Secondary prevention in patients with peripheral arterial disease: are we letting our patients down?
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Humans↗
Biomedical subjects
S Homer-Vanniasinkam
Publications and source records attributed to S Homer-Vanniasinkam.
Tissue engineering of vascular conduits.
BACKGROUND: Autologous conduits are not available in up to 40 per cent of patients with arteriopathy who require coronary or lower limb revascularization, and access sites for renal dialysis may eventually become exhausted. Synthetic prostheses achieve a poor patency rate in small-calibre anastomoses. This review examines how vascular tissue engineering may be used to address these issues. METHODS: A Medline search was performed, using the keywords "vascular tissue engineering", "small diameter vascular conduit", "vascular cell biology", "biomechanics", "cell seeding" and "graft endothelialization". Key references were hand-searched for relevant papers. RESULTS AND CONCLUSION: In vitro and in vivo approaches are currently being used for guided cell repopulation of both biological and synthetic scaffolds. The major clinical problem has been extended culture time (approximately 6 weeks), which precludes their use in the acute setting. However, recent advances have led not only to improved patency rates for prostheses, but also to a potential reduction in culture time. In addition, increased mobilization of endothelial progenitor cells in the presence of ischaemic tissue may increase the autologous cell yield for scaffold reseeding with further reduction in culture time.
Bioartificial Organs↗
The role of endothelial cell reactive antibodies in peripheral arterial disease.
OBJECTIVES: It is hypothesised that endothelial cell reactive antibodies (ECRA) play a role in the progression of PAD through activation of endothelial cells and the release of inflammatory cytokines. We aimed to test this hypothesis by assessing levels of ECRA, E-selectin and IL-6 in patients with PAD of varying severity in a case controlled study. DESIGN, MATERIALS, METHODS: Patients were assessed clinically and with ankle-brachial pressure indices. Patients with critical ischaemia (CI, n=30), stable claudicants (SC, n=30), and age-matched controls (AMC, n=20) were studied. Antibody, E-selectin and IL-6 levels were measured using ELISA. RESULTS: ECRA levels were significantly raised in the CI group over AMC. IL-6 levels were significantly elevated in both SC and CI over the control group and in CI over SC. There were no significant differences in E-selectin levels between the AMC, SC and CI. CONCLUSION: Our findings support the hypothesis that autoantibodies play a role in promoting PAD by elevating IL-6. The absence of an elevation in E-selectin in this study may be due to its short half-life, and casts doubt on its value as a marker of inflammation in atherosclerosis.
Aged↗
Ischaemic skeletal muscle increases serum ischaemia modified albumin.
OBJECTIVES: Ischaemia modified albumin (IMA) has been used as a marker of myocardial ischaemia but little is known about its production during ischaemia of other tissues. The clinical models of patients with intermittent claudication and major arterial surgery were used to investigate IMA production from ischaemic skeletal muscle. DESIGN: Prospective clinical study. MATERIALS AND METHODS: IMA was measured pre-operatively, at end ischaemia, and 5 min, 4, 24, 48, 72 and 144 h post-surgery in patients undergoing (a) revascularisation for intermittent claudication (IC, n=15), (b) abdominal aortic aneurysm repair (AAA, n=12) and controls (n=16). RESULTS: The median pre-operative IMA concentration in IC patients was significantly higher than the AAA group (88.3 versus 83.5 U/ml, p=0.036) and controls (88.3 versus 80.3 U/ml, p=0.031). IMA concentrations increased significantly during arterial clamping in both IC and AAA groups (88.3 versus 120.0 U/ml, p=0.001; 83.5 versus 118.8 U/ml, p=0.002, respectively) consistent with increased skeletal muscle ischaemia. In contrast, there was only a mild perioperative increase in the controls (80.3 versus 91.6 U/ml, p=0.012). CONCLUSIONS: Patients with intermittent claudication have significantly elevated IMA and skeletal muscle ischaemia during arterial surgery results in significantly increased circulating IMA. When IMA is used to detect myocardial ischaemia, ischaemic skeletal muscle must be excluded.
Adult↗
Effects of warm-up on exercise capacity, platelet activation and platelet-leucocyte aggregation in patients with claudication.
