Association Between Serum MicroRNAs and Abdominal Aortic Aneurysm Diagnosis and Growth.

OBJECTIVE: This study aimed to examine the association between serum microRNAs (miRNAs) and diagnosis and growth of abdominal aortic aneurysm (AAA), and to test their diagnostic and prognostic value. METHODS: The expression levels of 800 miRNA tags were assessed in 108 patients with AAA, 12 age and sex matched healthy controls (HCs), and 12 patients with peripheral artery disease (PAD) using NanoString technology. Findings were assessed in an independent sample of 66 patients with AAA and 29 age and sex matched HCs by reverse transcriptase polymerase chain reaction. AAA growth was assessed by a median of three (interquartile range [IQR] 2, 3) repeat ultrasound scans over a median follow up of 1.1 (IQR 1.0, 2.0) years. The association between the miRNA and AAA diagnosis and growth was examined by regression and linear mixed effects analyses. The diagnostic and prognostic potential of the miRNAs were examined using area under the receiver operator characteristic curve (AUC), net re-classification index (NRI), and Cox hazard analyses. RESULTS: In comparison with HCs, a model combining clinical risk factors, let-7b-5p and miR-548n had an AUC of 98.0% (95% confidence interval [CI] 95.6 - 100.0; p = .003) for diagnosing AAA, which was a significant improvement over clinical risk factors alone (NRI 1.74; 95% CI 1.61 - 1.87; p < .001). Compared with PAD, a model combining clinical risk factors and miR-548n had an AUC of 99.6% (95% CI 98.9 - 100.0, p = .037) for diagnosing AAA, which was a significant improvement over clinical risk factors alone (NRI 1.79, 95% CI 1.68 - 1.91; p < .001). In the longitudinal cohort, none of the miRNAs were able to predict the likelihood of reaching surgical threshold diameter better than clinical risk factors alone. CONCLUSION: Serum let-7b-5p and miR548n significantly improved the ability to diagnose AAA. None of the miRNAs had independent prognosis value in predicting AAA growth.

Systematic Review of Case Reports of Bacillus Calmette-Guerin Vascular Infections.

BACKGROUND: Bacillus Calmette-Guerin (BCG) is a live attenuated strain of Mycobacterium bovis that has been used as immunotherapy against several malignancies. In particular, intravesical instillation of BCG has become a well-accepted adjuvant treatment for bladder cancer. BCG vascular infections are a rare complication of BCG therapy. Many aspects of these infections, including the presentations, risk factors, and treatment strategies, are poorly understood. Through a systematic review of the existing literature, we aimed to identify potential associations between this condition and patient characteristics, presentations, its treatments, and outcomes. METHODS: We searched the PubMed, MEDLINE, and Embase databases for cases of BCG vascular infections from inception to June 2021. English-language reports of BCG vascular infections were included. RESULTS: A total of 74 cases of BCG vascular infections were included. Seventy-three (99%) cases were male patients, all of whom were exposed to BCG through bladder instillation. Fifty (68%) cases were diagnosed more than 12 months after exposure to BCG. Twenty-six (35%) cases presented with arterial rupture at the time of diagnosis. Concurrent BCG infections in nonvascular locations were present in 37 (50%) cases. The most common locations of BCG vascular infection were the abdominal aorta (57%), prosthetic grafts (15%), and thoracic aorta (12%). The most common treatment for BCG infection was open repair with synthetic graft in situ replacement for the abdominal aorta and endovascular repair for the thoracic aorta. The 30-day mortality, among the 59 cases where these data were reported, was 10%. CONCLUSIONS: We observed that many aspects of BCG vascular infections are similar to other forms of vascular infections. The high incidence of rupture or fistulation and the propensity toward abdominal aortic involvement and its prognosis are similar to those described in other vascular infections. However, our study also highlights 2 idiosyncratic features of BCG vascular infections: association with male sex and concurrent musculoskeletal infections.

Diagnosis and Management of a Chronic Lower-Limb Wound in a Patient with Felty Syndrome.

ABSTRACT: The authors report the case of a 55-year-old patient with a chronic lower-limb wound thought to be secondary to vasculitis. This case illustrates the importance of maintaining a high index of suspicion for vasculitic ulcers in patients with autoimmune disease. Management considerations in this context are also discussed.

Epigenetics and Peripheral Artery Disease.

