Dissertations / Theses: 'Peripheral arterial obliterative disease'

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TOLVA, VALERIO STEFANO. "A successful experimental model for intimal hyperplasia prevention using a resveratrol delivering balloon." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/76760.

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Restenosis due to intimal hyperplasia is a major clinical problem that compromises the success of angioplasty and endovascular surgery. The pathogenesis of restenosis is multifactorial, involving such events as endothelial injury, inflammation, platelet activation, and hyperplasia of the intima, primarily due to vascular smooth muscle cell replication (vSMC). The incidence of intimal hyperplasia varies in different risk populations, e.g., diabetic patients, up to 35% of whom require bare metal stent implantation; clinical evidence has shown that this value is reduced but continues to cause problems after the implantation of drug-eluting stents (DES). Overall, however, despite many years of clinical experience with drug-eluting balloons (DEB), the number of large, high-quality, randomised clinical trials is low, and further data are urgently needed across the spectrum of clinical indications. Taxol and other cytostatic drugs destroy a cell's ability to use its cytoskeleton in a flexible manner, and, considering the clinical results, further research on a more physiologic mechanism of action should be pursued. Antioxidants are currently under investigation due to their protective activity within the vessels. Rosenbaum et al. showed that the endothelialisation of prosthetic grafts was significantly reduced, and anastomotic hyperplasia, significantly increased in rabbits on a high cholesterol diet. Treatment with an antioxidant improves endothelial cell coverage, decreases intimal hyperplasia and reduces oxidative stress, promoting the patency of prosthetic grafts. Resveratrol is a polyphenolic phytoalexinic antioxidant that is produced by grapes and other plants in response to injurious infections. The molecular structure of RSV, unfortunately, reduces its immediate clinical application for three main reasons: 1) its status as a highly lipophilic molecule; 2) its fast drifting from the TRANS- to CIS-phase, representing an oxidised and inactive state, respectively; and 3) its low circadian bioavailability for rapid hepatic metabolism. As consequence of these features, the oral bioavailability of RSV is negligible since it is rapidly conjugated to improve the solubility of the compound. The disposition of 14C-labeled RSV, as orally and intravenously administered in normal, healthy volunteers, was evaluated to estimate the extent of the oral dose absorbed, the bioavailability of the unchanged drug, and the drug’s metabolic phase. RSV demonstrated a high oral absorption but a rapid and extensive metabolism, resulting in only trace amounts of unchanged RSV remaining until systemic circulation. Five major metabolites were detected in the urine samples14, plasma and colo-rectal cancer tissues, although all were only measured qualitatively due to a lack of available reference materials. Metabolite 1 (M1) was a RSV monoglucuronide, and metabolite 2, an isomeric RSV monoglucuronide (M2), was found in greater abundance. M3 was a dihydroresveratrol monoglucuronide, whereas M4 and M5 were two poorly resolved RSV sulphates, i.e., a resveratrol monosulphate (M4) and a dihydroresveratrol sulphate (M5). Despite the controversial results on the efficacy of RSV reported in the literature, very recent data obtained in colon cancer cells have supported the notion that RSV, in spite of its low bioavailability, is able to act through its metabolites, mainly the sulpho-conjugate but also the combination of sulphate/glucuronide derivatives. Despite the wide literature on RSV, only few preclinical studies have demonstrated the efficacy of RSV in an animal model or investigated the possibility of locally administering this antioxidant by eluting stents. Based on our experience, we decided to set up a sterile, injectable, and hydrophilic RSV-containing compound (RSV-c). This solution was locally administered in the common iliac artery of adult male New Zeeland white rabbits using a dedicated device.

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Sigvant, Birgitta. "Epidemiological aspects of peripheral arterial disease." Stockholm : Department of Molecular Medicine and Surgery, Karolinska Institutet, 2009. http://diss.kib.ki.se/2009/978-91-7409-670-5/.

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3

Askew, Christopher D. "Exercise intolerance in peripheral arterial disease." Thesis, Queensland University of Technology, 2002. https://eprints.qut.edu.au/15869/1/Christopher_Askew_Thesis.pdf.

