Potential of Novel EPO Derivatives in Limb Ischemia

Erythropoietin (EPO) has tissue-protective properties, but it increases the risk of thromboembolism by raising the haemoglobin concentration. New generation of EPO derivatives is tissue protective without the haematopoietic side effects. Preclinical studies have demonstrated their effectiveness and safety. This paper summarizes the development in EPO derivatives with emphasis on their potential use in critical limb ischaemia

Nitric Oxide Manipulation: A Therapeutic Target for Peripheral Arterial Disease?

Peripheral Arterial Disease (PAD) is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD

Toll-Like Receptors in Ischaemia and Its Potential Role in the Pathophysiology of Muscle Damage in Critical Limb Ischaemia

Toll-like receptors (TLRs) are key receptors of the innate immune system which are expressed on immune and nonimmune cells. They are activated by both pathogen-associated molecular patterns and endogenous ligands. Activation of TLRs culminates in the release of proinflammatory cytokines, chemokines, and apoptosis. Ischaemia and ischaemia/reperfusion (I/R) injury are associated with significant inflammation and tissue damage. There is emerging evidence to suggest that TLRs are involved in mediating ischaemia-induced damage in several organs. Critical limb ischaemia (CLI) is the most severe form of peripheral arterial disease (PAD) and is associated with skeletal muscle damage and tissue loss; however its pathophysiology is poorly understood. This paper will underline the evidence implicating TLRs in the pathophysiology of cerebral, renal, hepatic, myocardial, and skeletal muscle ischaemia and I/R injury and discuss preliminary data that alludes to the potential role of TLRs in the pathophysiology of skeletal muscle damage in CLI

Morphometric studies on pre- and paravertebral sympathetic neurons in the rat: Changes with age

Morphometric measurements have been made on rat sympathetic neurons at ages between 6 and 24 months. In neurons of the coeliac-superior mesenteric ganglion there is a marked decrease in the neuronal packing density between 12 and 18 months which is accompanied by increases in the size of the neurons and their nuclei. In the superior cervical ganglion, no changes in packing density are seen until 18 months after which a decrease occurs, accompanied by slight increases in the neuronal parameters. These post-maturation changes occurring throughout adult life reveal a continued dynamism of sympathetic neurons into old age as well as revealing further differences between populations of sympathetic neurons

Endovascular Aortic Aneurysm Repair (EVAR) Has Significantly Lower Perioperative Mortality in Comparison to Open Repair: A Systematic Review

Objective: The objective of this meta-analysis was to evaluate the effectiveness of endovascular abdominal aortic aneurysm repair (EVAR) in reducing inhospital mortality against open graft replace-ment for aortic aneurysm. Methods: Generic terms including EVAR, endovascular aneurysm repair and aortic endografting were used to search a variety of electronic databases. Based on selection criteria, decisions regarding inclusion and exclusion of primary studies were made. Results: A total of three randomized controlled trials on 1,468 patients were included. In the EVAR group, 12 of 759 (1.5%) patients died, compared to 33 of 709 (4.6%) patients who died in the open surgery group. In both the fixed and random effect models, EVAR was associated with statistically significantly lower perioperative mortality when compared to open surgical repair of aortic aneurysm. The risk ratio of 0.33 indicates that mortality is 3.3 times more likely in the open surgery group compared to the EVAR group. Conclusion: EVAR carries a threefold lower risk of perioperative death in comparison to open repair of abdominal aortic aneurysm. This early advantage must be offset against the increased need for later re-intervention and probable equivalence of long-term outcome. In older and high operative risk patients, EVAR should be the treatment of choice

Alterations in nitric oxide synthase isoforms in acute lower limb ischemia and reperfusion

Alterations in nitric oxide synthase (NOS) are implicated in ischemia and ischemia-reperfusion injury. Changes in the 3 NOS isoforms in human skeletal muscle subjected to acute ischemia and reperfusion were studied. Muscle biopsies were taken from patients undergoing total knee replacement. Distribution of the specific NOS isoforms within muscle sections was studied using immunohistochemistry. NOS mRNA levels were measured using real-time reverse transcription-polymerase chain reaction and protein levels studied using Western blotting. NOS activity was also assessed using the citrulline assay. All 3 NOS isoforms were found in muscle sections associated with muscle fibers and microvessels. In muscle subjected to acute ischemia and reperfusion, NOS I/neuronal NOS mRNA and protein were elevated during reperfusion. NOS III/endothelial NOS was also upregulated at the protein level during reperfusion. No changes in NOS II/inducible NOS expression or NOS activity occurred. In conclusion, alterations in NOS I and III (neuronal NOS and endothelial NOS) at different levels occurred after acute ischemia and reperfusion in human skeletal muscle; however, this did not result in increased NOS activity. In the development of therapeutic agents based on manipulation of the NO pathway, targeting the appropriate NOS isoenzymes may be important

Applicability of Glasgow Aneurysm Score and Hardman Index to Elective Endovascular Abdominal Aortic Aneurysm Repair

This retrospective study aimed to explore the role of Glasgow Aneurysm Score (GAS) and Hardman Index (HI) in predicting outcome after elective endovascular aneurysm repair (EVAR). Methods: All 71 patients who underwent elective EVAR in a single centre over 9 years were reviewed. Clinical data were used to classify patients into the three standard GAS tertiles and to score patients according to the HI. Results: Fifty-one patients scored ≥ 77 according to GAS. Actual and predicted mortality in this group were 3.9% and 9.3%. Seventeen patients scored between 69 and 77 with actual and predicted mortality of 0% and 4.1%. Three patients scored less than 69 with actual and predicted mortality of 0% and 2.4%. Ten patients scored ≥ 3 on the HI with actual and predicted mortality of 10% and 100%, respectively. Twenty-four patients scored 2 with actual and predicted mortality of 4.2% and 55%. Twenty-seven patients scored 1 with actual and predicted mortality of 0% and 28%, respectively. Ten patients scored 0 with actual and predicted mortality of 0% and 16%, respectively. The χ2 test showed extremely significant p value of 0.0001 in case of HI, and p value of 0.0800 for GAS, slightly less significant, probably due to the small sample size. Conclusion: Contrary to their role in ruptured and open aortic aneurysm repair, GAS and HI overestimate both mortality and morbidity following EVAR and are poor predictors of outcome