The term epigenetics is usually used to describe inheritable changes in gene function which do not involve changes in the DNA sequence. These typically include non-coding RNAs, DNA methylation and histone modifications. Smoking and older age are recognised risk factors for peripheral artery diseases, such as occlusive lower limb artery disease and abdominal aortic aneurysm, and have been implicated in promoting epigenetic changes. This brief review describes studies that have associated epigenetic factors with peripheral artery diseases and investigations which have examined the effect of epigenetic modifications on the outcome of peripheral artery diseases in mouse models. Investigations have largely focused on microRNAs and have identified a number of circulating microRNAs associated with human peripheral artery diseases. Upregulating or antagonising a number of microRNAs has also been reported to limit aortic aneurysm development and hind limb ischemia in mouse models. The importance of DNA methylation and histone modifications in peripheral artery disease has been relatively little studied. Whether circulating microRNAs can be used to assist identification of patients with peripheral artery diseases and be modified in order to improve the outcome of peripheral artery disease will require further investigation.

Barriers to screening and diagnosis of peripheral artery disease by general practitioners.

Peripheral artery disease (PAD) is a strong predictor of cardiovascular morbidity and mortality yet it is under-recognised and undertreated. General practitioners (GPs) are best positioned to detect patients with PAD. This article investigates awareness of PAD by GPs; the prevalence of screening for PAD and tools used for screening and diagnosis, in particular the ankle-brachial index (ABI); and the barriers to PAD screening and measurement of the ABI in the general practice setting. A cross-sectional survey of primary care practitioners was conducted between September 2011 and March 2012. A mail-out survey was distributed to 1120 GPs practising in Queensland, Australia: 287 (26%) responded; 61% of GPs reported screening for PAD; 58% of GPs reported 'never' measuring the ABI; and 70% reported using arterial duplex ultrasound as their first-line diagnostic tool. Equipment availability, time constraints and lack of training and skills were identified as the most significant barriers to screening and ABI testing. In conclusion, there are deficits in the utilisation of guideline recommendations relating to PAD screening and diagnosis by Australian GPs. Our data suggest that earlier detection of PAD may be achieved through GP education combined with increased access to ABI equipment or the availability of a more time-efficient test.

Peripheral arterial disease - screening in general practice.

BACKGROUND: As a manifestation of systemic atherosclerosis, peripheral arterial disease (PAD) signifies an increased risk of cardiovascular events. Peripheral arterial disease has received less attention than other atherosclerotic diseases, leading to under-diagnosis and under-treatment. Peripheral arterial disease affects approximately 10-15% of the general population, and approximately 50% of PAD patients are asymptomatic. OBJECTIVE: This article aims to review the literature on the rationale for screening for lower extremity PAD in the general practice setting, and to identify the barriers to screening for PAD experienced by general practitioners, with a focus on the Australian context. DISCUSSION: Screening for asymptomatic PAD among high risk groups has been recommended by major PAD authorities to increase early diagnosis. Screening for PAD using the ankle-brachial index can detect asymptomatic patients. Research into the effect of cardiovascular risk reduction therapies for asymptomatic patients is lacking, and available evidence is inconclusive. The prevalence of screening and barriers to screening experienced by Australian GPs has not yet been studied. Available data on the benefits of PAD screening is inconclusive, and further research is required to determine a survival benefit with treatment of asymptomatic PAD.

Ruptured Left Gastric Artery Aneurysm Associated with Fibromuscular Dysplasia.

Background: Fibromuscular dysplasia is a non-inflammatory, non-atherosclerotic vascular disease that commonly affects renal and carotid arteries but involvement of virtually any vascular territory has been observed.Research Design/ Study sample: This is a case report of a ruptured left gastric artery aneurysm as the first presentation of fibromuscular dysplasia.Data collection: After written consent from the patient, relevant clinical notes and imaging were retrospectively reviewed and critically analysed.Purpose: This case reiterates the importance of considering fibromuscular dysplasia as an uncommon cause of visceral artery aneurysms. In addition, this case shows that the impact of visceral artery vasospasm on endovascular access should not be underestimated and subsequent attempts can be successful after a period of resuscitation.Results: After initial difficulty in endovascular treatment due to visceral vasospasm, the case was successfully managed with with staged open ligation and endovascular embolization after a period of resuscitation.Conclusions: FMD is an important differential diagnosis to consider in cases of visceral aneurysms.