BACKGROUND: The effects of exercise and warm-up were investigated in patients with claudication. METHODS: This case-control crossover study involved two treadmill exercise tests, one preceded by a warm-up. Exercise continued until maximal leg pain (patients with claudication) or exhaustion (controls). Blood was taken before, and 5 and 60 min after exercise for flow cytometric analysis of platelet activation and platelet-leucocyte aggregation. RESULTS: Both cohorts (eight patients with claudication of median age 63 years and eight healthy controls of median age 63.5 years) demonstrated improvement in exercise capacity after warm-up (13.1 per cent, P = 0.012 and 15.6 per cent, P = 0.008 respectively). Platelet activation increased after exercise in patients with claudication (fibrinogen binding: 1.11 per cent before exercise versus 2.63 per cent after exercise, P = 0.008; P-selectin: 0.68 versus 1.11 per cent, P = 0.028). Neither agonist stimulation nor warm-up altered this trend. Platelet-leucocyte (PLA) and platelet-neutrophil (PNA) aggregation were similarly increased immediately after exercise in patients with claudication (PLA: 7.6 versus 13.0 per cent, P = 0.004; PNA: 6.8 versus 10.2 per cent, P = 0.012). These remained high 60 min after exercise only in patients with claudication, but recovered to baseline levels when preceded by warm-up. Warm-up significantly desensitized PNA after stimulation with 10 micromol/l adenosine 5'-diphosphate at all time points. CONCLUSION: Warm-up increased the exercise capacity of patients with claudication. Exercise induced a thromboinflammatory response, with PLA and PNA persistently increased after 60 min in patients with claudication, an effect diminished after warm-up.
Adenosine Diphosphate↗
Ischaemic preconditioning in transplantation and major resection of the liver.
BACKGROUND: Ischaemia-reperfusion injury (IRI) contributes significantly to the morbidity and mortality of transplantation and major resection of the liver. Its severity is reduced by ischaemic preconditioning (IP), the precise mechanisms of which are not completely understood. This review discusses the pathophysiology and role of IP in this clinical setting. METHODS: A Medline search was performed using the keywords 'ischaemic preconditioning', 'ischaemia-reperfusion injury', 'transplantation' and 'hepatic resection'. Additional articles were obtained from references within the papers identified by the Medline search. RESULTS AND CONCLUSION: The mechanisms underlying hepatic IRI are complex, but IP reduces the severity of such injury in several animal models and in recent human trials. Increased understanding of the cellular processes involved in IP is of importance in the development of treatment strategies aimed at improving outcome after liver transplantation and major hepatic resection.
Adenosine Triphosphate↗
Ischaemic preconditioning protects against ischaemia/reperfusion injury: emerging concepts.
INTRODUCTION: Ischaemic preconditioning (IP) has emerged as a powerful method of ameliorating ischaemia/reperfusion (I/R) injury to the myocardium. This review investigates whether this phenomenon is universally applicable in modulating I/R injury to other tissues. METHODS: A Medline search was conducted to identify both animal and human studies that described IP-induced protection from I/R injury in a variety of non-cardiac organ systems. Particular emphasis was placed on elucidation of underlying physiological concepts. RESULTS AND CONCLUSIONS: IP utilises endogenous mechanisms in skeletal muscle, liver, lung, kidney, intestine and brain in animal models to convey varying degrees of protection from I/R injury. To date there are few human studies, but recent reports suggest that human liver, lung and skeletal muscle acquire similar protection after IP. Specifically, preconditioned tissues exhibit reduced energy requirements, altered energy metabolism, better electrolyte homeostasis and genetic re-organisation, giving rise to the concept of 'ischaemia tolerance'. IP also induces 'reperfusion tolerance' with less reactive oxygen species and activated neutrophils released, reduced apoptosis and better microcirculatory perfusion compared to non-preconditioned tissue. Systemic I/R injury is also diminished by preconditioning. IP is ubiquitous but more research is required to fully translate these findings to the clinical arena.
Adaptation, Physiological↗
Increased nitrotyrosine production in patients undergoing abdominal aortic aneurysm repair.