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Patients with Peripheral Arterial Disease have a reduced capacity for exercise, the exact causes of which are poorly understood. This thesis investigated alternative testing procedures that aim to provide a more complete and precise description of the exercise capacities of these patients. Furthermore, the potential roles of gastrocnemius muscle fibre morphometry, capillary supply and glycogen stores in the exercise tolerance of PAD patients were studied. Study one aimed to determine the effect of test repetition on maximal exercise performance and test-to-test variability in PAD patients using an incremental treadmill walking test (T) (n=5), an incremental cycle test (C) (n=5), and incremental endurance (PF-endurance) and maximal strength (PF-strength) plantar flexion tests (n=5). Tests were conducted once per week for eight weeks. Performance was stable on the T (~530 s) and C (~500 s) tests across the eight weeks. Test-to-test variance on T decreased from 16%CV (CV: coefficient of variation) to 6%CV (p=.21,NS), and from ~8%CV to 2%CV on C (p<.05) over the eight week period. Variance of peak gas exchange variables tended to decrease with performance variance on both tests; however, other physiological variables, and the associated variance levels, were stable throughout the study. PF strength (635-712N) gradually increased over the initial 2-3 weeks (p<.05) which was accompanied by a reduction in variance from ~8%CV to ~3%CV (p<.05). Similarly, PF endurance increased over the first two weeks (~32,000 to 41500 N.s-1) while variance of this measure fell from ~21%CV to ~10%CV (p<.05) over the study duration. It is concluded that the implementation of familiarisation sessions leads to a reduction in whole body and local calf muscular performance variance in patients with PAD. Using a randomised crossover design, study two aimed to compare performance and the physiological and symptomatic responses between a T test and a C test in 16 patients with PAD. Peak exercise time on C (690 s) was greater than that on T (495 s); however the two were significantly correlated (n=16, r=.69, p<.05). Peak HR (120 bpm), VO2 (~1.22 l.min-1) and rate pressure product (~20') did not differ between the two tests, nor did the post exercise ankle pressure (T: 56; C: 61 mmHg). In two subjects with lower back pain during C, the ankle pressure of their "worst" limbs failed to fall by >10mmHg. Performance on both the T and C tests was closely related to the onset of leg symptoms; however the site of pain during C was much more variable than during T. Incremental cycle testing would overcome some of the limitations of treadmill testing (e.g. measurement of mechanical work), and it appears to be an acceptable alternative for measuring the exercise capacity and physiological exercise responses in known claudicants. Use of cycle ergometry for the diagnosis of PAD requires testing in the general population. Study three aimed to compare whole body (T test and C test) and local calf muscular (PF strength and endurance) exercise performance between 16 PAD patients (age: 63 ± 2; BMI: 25.9 ± 1.1) and 13 healthy, sedentary control (CON) subjects (age: 62 ± 1; BMI: 25.9 ± 0.4), and to describe relationships between the whole body and local calf muscular exercise capacities within the two groups. Furthermore, this study aimed to compare several histochemical characteristics of the medial gastrocnemius muscle fibres between PAD and CON, and to establish whether these factors were related to the exercise capacities of both groups. Maximal performance on T was 59% lower in the PAD group compared with the CON group, as was performance on C (50%), PF strength (25%), and PF endurance (58%). Compared with CON, PAD patients had a lower estimated calf muscle mass and a slight reduction (10%) in muscle fibre size (p=.14, NS). They also had a lower proportion of type I fibres (PAD: 49%; CON: 62%) that was offset by a greater proportion of type IIA fibres (PAD: 27%; CON: 16%), and a reduction in the capillary contacts per muscle fibre (PAD: 1.63; CON: 2.12) compared with CON. When expressed relative to fibre area there were no differences in capillarisation between PAD and CON; however this index was significantly related to resting and post exercise ABI in the PAD patients. There were no differences in the mixed muscle [glycogen], nor the optical density of glycogen in the individual fibres, between the two groups. PF endurance was poorly predictive of walking performance, and did not correlate with any of the morphological variables in both groups. Calf muscle mass correlated with PF strength (r=.59 - .62), and strength was correlated with T performance (r= .61 - .63) in both groups. In the PAD patients, T performance was correlated with the cross sectional area (n=12, r=.72, p<.05), capillary contacts (n=10, r=.81, p<.05) and glycogen density (n=9, r=.81, p<.05) of type I fibres. This study confirms that a reduction in calf strength, which appears to be mediated through muscle atrophy, plays some role in the reduced exercise capacity of claudicants. While both fibre area and capillary supply seem to be of relevance to the exercise capacity of PAD patients, these two factors are closely linked and further research is required to establish the determinants, and relative importance of both. An important, and possibly limiting role of carbohydrate oxidisation in PAD patients is supported by the strong relationship between type I glycogen stores and whole body exercise capacity.

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4

Askew, Christopher D. "Exercise intolerance in peripheral arterial disease." Queensland University of Technology, 2002. http://eprints.qut.edu.au/15869/.