Intraoperative neurological changes in 1665 regional anaesthetic carotid endarterectomies predicts postoperative stroke.

BACKGROUND: To maximize the benefit of carotid endarterectomy (CEA) in stroke prevention its complication rate must be minimized. The purpose of this study was to report the outcomes of a large series of CEA carried out under regional anaesthesia with selective shunting, with particular emphasis on identifying predictors for perioperative stroke and mortality. METHODS: Between 1987 and 2003 the data for 1665 consecutive regional anaesthetic CEA carried out in 1495 patients were collected prospectively; awake neurological testing facilitated selective shunting. Preoperative data, intraoperative events and postoperative in-hospital complications were recorded and analysed. RESULTS: There were 38 non-fatal strokes (2.3%) and 10 deaths (0.6%), giving a combined stroke and mortality rate of 2.9%. Only patients who needed shunting were found to have significantly higher rate of postoperative stroke and mortality (7.0 vs 1.9%, P < 0.001). Patient characteristics, comorbidities, indication for operation (P = 0.34) and the degree of stenosis of the contralateral carotid artery (P = 0.65) were not found to be predictive of perioperative stroke or mortality, although the latter two were found to be predictive of the need for shunting (P < 0.001 and P = 0.002). CONCLUSION: Regional anaesthetic CEA is a safe and effective technique with excellent morbidity and mortality rates. The technique can be undertaken safely regardless of the indication for endarterectomy or the status of the contralateral carotid artery. Patients who developed intraoperative neurological changes requiring shunting are identified as high risk for perioperative stroke or mortality and should therefore be carefully monitored postoperatively.

A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms.

BACKGROUND AND AIMS: There is increasing interest in identifying novel methods for abdominal aortic aneurysm (AAA) diagnosis. Non-coding RNA molecules such as microRNAs (miRNAs) are stable within the circulation and may serve as biomarkers for AAA. This systematic review aimed to identify miRNAs associated with a diagnosis of human AAA based on currently published original research. METHODS: A systematic search of the MEDLINE and EMBASE databases identified studies assessing miRNA expression in abdominal aortic tissue or circulating blood from human AAA cases compared to non-aneurysmal controls. Data from included studies were extracted to assess methods and results after independent quality assessment by two reviewers. RESULTS: 15 studies were included in this review. 11 studies obtained aortic tissue samples from 195 AAA cases and 104 controls with normal aortas. Nine studies obtained circulating blood samples from 526 AAA cases and 441 controls. miR-21 was differentially expressed in AAA tissue in five separate studies, with four studies reporting upregulation and one reporting downregulation. Seven other miRNAs were differentially expressed in AAA tissue in two separate studies. 15 circulating miRNAs were differentially expressed in two or more separate studies. miR-155 and miR-29b were the only miRNAs differentially expressed in two separate tissue- and blood-based studies. 11 studies offered mechanistic explanations of the role of miRNAs in AAA pathology through exploration of gene targets. Three studies assessed the diagnostic potential of circulating miRNAs with receiver operating characteristic curves. Only one study assessed the prognostic potential of circulating miRNAs in predicting AAA growth. CONCLUSIONS: Several miRNAs have been found to be associated with human AAA. Their utility as AAA biomarkers requires further investigation.

Blockade of vascular smooth muscle cell proliferation and intimal thickening after balloon injury by the sulfated oligosaccharide PI-88: phosphomannopentaose sulfate directly binds FGF-2, blocks cellular signaling, and inhibits proliferation.