BACKGROUND: Vascular inflammation is implicated in the pathogenesis of atherosclerosis and abdominal aortic aneurysm (AAA), and is thought to involve reactive species such as the nitric oxide-derived oxidant peroxynitrite. In the present study nitrotyrosine was measured as a stable marker of peroxynitrite production in vivo. METHODS: Perioperative blood samples were obtained from patients undergoing elective open or endovascular repair of an AAA and from patients with intermittent claudication, smoking aged-matched controls, non-smoking aged-matched controls and non-smoking young healthy controls. Plasma nitrotyrosine was measured by an enzyme-linked immunosorbent assay. RESULTS: The median plasma nitrotyrosine concentration in patients with an AAA (0.46 nmol nitrated bovine serum albumin equivalents per mg protein) was significantly higher than that in patients with intermittent claudication (0.35 nmol; P = 0.002), smoking controls (0.36 nmol; P = 0.001), non-smoking controls (0.35 nmol; P = 0.002) and young healthy controls (0.27 nmol; P < 0.001). Nitrotyrosine concentrations increased during early reperfusion in open AAA repair, but not during endovascular repair. AAA exclusion from the circulation reduced levels to control values (P = 0.001). CONCLUSION: Patients with an AAA had raised levels of circulating nitrated proteins compared with patients with claudication and controls, suggesting a greater degree of ongoing inflammation that was not related to smoking.
Adult↗
Treatment of venous leg ulcers with Dermagraft.
BACKGROUND: A number of different treatment approaches have been recommended for the treatment of venous ulceration, including local ulcer treatment, compression and drug therapy. Recent advances in tissue engineering have resulted in living tissues being developed for cutaneous wound repair and skin replacement. The aim of this pilot study was to compare the rate of healing of venous ulcers in patients treated with Dermagraft (a human fibroblast-derived dermal replacement) and compression therapy or compression therapy alone. METHODS: A total of 18 patients with venous ulceration of the leg were recruited into the pilot study. Ten patients were treated with Dermagraft and compression therapy, and eight patients were treated with compression therapy alone. Healing was assessed by ulcer tracing and computerised planimetry. Skin perfusion was measured by laser Doppler. RESULTS: Five (50%) of the patients treated with Dermagraft and one (12.5%) control patient had healed by the end of the 12-week study period (NS). The total ulcer area rate of healing and linear rate of healing was significantly improved in patients treated with Dermagraft (P=0.001 and P=0.006, respectively, Mann-Whitney U-test). The number of capillaries increased in both the treatment and control group. Peri-ulcer skin perfusion increased by 20% in patients treated with Dermagraft, compared with 4.9% in the control group. CONCLUSION: The data from this small pilot study suggests that Dermagraft is associated with improved healing of venous ulceration. Following this pilot study, further clinical studies are needed to confirm the validity of these results in 'hard to heal' venous leg ulcers.
Bandages↗
The role of endothelial cell reactive antibodies in peripheral vascular disease.
The mechanism by which a small but significant proportion of patients with peripheral vascular disease (PVD) rapidly progress to critical ischaemia is unclear. Both experimental and clinical data suggest a role for autoantibodies in the pathogenesis of atherosclerotic disease, particularly in the accelerated atherosclerosis seen in patients with systemic lupus erythematosus and the anti-phospholipid syndrome. This review examines the evidence for a role for endothelial cell reactive autoantibodies in PVD and the potential mechanisms by which these autoantibodies could contribute to the acceleration of atherosclerosis in a proportion of patients. The identification of such markers could lead to the identification of patients with PVD who are at risk of developing critical ischaemia and may warrant early and aggressive intervention.
Animals↗
The role of cilostazol in the treatment of intermittent claudication.