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Patients with Peripheral Arterial Disease have a reduced capacity for exercise, the exact causes of which are poorly understood. This thesis investigated alternative testing procedures that aim to provide a more complete and precise description of the exercise capacities of these patients. Furthermore, the potential roles of gastrocnemius muscle fibre morphometry, capillary supply and glycogen stores in the exercise tolerance of PAD patients were studied. Study one aimed to determine the effect of test repetition on maximal exercise performance and test-to-test variability in PAD patients using an incremental treadmill walking test (T) (n=5), an incremental cycle test (C) (n=5), and incremental endurance (PF-endurance) and maximal strength (PF-strength) plantar flexion tests (n=5). Tests were conducted once per week for eight weeks. Performance was stable on the T (~530 s) and C (~500 s) tests across the eight weeks. Test-to-test variance on T decreased from 16%CV (CV: coefficient of variation) to 6%CV (p=.21,NS), and from ~8%CV to 2%CV on C (p<.05) over the eight week period. Variance of peak gas exchange variables tended to decrease with performance variance on both tests; however, other physiological variables, and the associated variance levels, were stable throughout the study. PF strength (635-712N) gradually increased over the initial 2-3 weeks (p<.05) which was accompanied by a reduction in variance from ~8%CV to ~3%CV (p<.05). Similarly, PF endurance increased over the first two weeks (~32,000 to 41500 N.s-1) while variance of this measure fell from ~21%CV to ~10%CV (p<.05) over the study duration. It is concluded that the implementation of familiarisation sessions leads to a reduction in whole body and local calf muscular performance variance in patients with PAD. Using a randomised crossover design, study two aimed to compare performance and the physiological and symptomatic responses between a T test and a C test in 16 patients with PAD. Peak exercise time on C (690 s) was greater than that on T (495 s); however the two were significantly correlated (n=16, r=.69, p<.05). Peak HR (120 bpm), VO2 (~1.22 l.min-1) and rate pressure product (~20') did not differ between the two tests, nor did the post exercise ankle pressure (T: 56; C: 61 mmHg). In two subjects with lower back pain during C, the ankle pressure of their "worst" limbs failed to fall by >10mmHg. Performance on both the T and C tests was closely related to the onset of leg symptoms; however the site of pain during C was much more variable than during T. Incremental cycle testing would overcome some of the limitations of treadmill testing (e.g. measurement of mechanical work), and it appears to be an acceptable alternative for measuring the exercise capacity and physiological exercise responses in known claudicants. Use of cycle ergometry for the diagnosis of PAD requires testing in the general population. Study three aimed to compare whole body (T test and C test) and local calf muscular (PF strength and endurance) exercise performance between 16 PAD patients (age: 63 ± 2; BMI: 25.9 ± 1.1) and 13 healthy, sedentary control (CON) subjects (age: 62 ± 1; BMI: 25.9 ± 0.4), and to describe relationships between the whole body and local calf muscular exercise capacities within the two groups. Furthermore, this study aimed to compare several histochemical characteristics of the medial gastrocnemius muscle fibres between PAD and CON, and to establish whether these factors were related to the exercise capacities of both groups. Maximal performance on T was 59% lower in the PAD group compared with the CON group, as was performance on C (50%), PF strength (25%), and PF endurance (58%). Compared with CON, PAD patients had a lower estimated calf muscle mass and a slight reduction (10%) in muscle fibre size (p=.14, NS). They also had a lower proportion of type I fibres (PAD: 49%; CON: 62%) that was offset by a greater proportion of type IIA fibres (PAD: 27%; CON: 16%), and a reduction in the capillary contacts per muscle fibre (PAD: 1.63; CON: 2.12) compared with CON. When expressed relative to fibre area there were no differences in capillarisation between PAD and CON; however this index was significantly related to resting and post exercise ABI in the PAD patients. There were no differences in the mixed muscle [glycogen], nor the optical density of glycogen in the individual fibres, between the two groups. PF endurance was poorly predictive of walking performance, and did not correlate with any of the morphological variables in both groups. Calf muscle mass correlated with PF strength (r=.59 - .62), and strength was correlated with T performance (r= .61 - .63) in both groups. In the PAD patients, T performance was correlated with the cross sectional area (n=12, r=.72, p<.05), capillary contacts (n=10, r=.81, p<.05) and glycogen density (n=9, r=.81, p<.05) of type I fibres. This study confirms that a reduction in calf strength, which appears to be mediated through muscle atrophy, plays some role in the reduced exercise capacity of claudicants. While both fibre area and capillary supply seem to be of relevance to the exercise capacity of PAD patients, these two factors are closely linked and further research is required to establish the determinants, and relative importance of both. An important, and possibly limiting role of carbohydrate oxidisation in PAD patients is supported by the strong relationship between type I glycogen stores and whole body exercise capacity.

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5

Barker, Glenn A. "Carbohydrate metabolism in peripheral arterial disease." Thesis, Queensland University of Technology, 2003. https://eprints.qut.edu.au/36790/1/36790_Digitised%20Thesis.pdf.

