.1% in open repair and FEVAR case series (odds ratio for open repair with FEVAR, 1.059; 95% confidence interval, 0.642-1.747; P = .822). Postoperative renal insufficiency was not significantly different (odds ratio for open repair with FEVAR, 1.136; 95% confidence interval, 0.754-1.713; P = .542). FEVAR patients had higher rates of secondary reintervention, renal impairment during follow-up, and a lower long-term survival compared with open repair patients. CONCLUSIONS FEVAR and open repair have similar short-term outcomes but have diverging long-term outcomes that may be secondary to the selection bias of FEVAR being offered to high-risk patients. FEVAR is a favorable option in high-risk patients, and open repair remains viable as the gold standard.

Smooth muscle cells in human atherosclerosis: Proteomic profiling reveals differences in expression of Annexin A1 and mitochondrial proteins in carotid disease

Smooth muscle cells (SMC) contribute to the development and stability of atherosclerotic lesions. The molecular mechanisms that mediate their properties are incompletely defined. We employed proteomics and in vitro functional assays to identify the unique characteristics of intimal SMC isolated from human carotid endarterectomy specimens and medial SMC from thoracic aortas and carotids. We verified our findings in the Tampere Vascular Study. Human atheroma-derived SMC exhibit decreased expression of mitochondrial proteins ATP Synthase subunit-beta and Aldehyde dehydrogenase 2, and decreased mitochondrial activity when compared to control SMC. Moreover, a comparison between plaque-derived SMC isolated from patients with or without recent acute cerebrovascular symptoms uncovered an increase in Annexin A1, an endogenous anti-inflammatory protein, in the asymptomatic group. The deletion of Annexin A1 or the blockade of its signaling in SMC resulted in increased cytokine production at baseline and after stimulation with the pro-inflammatory cytokine Tumor Necrosis Factor α. In summary, our proteomics and biochemical analysis revealed mitochondrial damage in human plaque-derived SMC as well as a role of Annexin A1 in reducing the production of pro-inflammatory mediators in SMC.

Systematic review of sonographic chronic cerebrospinal venous insufficiency findings in multiple sclerosis

Objective The sonographic findings of chronic cerebrospinal venous insufficiency (CCSVI) are used by some as selection criteria for venography. We performed a systematic review to establish the prevalence and strength of association between sonographic CCSVI and multiple sclerosis (MS). Method Two reviewers searched PubMed and EMBASE from 1948 to date using the keywords ‘chronic cerebrospinal venous insufficiency’ according to PRISMA guidelines. Results Four cross-sectional studies met the criteria for inclusion. The prevalence of CCSVI ranged from 7% to 100% in MS patients and from 2% to 36% in healthy controls. Diagnostic odds ratios for MS varied between 2 and 26, 499 (I 2 = 94%). Sensitivities of CCSVI for MS varied between 7% and 100% (I 2 = 98%). Specificities varied between 64% and 100% (I 2 = 95%). Conclusion There is substantial variation in the strength of association between CCSVI and MS beyond that explained by demographic differences or sonographer training. Reliable evidence on which to base decisions requires sonographic consensus and assessment of the reproducibility of individual criteria between trained sonographers.

The European burden of primary varicose veins.

Background: The treatment of varicose veins has been demonstrated to improve quality of life, alleviate symptoms of depression and treat the complications of venous disease. This study aims to show the studies which contain information regarding the prevalence and distribution of venous disease. Then using the population and prevalence data for venous disease, and considering the cost of treating varicose veins, this study aims to analyse the treatment of varicose veins and assess whether there is a disparity between European countries. Methods: Relevant papers regarding the prevalence or incidence of venous disease were identified through searches of PubMed (1966 to October 2010). The search terms ‘prevalence OR incidence’ AND ‘varicose veins or venous disease’ were used. Population data, prevalence data and the number of varicose vein procedures performed in each country was obtained for 2010. Results: Four studies were included. From calculated values comparing the predicted and actual number of patients requiring treatment for venous disease, the UK, Finland and Sweden are potentially not treating all patients with C2 disease. In contrast to this, all other European countries represented are treating more patients, suggesting that they may be treating additional patients. There was up to a four-fold difference in the numbers of procedures per million population that were performed for varicose veins in different European countries. Conclusion: There is a marked disparity across Europe between the predicted number of patients with varicose veins requiring treatment and the actual care given. The factors influencing this need more detailed investigation.