This paper represents a review, by experts, of current opinion and information on intermittent claudication (IC) and the role that cilostazol plays in its treatment. IC is a common and debilitating condition that has a significant adverse impact on health-related quality of life (HR-QoL). It is currently under-recognised as a powerful marker of increased cardiovascular (CV) risk. The clinical priority is secondary prevention -- sometimes referred to as best medical therapy aimed at reducing CV risk. However, the priority for most patients (often overlooked by clinicians) is symptom relief: an increase in walking distance leading to an improvement in HR-QoL. The symptoms of IC may be improved by exercise, pharmacotherapy, and when these are unsuitable or unsuccessful, endovascular or surgical intervention. Cilostazol is indicated for the improvement of maximal and pain-free walking distance in patients with IC who do not have rest pain or tissue necrosis. In clinical trials, cilostazol improved symptoms both objectively and subjectively, and also improved HR-QoL. Cilostazol is usually well tolerated, with adverse events being generally mild to moderate in intensity, and transient or resolved after symptomatic treatment (e.g. non-prescription analgesics). Such events only infrequently require permanent drug withdrawal. There are no interactions with other drugs commonly prescribed in patients with IC, such as statins and anti-platelet agents. Cilostazol also has a range of potentially beneficial effects that may in the future be proven to decrease CV risk and modify the underlying process of atherosclerosis. Cilostazol represents the best evidence-based pharmacological therapy available for the symptoms of IC and should be the first-line treatment for symptom improvement in appropriate patients. Based on the available treatment strategies, the paper presents a suggested algorithm for the management of IC highlighting the role of cilostazol.
Algorithms↗
The effects of margination and red cell augmented platelet diffusivity on platelet adhesion in complex flow.
The effects of platelet margination and enhanced platelet diffusivity, as induced by red blood cells, on the adhesion of platelets, were investigated for a range of haematocrits, under 2D axi-symmetric flow, simulating previous in vitro experiments [Microvasc. Res. 17 (1979), 238-262]. The effect of margination was incorporated via use of an elevated platelet inlet mass fraction, Phie, in a manner similar to that of Wootton [Ann. Biomed. Eng. 29 (2001), 321-329], and a shear and haematocrit dependent platelet diffusivity, according to the model presented by Zydney and Colton [Physico Chem. Hydrodyn. 10 (1988), 77-96] was used. A combination of the two models was required to simulate the deposition of platelets to a collagen coated surface, under the complex flow, which exhibited a recirculation zone and stagnation point. Results obtained showed qualitative agreement with in vitro results, for a range of haematocrits (11-50%), and also showed that the effects of margination were not linearly dependent on haematocrit. Agreement may be improved in future simulations by incorporating the effects of depleted cell concentrations in the vortex which have been observed previously [Phil. Trans. Roy. Soc. (Lond.) B279 (1977), 413-445]. It would also be advantageous to devise a full mathematical description for platelet margination effects as a function of shear rate and haematocrit and a description of the accompanying effect of apparent blood viscosity.
Blood Platelets↗
Effect of homocysteine on cytokine production by human endothelial cells and monocytes.
BACKGROUND: Hyperhomocysteinaemia is an independent risk factor in the development of cardiovascular disease. Although homocysteine has been shown to affect endothelial cell function, the mechanisms by which it induces disease states are still poorly understood. Here, we report the ability of homocysteine to influence inflammatory cytokine/chemokine production by human saphenous vein endothelial cells, peripheral blood monocytes and monocyte-derived macrophages. METHODS: Human saphenous vein endothelial cells, peripheral blood monocytes and monocyte-derived macrophages were treated with homocysteine (0.1-5 mmol/L) for 4 and/or 24h. Tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-8 production was measured in the cell culture media using commercially available enzyme-linked immunosorbent assays. RESULTS: Interleukin-6 production by human saphenous vein endothelial cells was significantly stimulated following a 24-h treatment with homocysteine, whilst IL-8 concentrations were inhibited after both 4- and 24-h treatments. Homocysteine was also found to stimulate IL-1beta production by human peripheral blood monocytes and TNF-alpha production by monocyte-derived macrophages. CONCLUSIONS: Overall, results from this study suggest that homocysteine alters the profile of cytokine/chemokine production by endothelial cells and macrophages. This altered profile may be important in the inflammatory events that initiate or enhance the development of atherosclerotic lesions.
Cell Size↗
Bacterial colonisation of Doppler probes on vascular surgical wards.