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Peripheral arterial disease results in varying degrees of functional disability. Although principally a disease of the vascular tree, evidence demonstrates a significant contribution from metabolic alterations within ischaemically affected skeletal muscle. This thesis was concerned with better characterising the nature of these metabolic alterations, and their contribution to the functional disability in PAD patients. It also examined the efficacy of dietary carbohydrate supplementation as a therapeutic intervention in PAD. The activity of the pyruvate dehydrogenase complex (PDH) is an important determinant of carbohydrate metabolism, experiment I examined the possibility that the active fraction of PDH (PDHa) is lower than normal in skeletal muscle of patients with intermittent claudication (IC) or patients with chronic limb ischaemia and rest pain (RP). A resting muscle biopsy was taken from the medial gastrocnemius of 11 patients with IC, seven patients with RP and eight healthy control subjects (CON). Biopsies were analysed for PDHa, acetylcarnitine, glycogen and phosphocreatine. In the RP group resting PDHa was 60 percent lower than CON (0.19 ± 0.21 versus 0.53 ± 0.27 mmol.min·1.kg·1 wet wt), but not significantly different (p = 0.09) from IC (0.42 ± 0. i 7 mmol.min·1.kg·1 wet wt); PDHa was not different between IC and CON (p = 0.54). There was no difference in muscle acetylcarnitine and glycogen between the groups, nor were there any associations between PDHa and resting acetylcamitine. Further work is warranted in determining the significance of the reduction in PDHa in the RP group, its relationship to symptoms and amenability to treatment. Study two examined the extent to which resting metabolic changes within ischaemic muscle account for the exercise intolerance in PAD patients with intermittent claudication. Specifically, study two tested the hypothesis that walking intolerance in intermittent claudication (IC) is related to both slowed whole body V02 kinetics and depressed activity of the active fraction of pyruvate dehydrogenase (PDHa) in skeletal muscle. Ten patients displaying IC and eight healthy controls performed two familiarisation and then three maximal incremental walking tests. From these tests averaged estimates of walking time, peak V02 and the time constant of V02 ('t) during submaximal walking were obtained. A muscle sample was taken from the medial gastrocnemius muscle at rest and analysed for PDHa and several other biochemical variables. Walking time and peak V02 were -50 percent lower in IC than controls, and 't was 2-fold higher (p < 0.05). 't was significantly correlated with walking time (r = - 0.72) and peak V02 (r = -0.66) in IC; but not in controls. Resting muscle PDHa tended to be correlated with 't (r = -0.56; p = 0.09) in IC; but not in controls (r = -0.14). A similar correlation was observed between resting ABI and 't (r = -0.63, p = 0.05) in IC. This data demonstrates that impaired V02 kinetics contribute to the reduced walking capacity in IC, and that slowed V02 kinetics may result from both haemodynamic and metabolic factors in claudicants. The final experiment examined the effects of a three-day dietary carbohydrate supplementation regime on walking capacity in claudications and in healthy control subjects. Previous work has demonstrated an ergogenic effect of CHO loading in claudicants, but failed to accurately quantify the magnitude of the improvement in walking capacity, or potential mechanisms involved in the effect. Continuing from study II, eleven PAD patients with intermittent claudication and eight control subjects performed a further two maximal treadmill tests, each preceded by a three day supplemental period. In a randomised blinded fashion, all subjects consumed a total of 700g of glucose polymer dissolved into 6 L of water (CHO), or an equal volume of artificially sweetened water (PLAC) (2Uday with meals). From baseline, walking time was significantly improved in the IC group (660 ± 331 s to 697 ± 313 s) and significantly reduced in the CON group (1335 ± 264 s to 1290 ± 250 s) following CHO. In the IC group the improvement in walking capacity was inversely associated with the initial walking capacity of the patient (r = -0.73, p < 0.05) such that for patients with an initial walking capacity of less than 400 s (n=4) there was a 23% improvement following CHO. Resting, steady state, peak V02 and the kinetics of the transitional response ('t) were unaffected by CHO, however there was an association between the change in walking time and change in 't in the IC group only (r = -0.70, p < 0.05). Resting, steady-state and maximal RER was significantly elevated following CHO in both groups. In the CON group the reduction in walking time was strongly associated with increases in body weight (r = 0.87, p < 0.05). There was no association between the change in walking performance and any muscle measure in the CON group, but in IC the improvement in walking time was inversely associated with resting PDHa (r = -0.65, p < 0.05). This data demonstrates the benefits of CHO supplementation are mainly confined to those patients with greater functional impairments and may be mediated via improvements in V02 uptake kinetics resulting from metabolic alterations within the exercising musculature.

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Bauer, Timothy Alan. "Oxygen uptake kinetics in peripheral arterial disease." Diss., Manhattan, Kan. : Kansas State University, 2005. http://hdl.handle.net/2097/125.

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Welten, Gijs. "Prognosis of patients with peripheral arterial disease." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/13949.

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8

Widener, Jeanne Malcom. "Disease Severity and Disability in Persons with Peripheral Arterial Disease." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1204652303.

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9

Cleanthis, T. M. "Platelet function in lower limb peripheral arterial disease." Thesis, University of Newcastle upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432504.

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Koelemay, Mark Jan Wilhelm. "Non-invasive assessment of peripheral arterial occlusive disease." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/85398.

