Theophilus I. Emeto

Diagnosis and Monitoring of Abdominal Aortic Aneurysm: Current Status and Future Prospects

Abdominal aortic aneurysm (AAA) remains an important cause of morbidity and mortality in elderly men, and prevalence is predicted to increase in parallel with a global aging population. AAA is commonly asymptomatic, and in the absence of routine screening, diagnosis is usually incidental when imaging to assess unrelated medical complaints. In the absence of approved diagnostic and prognostic markers, AAAs are monitored conservatively via medical imaging until aortic diameter approaches 50-55 mm and surgical repair is performed. There is currently significant interest in identifying molecular markers of diagnostic and prognostic value for AAA. Here we outline the current guidelines for AAA management and discuss modern scientific techniques currently employed to identify improved diagnostic and prognostic markers.

Proteomic analysis of intra-arterial thrombus secretions reveals a negative association of clusterin and thrombospondin-1 with abdominal aortic aneurysm

OBJECTIVE Abdominal aortic aneurysm (AAA) is usually accompanied by the formation of a large volume of intra-luminal thrombus (ILT). ILT-derived proteins have been suggested as circulating markers for AAA. We conducted a proteomic study screening whole and hexapeptide ligand library (HLL) treated ILT explant secretions to identify potential ILT-derived markers for AAA. METHODS Unfractionated and HLL-treated ILT secretions from 3 AAA patients were analysed in parallel using liquid chromatography tandem mass spectrometry (LC-MS/MS). In silico analyses were employed to identify proteins with biomarker potential. Proteomic findings were validated by measuring serum concentrations of 2 representative ILT proteins in 313 AAA patients and 690 controls. RESULTS A total of 150 proteins were identified from thrombus conditioned media; HLL treatment enabled the detection of 53 previously unseen polypeptides. Gene ontology analysis revealed high representation of platelet-secreted proteins. Thrombospondin-1 (TSP-1) and clusterin were selected for further assessment. Serum TSP-1 and clusterin were negatively associated with AAA after adjusting for other risk factors. Odds ratio and 95% confidence intervals were 0.62, 0.41-0.94, and 0.50, 0.33-0.75, for men with serum TSP-1 and clusterin in the fourth compared to first quartiles, respectively. CONCLUSION This proteomic analysis has identified a group of proteins concentrated in AAA ILT. Assessment of circulating concentrations of two representative polypeptides suggests for the first time that the ILT selectively sequesters proteins rather than actively releasing them. Further work is required to assess the mechanisms underpinning this observation and the associated clinical implications.

Relevance of urocortins to cardiovascular disease.

Acquired cardiovascular diseases such as coronary heart disease, peripheral artery disease and related vascular problems contribute to more than one-third of worldwide morbidity and mortality. In many instances, particularly in the under developed world, cardiovascular diseases are diagnosed at a late stage limiting the scope for improving outcomes. A range of therapies already exist for established cardiovascular disease, although there is significant interest in further understanding disease pathogenesis in order to improve diagnosis and achieve primary and secondary therapeutic goals. The urocortins are a group of recently defined peptide members of the corticotrophin-releasing factor family. Previous pre-clinical work and human association studies suggest that urocortins have potential to exert some beneficial and other detrimental effects on the heart and major blood vessels. More current evidence however favours beneficial effects of urocortins, for example these peptides have been shown to inhibit production of reactive oxygen species and vascular cell apoptosis, and thus may have potential to antagonise the progression of cardiovascular disease. This review summarises published data on the potential role of urocortins in cardiovascular disease.

Oxidative stress and abdominal aortic aneurysm: potential treatment targets

Abdominal aortic aneurysm (AAA) is a significant cause of mortality in older adults. A key mechanism implicated in AAA pathogenesis is inflammation and the associated production of reactive oxygen species (ROS) and oxidative stress. These have been suggested to promote degradation of the extracellular matrix (ECM) and vascular smooth muscle apoptosis. Experimental and human association studies suggest that ROS can be favourably modified to limit AAA formation and progression. In the present review, we discuss mechanisms potentially linking ROS to AAA pathogenesis and highlight potential treatment strategies targeting ROS. Currently, none of these strategies has been shown to be effective in clinical practice.

Targets for medical therapy to limit abdominal aortic aneurysm progression

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Most AAAs are asymptomatic and screening programs have been introduced to identify AAAs at an early stage in some countries. There is currently no accepted therapy for early stage or small AAAs, which are frequently identified by such programs. In this review, we discuss work underway to identify targets for medical treatments to limit progression of small AAAs. Specifically we discuss studies, which have examined the potential of targeting inflammation, proteolysis, the renin-angiotensin system, the coagulation system and sex hormones as approaches to limiting AAA pathogenesis. As yet, none of the treatment targets have translated into an agent, which can effectively reduce AAA progression in clinical practice.

Proteomic and genomic analyses suggest the association of apolipoprotein C1 with abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is an important cause of mortality in the elderly. Mouse models are widely used to investigate AAA pathogenesis but their suitability for biomarker discovery is unexplored.

Mouse Models of Intracranial Aneurysm

Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell‐derived factor‐1, tumor necrosis factor‐α, the renin‐angiotensin system and the β‐estrogen receptor. An agreed clear, precise and reproducible definition of what constitutes an aneurysm in the models would assist in their use to better understand the pathology of intracranial aneurysm and applying findings to patients.

Emerging Therapeutic Potential of Nanoparticles in Pancreatic Cancer: A Systematic Review of Clinical Trials

Pancreatic cancer is an aggressive disease with a five year survival rate of less than 5%, which is associated with late presentation. In recent years, research into nanomedicine and the use of nanoparticles as therapeutic agents for cancers has increased. This article describes the latest developments in the use of nanoparticles, and evaluates the risks and benefits of nanoparticles as an emerging therapy for pancreatic cancer. The Preferred Reporting Items of Systematic Reviews and Meta-Analyses checklist was used. Studies were extracted by searching the Embase, MEDLINE, SCOPUS, Web of Science, and Cochrane Library databases from inception to 18 March 2016 with no language restrictions. Clinical trials involving the use of nanoparticles as a therapeutic or prognostic option in patients with pancreatic cancer were considered. Selected studies were evaluated using the Jadad score for randomised control trials and the Therapy CA Worksheet for intervention studies. Of the 210 articles found, 10 clinical trials including one randomised control trial and nine phase I/II clinical trials met the inclusion criteria and were analysed. These studies demonstrated that nanoparticles can be used in conjunction with chemotherapeutic agents increasing their efficacy whilst reducing their toxicity. Increased efficacy of treatment with nanoparticles may improve the clinical outcomes and quality of life in patients with pancreatic cancer, although the long-term side effects are yet to be defined. The study registration number is CRD42015020009.

Use of Nanoparticles As Contrast Agents for the Functional and Molecular Imaging of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta common in adults older than 65 years of age. AAA is usually imaged using ultrasound or computed tomography. Molecular imaging technologies employing nanoparticles (NPs) have been proposed as novel ways to quantify pathological processes, such as inflammation, within AAAs as a means to identify the risk of rapid progression or rupture. This article reviews the current evidence supporting the role of NP-based imaging in the management of AAA. Currently, ultrasmall superparamagnetic NPs enhanced magnetic resonance imaging appears to hold the greatest potential for imaging macrophage-mediated inflammation in human AAA.

High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency promotes angiotensin-II induced aneurysm in mice

Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearmans rho -0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19-0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1-/-ApoE-/-, n=20) and control mice (ApoE-/-, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1-/- ApoE-/- mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1-/-ApoE-/- mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1-/-ApoE-/- mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1-/-ApoE-/- mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.