AIM: hospital acquired infections cost the NHS 1 pound sterling billion each year and medical equipment may act both as source and vector of nosocomial infection. This study examined bacterial contamination of Doppler ultrasound probes (USP) in routine use on vascular surgical wards in six hospitals and the knowledge of staff about the potential for cross infection from contaminated probes. METHODS: probe head impressions and swab cultures of probe holders were plated on mannitol salt agar before and after cleaning with a paper towel. Putative S. aureus isolates were identified to species level and susceptibility to selected antimicrobials tested. Concurrently, junior medical staff were surveyed about probe cleaning protocols. RESULTS: methicillin susceptible S. aureus was isolated from 2/21 (10%) with near confluent bacterial growth from six others (28%). The latter may have obscured low numbers of S. aureus. Further since swabs were plated without prior enrichment culture, it is likely that contamination with S. aureus might have been underestimated. No positive cultures were obtained after wiping the USP with a paper towel. 22/23 (95%) junior doctors failed to clean the USP prior to use. CONCLUSION: USP contamination with pathogenic bacteria occurs under "in-use" conditions and junior medical staff are unaware of simple measures to prevent this. Strict guidelines for USP cleaning between patient use should, therefore, be adopted particularly when monitoring postoperative graft patency.
Colony Count, Microbial↗
Graft infection.
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Blood Vessel Prosthesis↗
Patients with chronic critical limb ischaemia have reduced total antioxidant capacity and impaired nutritional status.
INTRODUCTION: it has previously been demonstrated that total antioxidant capacity (TAC) can help predict which patients undergoing femoro-distal reconstruction are susceptible to postoperative infections. AIMS: the aims of this study were to examine if TAC is influenced by the nutritional state of the patient and the degree of ischaemia. PATIENTS AND METHODS: thirty patients with rest pain (21 men and 9 women), with a median age of 69 years and fifteen controls (9 men and 6 women), median age of 66 years, were studied. Nutritional status was assessed using serum albumin, body mass index (BMI), maximum voluntary contraction using a hand grip dynamometer and bioelectrical impedance to determine lean body mass. Blood was also taken for total antioxidant capacity (TAC). RESULTS: patients with chronic critical limb ischaemia (CCLI) had a lower TAC than controls (752 vs 1,130 micromol/l, p<0.05 Mann-Whitney U -test). There was no difference in serum albumin concentration between the CCLI group compared with controls (31 mmol/L vs 35 mmol/L, p>0.05 Mann-Whitney U-test). There was also no difference in BMI (23 vs 27, p>0.05 U-test) between the two groups. The other markers of nutrition including, maximum voluntary contractions (28.6 kg/m(2)vs 37.4 kg/m(2), p<0.05 M-W U-test), and lean body mass (3.0 vs 3.8 M-W U-test), showed a significant reduction in the vascular patients. CONCLUSION: TAC is significantly reduced in patients with CCLI and this may, in part, be explained by their impaired nutritional status.
Aged↗
Evaluation of dermagraft as an alternative to grafting for open fasciotomy wounds.
Wounds produced following open fasciotomy can be healed by grafting but this requires a second operation. Is Dermagraft, a tissue-engineered human fibroblast-derived dermis that can be applied on an outpatient basis, a viable alternative?
Fasciotomy↗
Differences in the detection of cyclo-oxygenase 1 and 2 proteins in symptomatic and asymptomatic carotid plaques.
BACKGROUND: The expression of cyclo-oxygenase (COX) 1 and 2 has been demonstrated in atherosclerotic arteries. In the present study this was correlated with symptoms arising from a carotid plaque. METHODS: Carotid plaques from 12 asymptomatic patients were compared with 11 plaques from patients who had had neurological symptoms within the preceding 30 days. Sections were stained with haematoxylin and eosin, elastin van Gieson and goat antihuman antibodies to COX-1 and COX-2. Plaque morphology was correlated with neurological symptoms. The area with positive COX-1 and COX-2 staining was measured by computerized planimetry in entire cross-sections and in specific areas of the plaque. RESULTS: There was a significant association between cap thinning and plaque rupture with symptoms (P = 0.003). The percentage area of positive staining in entire cross-sections for both COX-1 and COX-2 was significantly greater in symptomatic plaques (P = 0.001 and 0.0004 respectively). Staining in symptomatic plaques was significantly greater in the cap (COX-1: P = 0.001; COX-2: P = 0.0001) and shoulder (COX-1: P = 0.008; COX-2: P = 0.007) regions of the plaque. COX-1 expression in the sclerotic area was not increased (P = 0.15) although COX-2 staining was significantly greater (P = 0.04). CONCLUSION: Both COX-1 and COX-2 detection was increased in symptomatic plaques. COX may contribute to plaque rupture and the onset of symptoms.
Aged↗