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11

Lewis, M. H. "Peripheral arterial disease from aetiology to surgical management." Thesis, University of South Wales, 2013. https://pure.southwales.ac.uk/en/studentthesis/peripheral-arterial-disease-from-aetiology-to-surgical-management(7defd31a-6995-4fc7-9302-2fced42b5982).html.

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The work presented includes over thirty peer reviewed published manuscripts based on studies undertaken during my surgical career. As Principal Investigator, I led the study conception/design/data acquisition/analysis/interpretation and was involved with writing the final drafts of all manuscripts prior to their formal submission to high impact factor peer-reviewed specialist journals. The thesis is divided into subsections reflecting my development and different interests within surgery. The subsections start with my learning basic research principles, moving onto clinical problem solving in general surgical dilemmas, followed by a collection of papers in my subspecialty of vascular surgery. The work culminates with a group of papers focused on aneurysmal disease, specifically, abdominal aortic aneurysms (AAA), the clinical impact of which has had a bearing on the introduction of a National AAA Screening Program in Wales in 2013. I conclude these sections with a collection of papers that reflect my long term commitment to surgical training both at regional level (as Secretary and Deputy Chairman to the Higher Surgical Training Committee and Chairman of the Basic Surgical Training Committee) and national level including my involvement with the Four Royal Colleges of Surgeons for the Intercollegiate Examinations in General Surgery. This examination is undertaken at completion of junior surgical training and used to confirm a doctor's competence for safe independent practice as a consultant. In conclusion, over forty years of academic research during my career as a vascular surgeon has provided unique insight into the pathophysiology, treatment and ultimately prevention of artherosclerotic disease. These findings have improved health policies in Wales and significantly reduced patient morbidity and mortality.

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Christman, Sharon K. "Intervention to slow progression of peripheral arterial disease." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1054059524.

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Christman, Sharon Klopfenstein. "Intervention to slow progression of peripheral arterial disease." Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1054059524.

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Thesis (Ph. D.)--Ohio State University, 2003.
Title from first page of PDF file. Document formatted into pages; contains xiii, 123 p.; also includes graphics (some col.). Includes bibliographical references (p. 114-123). Available online via OhioLINK's ETD Center

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Archer, Colleen E. "Accommodating pain-free exercise therapy for peripheral arterial disease." [Gainesville, Fla.] : University of Florida, 2006. http://purl.fcla.edu/fcla/etd/UFE0015221.

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Aly, Sayed Awad Abdel Fattah. "Duplex ultrasound in the assessment of peripheral arterial disease." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299775.

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O'Brien, Claire Margaret. "Antioxidants and peripheral arterial disease : a case-control study." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428704.

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Maan, Neeti. "i-Nitrite Therapy for Treatment of Peripheral Arterial Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1339162099.

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Donnan, Peter Thomas. "A study of risk factors for peripheral arterial disease." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/19694.

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This thesis set out to consider risk factors, in isolation and in combination, for symptomatic and asymptomatic Peripheral Arterial Disease (PAD), which unlike Coronary Heart Disease, has not been undertaken in a random sample from the general population aged 55-74 years. The results showed that the risk factors in relationship to the Ankle Brachial Pressure Index (ABPI), an indicator of the extent of asymptomatic and symptomatic PAD, differed for men and for women and for smokers and non-smokers. In women smoking was the main risk factor, while blood viscosity and fibrinogen although univariately related to the ABPI, were not independent risk factors. In men who had never smoked, nonHDL cholesterol and diabetes were the important risk factors. In men who had ever smoked there were synergistic effects of smoking on the relationships between the ABPI and fibrinogen, blood viscosity, leisure activity, and energy adjusted vitamin C. Other independent risk factors for men who had ever smoked were diabetes, social class, nonHDL and HDL cholesterol. This suggests that in considering arterial disease, analyses should be carried out separately for men and women and perhaps for smokers and non-smokers. These results indicated that some health education programmes could be aimed at specific groups, such as female smokers. On the other hand dietary programmes to reduce cholesterol level could be aimed at the general population. Finally, the calculation of power and sample size for epidemiological studies showed that the simple two group comparison calculations generally used underestimated the sample size required when adjusting for numerous confounders and when subgroup analyses are likely, as in a cross-sectional study.

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Hou, Xiang-Yu. "Exercise performance and mitochondrial function in peripheral arterial disease." Thesis, Queensland University of Technology, 2002. https://eprints.qut.edu.au/36778/1/36778_Digitised%20Thesis.pdf.