Internal jugular thrombosis post venoplasty for chronic cerebrospinal venous insufficiency.

Chronic cerebrospinal venous insufficiency (CCSVI) is a hypothesis through which cerebral venous drainage abnormalities contribute towards the pathogenesis of multiple sclerosis. CCSVI venoplasty is already practised worldwide. We report the case of a 33-year-old lady with multiple sclerosis who underwent left internal jugular venoplasty resulting in iatrogenic jugular thrombosis requiring open thrombectomy for symptom relief. This occurred without insertion of a stent and while fully anticoagulated. Clinicians should be aware that endovenous treatment of CCSVI could cause paradoxical deterioration of cerebral venous drainage. Patients with complications post venoplasty are now presenting to geographically distant vascular units.

Ambulatory varicosity avulsion later or synchronized (AVULS): a randomized clinical trial.

OBJECTIVE A randomized clinical trial assessing the difference in quality of life and clinical outcomes between delayed and simultaneous phlebectomies in the context of endovenous truncal vein ablation. BACKGROUND Endovenous ablation has replaced open surgery as the treatment of choice for truncal varicose veins. Timing of varicosity treatment is controversial with delayed and simultaneous pathways having studies advocating their benefits. A previous small randomized study has shown improved outcomes for simultaneous treatment. METHODS Patients undergoing local anesthetic endovenous thermal ablation were randomized to either simultaneous phlebectomy or delayed varicosity treatment. Patients were reviewed at 6 weeks, 6 months, and 1 year with clinical and quality of life scores completed, and were assessed at 6 weeks for need for further varicosity intervention, which was completed with either ultrasound-guided foam sclerotherapy or local anesthetic phlebectomy. Duplex ultrasound assessment of the treated trunk was completed at 6 months. RESULTS 101 patients were successfully recruited and treated out of 221 suitable patients from a screened population of 393. Patients in the simultaneous group (n = 51) showed a significantly improved Venous Clinical Severity Score at all time points, 36% of the delayed group required further treatment compared with 2% of the simultaneous group (P < 0.001). There were no deep vein thromboses, with 1 superfificial venous thrombosis in each group. CONCLUSIONS Combined endovenous ablation and phlebectomy delivers improved clinical outcomes and a reduced need for further procedures, as well as early quality of life improvements.

The disparate management of superficial venous thrombosis in primary and secondary care

Objectives Superficial venous thrombosis is common and traditionally considered a benign condition requiring only symptomatic treatment. Recent evidence, however, advocates more aggressive management. Extensive guidance is available but actual practice is unknown. This study aimed to assess the management of superficial venous thrombosis by general practitioners (primary care physicians) and vascular surgeons. Methods A 19-question validated electronic survey was created and circulated by e-mail to general practitioners and vascular surgeons in the United Kingdom. The survey evaluated presentation, investigation and treatment of superficial venous thrombosis. Results Three hundred sixty-nine surveys were returned from 197 vascular surgeons and 172 general practitioners. Most clinicians saw less than 20 cases a year, with 40% of clinicians not performing any investigations. Venous duplex was the investigation of choice in over 55%. Treatment with anti-inflammatory drugs was widespread, but anticoagulation and compression were seldom prescribed. Follow-up and treatment duration were disparate. Discussion The management of superficial venous thrombosis varies widely despite good levels of evidence and guidance. Investigation and treatment of superficial venous thrombosis show marked differences both between and within groups. Improvements in education are required to optimise the treatment pathway and advance patient care.