Percutaneous transluminal coronary angioplasty is a frequently used interventional technique to reopen arteries that have narrowed because of atherosclerosis. Restenosis, or renarrowing of the artery shortly after angioplasty, is a major limitation to the success of the procedure and is due mainly to smooth muscle cell accumulation in the artery wall at the site of balloon injury. In the present study, we demonstrate that the antiangiogenic sulfated oligosaccharide, PI-88, inhibits primary vascular smooth muscle cell proliferation and reduces intimal thickening 14 days after balloon angioplasty of rat and rabbit arteries. PI-88 reduced heparan sulfate content in the injured artery wall and prevented change in smooth muscle phenotype. However, the mechanism of PI-88 inhibition was not merely confined to the antiheparanase activity of this compound. PI-88 blocked extracellular signal-regulated kinase-1/2 (ERK1/2) activity within minutes of smooth muscle cell injury. It facilitated FGF-2 release from uninjured smooth muscle cells in vitro, and super-released FGF-2 after injury while inhibiting ERK1/2 activation. PI-88 inhibited the decrease in levels of FGF-2 protein in the rat artery wall within 8 minutes of injury. PI-88 also blocked injury-inducible ERK phosphorylation, without altering the clotting time in these animals. Optical biosensor studies revealed that PI-88 potently inhibited (Ki 10.3 nmol/L) the interaction of FGF-2 with heparan sulfate. These findings show for the first time the capacity of this sulfated oligosaccharide to directly bind FGF-2, block cellular signaling and proliferation in vitro, and inhibit injury-induced smooth muscle cell hyperplasia in two animal models. As such, this study demonstrates a new role for PI-88 as an inhibitor of intimal thickening after balloon angioplasty. The full text of this article is available online at http://www.circresaha.org.

Leukaemia inhibitory factor retards the progression of atherosclerosis.

OBJECTIVE: Our previous studies showed that the pleiotropic cytokine leukaemia inhibitory factor (LIF) inhibits the de novo formation of experimental atherosclerotic lesions. The present study examined whether LIF also inhibits progression of pre-existing atheroma. METHODS: Balloon angioplasty was performed on the right carotid arteries of 18 rabbits immediately before placing animals on a cholesterol-enriched diet. After 4 weeks, at which time the intima:media ratio (I:M) was 0.99+/-0.12 (n=6), osmotic minipumps containing LIF (n=6) or saline control (n=6) were inserted into the peritoneal cavity of each of the remaining rabbits for a further 4 weeks. Arteries were then harvested for analysis. RESULTS: Continuous administration of LIF for the final 4 weeks of an 8-week cholesterol-enriched diet completely inhibited lesion progression in injured carotid arteries (I:M 1.05+/-0.16) compared with the saline-treated group at 8 weeks (1.62+/-0.13; P<0.05). Similarly in contralateral uninjured carotid arteries, LIF treatment prevented an increase in I:M from a baseline of 0.11+/-0.01 at 4 weeks to 0.15+/-0.02 at 8 weeks compared with 0.40+/-0.04 for the saline-treated group at 8 weeks (P<0.05). LIF reduced the number of macrophages in the neointima of uninjured arteries, but had no effect on the cellular composition of injured arteries. LIF treatment normalised smooth muscle-dependent vasoreactivity to phenylephrine and sodium nitroprusside in both injured and uninjured arteries. Expression and activity of inducible nitric oxide synthase (iNOS) were up-regulated in response to hypercholesterolemia with levels further increased following endothelial denudation. With LIF treatment, iNOS expression was increased in uninjured arteries but marginally reduced in injured arteries. LIF receptors were expressed in both uninjured and injured arteries, with LIF treatment having no significant effect on expression levels. CONCLUSION: LIF prevents progression of pre-formed atherosclerotic plaques, affecting lesion size and vascular reactivity. LIF treatment has differential effects within the artery wall, depending on the presence or absence of de-endothelialisation injury.

Expression of heparan sulphate N-deacetylase/N-sulphotransferase by vascular smooth muscle cells.

Heparan sulphate is an important mediator in determining vascular smooth muscle cell (SMC) phenotype. The sulphation pattern of the heparan sulphate chains is critical to their function. We have examined the initial step in the biosynthesis of the sulphated domains mediated by the enzyme heparan sulphate N-deacetylase/N-sulphotransferase (NDST). Rabbit aortic SMC in primary culture exhibited NDST enzyme activity and expressed NDST-1 in their Golgi apparatus, with maximal expression in SMC 2 days after dispersal in primary culture confirmed by Western blot analysis. Endothelial cells, macrophages and fibroblasts expressed NDST-1 but had generally less intense staining than SMC, although SMC expression decreased with culture. The uninjured rat aorta also showed widespread expression of NDST-1. After balloon de-endothelialisation, NDST-1 could not be detected in SMC of the neointima in the early stages of neointimal formation, but was re-expressed at later time points (after 12 weeks). In human coronary arteries, SMC of the media and the diffuse intimal thickening expressed NDST-1, while SMC in the atherosclerotic plaque were negative for NDST-1. We conclude that SMC may regulate their heparan sulphate sulphation at the level of expression of the enzyme heparan sulphate NDST in a manner related to their phenotypic state.