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Peripheral arterial disease (PAD) is an atherosclerotic disease in the peripheral arteries, which reduces blood supply to the lower extremities. Intermittent claudication is the symptom that develops early in PAD patients and is accompanied by the haemodynamic finding of a fall in systolic blood pressure at the ankles following exercise. In PAD patients, exercise performance is not well correlated with haemodynamic measurements and other mechanisms have been suggested to account for the impairment. There have been reports about the impaired mitochondrial metabolism (eg, decreased activities of mitochondrial enzymes) and abnormal mitochondrial structure in the skeletal muscle in PAD patients. It is not known, however, whether mitochondrial ATP production is impaired in the skeletal muscle in PAD. Whether the mitochondrial function is impaired in PAD patients, and whether the impaired mitochondrial function in the muscle contributes to the impaired exercise performance in PAD patients is unknown. The object of this work is to explore the mitochondrial function in the skeletal muscle of PAD patients and its relationship to exercise performance. Impaired exercise performance in PAD patients is evaluated using a treadmill walking performance test, which is closely correlated to patients' daily activity performance. Treadmill walking however, in addition to being influenced by local muscle factors, is influenced by central contributions, such as cardiac output and the central nervous system. As walking is limited by intermittent claudication in PAD patients localized in the legs, it would be valuable to develop a local calf muscle performance test to better understand the underlying pathophysiology in PAD. Such a protocol has not been used previously in experiments involving PAD patients. Hence, the research aim for Study 1 was to establish a calf muscle performance test protocol and to investigate its variability. Fourteen healthy control subjects and eight PAD patients undertook the maximal plantar flexion test once a week for five weeks using a Kin-Com Dynamometer. In the traditional assessment, the total impulse and peak impulse are the variables that were measured as representing the calf muscle performance. Both these variables are significantly lower in PAD patients than in controls. Alternatively, by applying simple mathematical models, the muscle function dimensions of endurance, strength and fatigability can be investigated in a single test. Compared with control subjects the PAD patients had lower muscle endurance, lower muscle strength, higher fatigue index, but no difference were found in magnitude or rate-of-fatigue. The variability of the test was different for different estimated parameters of the models, with the highest variability in muscle fatigability (rate of fatigue, CV=75% in controls) and the lowest variability in muscle strength (CV=16% in controls). The variability of the traditional assessment parameters, which included total impulse and peak impulse, was around 13% in controls and 18- 24% in PAD patients for the five tests. Based on these findings the calf muscle performance test can be applied in PAD patients to investigate different muscle function dimensions. While many of the dimensions were impaired in PAD patients compared with controls, the high variability of some of the parameters have to be considered during its application. Having established a local calf muscle performance test, the aim of Study 2 was to explore the relationship between the calf muscle performance and the traditional treadmill walking performance. Seventeen PAD patients and fourteen control subjects were tested using both the calf muscle performance test described earlier and walking performance test. The walking performance was tested using a graded treadmill protocol. The total walking time was significantly lower in PAD than that in control subjects. No variable of calf muscle performance correlated with walking performance in control subjects. However, in PAD patients, a number of calf muscle performance variables correlated with walking performance. The total impulse and the peak impulse in the best legs (higher ABI) tended to correlate with pain-time. In simple mathematical models, the muscle endurance in the worst legs (lower ABI) correlated positively with pain-walking time, and the muscle fatigue-index in the worst legs correlated negatively with total walking time. In conclusion, in PAD patients, some dimensions of calf muscle performance correlated with walking performance. This suggests that some factors of local calf muscle performance might contribute to the impaired walking performance in PAD patients. The research aim for Study 3 was to investigate a number of calf muscle physiological factors, and to ascertain their relationship with calf muscle and walking performance in PAD patients and control subjects. The physiological factors examined include ankle brachial pressure index (ABI), calf muscle weight, calf blood flow, and skeletal muscle mitochondrial ATP production rate (MAPR) in vitro. The calf muscle weight in PAD patients was significantly lower than that in control subjects. In PAD patients, the calf muscle weight was significantly lower in the worst legs than that in the best legs. The ABI was lower in PAD than in controls and significantly lower in PAD worst legs than in PAD best legs. The leg blood flow (measured by venous-occlusion plethysmography) was lower in PAD than that in controls, but there was no significant difference between PAD best legs and PAD worst legs. The MAPR was measured using different substrate combinations. The MAPR (PM, pyruvate + malate), MAPR (PCM, palmitoyl-carnitine + malate) and MAPR (PPKM, pyruvate + palmi_toyl-carnitine + alpha-ketoglutarate + malate) shows the capacity of mitochondria to produce ATP by oxidising glucose or fatty acids or both of these substrates respectively. The MAPR for the three substrate combinations in PAD patients was no different from controls. The relationship between these physiological measurements and exercise performance differed between PAD and controls. In control subjects, the calf muscle weight, ABI, leg blood flow and MAPR were not significantly correlated with walking performance, but correlated with some variables of local calf muscle performance. In PAD patients, the calf muscle weight, ABI and blood flow did not correlate with walking performance. However, the MAPR (PMkg) was positively correlated with total walking time, and MAPR (PPKMg) was positively correlated with pain-free walking time. In calf muscle performance, in the best legs, the body weight was positively correlated with total impulse and peak impulse; the calf muscle weight was positively correlated with contraction number and peak impulse; and the blood flow correlated with peak impulse. In the worst legs, the calf muscle weight and ABI were not significantly correlated with any variables; the leg blood flow was negatively correlated with contraction number; the mitochondrial protein content correlated with total impulse; the MAPR (PM) tended to correlate with peak impulse. These results suggest the importance of all these local muscle physiological factors in calf muscle performance. However, only MAPR was important in the walking performance in PAD patients. The aim of Study 4 was to further explore the relationship between MAPR and exercise performance in PAD patients after exercise training. The effect of 16 weeks of treadmill exercise training on exercise performance and MAPR was evaluated in five PAD patients. In the treadmill walking performance test, total walking time increases ranged from 100 to 150% in these five patients. The pain-free walking time increased in three patients but did not change in the other two. In the calf muscle performance test, the total impulse and contraction number increased in both legs of four patients and decreased in both legs of one patient, but the magnitude of improvement was less than 5% and the peak impulse did not change in a consistent trend. The changes in body weight, calf muscle weight, and ABI in these five patients were less than 5%. However, the increased blood flow measured by venousocclusion plethysmography in both legs ranged from 100 to 150%. The MAPR by oxidising glucose was significantly higher in trained patients than that in untrained patients, which suggested a possible change in mitochondrial function in response to exercise training. Such change in mitochondrial function may have a potential role in contributing to calf muscle performance and walking performance after exercise training. In summary, for the first time, a local calf muscle performance test has been established to allow better understanding of calf muscle pathophysiology in PAD patients. Using this test, it has been shown that calf muscle performance is significantly impaired in PAD patients compared with control subjects. The impairment is characterised by lower muscle endurance, lower muscle strength and higher fatigability. The impaired local calf muscle performance might contribute to the impaired overall walking performance in PAD patients. The MAPR, especially 5 through oxidising glucose, contributed to walking performance. In this pilot exercise training study, a 20 weeks exercise training program failed to improve the calf muscle performance and walking performance in PAD patients. The higher MAPR in oxidising glucose in trained PAD patients again suggested the importance of muscle glucose oxidation as a contributing factor in the exercise performance in PAD patients.

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Morsey, Hesham. "Ischaemia reperfusion injury in patients with peripheral arterial occlusive disease." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516556.

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Triola, Laura Walter. "Peripheral Arterial Disease Screening of an Underserved High Risk Population." UNF Digital Commons, 2006. http://digitalcommons.unf.edu/etd/333.

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Disparity in access to health care and preventive services places a heavier burden of morbidity on those with limited access and resources. Underserved populations with decreased access to appropriate health screening and therapeutic interventions often present with increased risks for peripheral arterial disease. Some patients with peripheral arterial disease are asymptomatic and may defer treatment while others present with occlusive disease requiring immediate therapy. Delaying diagnosis and treatment reduces quality of life and functional status. The prevalence of peripheral arterial disease has been extensively studied in the elderly population but the prevalence in the high-risk underserved population is unknown. The purpose of this study was to identify the prevalence of peripheral arterial disease in an underserved, high-risk, predominantly African American population and to determine if providers using an electronic blood pressure machine could accurately measure the ankle-brachial index. The sample population of forty adult residents at a homeless shelter in northeast Florida was screened for peripheral arterial disease. Inclusion criteria consisted of a diagnosis of hypertension, hyperlipidemia, diabetes or a history of smoking. The ankle-brachial index was assessed using the vascular Doppler method and an electronic blood pressure machine though the latter was found to be an insensitive screening tool. The ankle-brachial index, the San Diego Claudication Questionnaire and a physical assessment were used in this crosssectional study to determine the prevalence of peripheral arterial disease. An abnormal ankle-brachial index value (≤ 0.90), indicating a high suspicion of peripheral arterial disease, was assessed in 22.5% of the sample population, all of whom were found to have a history of smoking crack cocaine.

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Lu, Liya. "Association between active smoking, secondhand smoke and peripheral arterial disease." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8059/.

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Worldwide, cardiovascular disease (CVD) is the leading cause of death. It is widely accepted that both active smoking and exposure to secondhand smoke (SHS) are associated with CVD. About 20% of the global population smoke tobacco or tobacco-related products. The global prevalence of smoking is increasing, although it is decreasing in some high-income and upper middle-income countries. Globally, about a third of adults and 40% children are regularly exposed to SHS. According to the World Health Organisation (WHO), only 16% of the global population is protected by a comprehensive smoke-free legislation. Coronary heart disease (CHD), stroke and peripheral arterial disease (PAD) are all types of atherosclerosis and often co-exist in the same patients. Therefore, they share many common risk factors including cigarette smoking. However, previous epidemiological studies on CVD including those on cigarette smoking mainly focused on CHD and stroke and pay little attention to PAD. Evidence is increasing in support of the association between exposure to SHS and both CHD and stroke. In contrast, there is a paucity of studies on SHS and the risk of PAD. The overarching aim of this thesis was to collate the published evidence on the association between active cigarette smoking and PAD, and examine the association between exposure to SHS and PAD in the general population. This thesis starts with a systematic review on the association between active cigarette smoking, SHS and PAD undertaken using four databases: Medline, Embase, PubMed and Web of Science to identify existing published evidence up to 30 April 2012 (Chapter 2). Prior to the published studies contained in this thesis, there had been no meta-analyses on the association between active cigarette smoking and PAD and only two studies published on the association between SHS and PAD. Therefore, this systematic review was followed by a meta-analysis on the association between active cigarette smoking and PAD. This meta-analysis identified 55 studies: 43 cross-sectional, 10 cohort and 2 case-control. Of the 68 results for current smokers, 59 (86.8%) were statistically significant and the pooled odds ratio (OR) was 2.72 (95% confidence interval [CI] 2.28-3.21). Of the 40 results for ex-smokers, 29 (72.5%) were statistically significant and the pooled OR was 1.67 (95% CI 1.54-1.81). Active cigarette smoking significantly increases the risk of PAD, compared with never smokers. The magnitude of association between active cigarette smoking and PAD was greater in current smokers than ex-smokers. In contrast, prior to my studies in this thesis, only two studies on SHS were identified. Only one showed an overall association between self-report SHS and PAD in Chinese never smokers, with a clear dose-response relationship. The other study used serum cotinine as measure for SHS exposure and found neither an overall association nor a dose-response relationship but suggested a very high cotinine concentration as threshold. Chapter 3 examines the association between SHS exposure and PAD in adult non-smokers in Scotland. This chapter includes two cross-sectional studies using the Generation Scotland: Scottish Family Health Study (GS: SFHS) and the Scottish Health Survey (SHeS), and one retrospective cohort study using the record linkage of the SHeS. In the cross-sectional study using SFHS, PAD was measured using ankle brachial pressure index (ABPI) but SHS exposure was self-report. Of the 5,686 never smokers, 134 (2.4%) had PAD (defined as an ABPI < 0.9). Participants who reported overall high level of SHS exposure (exposed to ≥40 hours per week) were more likely to have PAD, compared with those who reported no exposure to SHS. After adjustment for potential confounders, the association between SHS and PAD persisted (adjusted OR 4.53, 95% CI 1.51-13.56, p=0.007), with suggestion of a dose-response relationship. In the other cross-sectional study using SHeS, SHS exposure was measured objectively using cotinine concentration but PAD was based on self-report symptoms of intermittent claudication (IC) using the Edinburgh Claudication Questionnaire. Of the 4,231 non-smokers (defined as self-reported non-smokers with a salivary cotinine concentration <15 ng/mL), 134 (3.2%) had IC. Participants with high exposure to SHS (cotinine ≥2.7 ng/mL) were at significantly higher risk of IC, after adjustment for potential confounders (adjusted OR 1.76, 95% CI 1.04-3.00, p=0.036). A dose-response relationship was suggested, whereby the risk of IC increased with increasing cotinine concentration. However, the association varied by age category. Participants aged <60 were more strongly associated with PAD. This may be explained by survival bias. For the third, retrospective cohort study in Chapter 3, I used record linkage of SHeS to Scottish Morbidity Record 01 (SMR01) records and death certificates to identify the first hospital admission/death following the SHeS in which PAD was recorded as the primary or secondary cause. Of the 4,045 confirmed non-smokers who were free of baseline IC were included. Over the follow-up period (mean follow-up 9 years), there were 568 deaths, none of which were coded as due to PAD, and 64 participants were hospitalised for PAD. High exposure to SHS was associated with increased risk of all-cause mortality (adjusted hazard ratio [HR] 1.42, 95% CI 1.09- 1.86, p=0.011) among all non-smokers and increased risk of incident PAD (adjusted HR 2.82, 95% CI 1.14-6.96, p=0.024) among male non-smokers. Increased cotinine concentrations at baseline were associated with increased risk of all-cause mortality, with a dose-response relationship. SHS contains both sidestream smoke, from burning cigarette tips, and exhaled mainstream smoke. Shortened telomere length is broadly viewed as a biomarker for biological ageing including atherosclerosis phenotypes such as PAD. Evidence is strong that active smoking increases telomere length attrition but whether such association occurs between SHS and telomere length is unknown. Therefore, Chapter 4 aimed to add to growing evidence that exposure to SHS is associated with disproportionately higher biomarkers of cardiovascular risk compared with active smoking and may accelerate normal biological ageing. This chapter includes two cross-sectional studies. The first study investigated the relationship between salivary cotinine and several preclinical cardiovascular biomarkers: C-reactive protein (CRP), high-density lipoprotein (HDL) cholesterol, TC/HDL cholesterol ratio and fibrinogen in 10,081 adults from the SHeS. CRP concentration and the TC/HDL cholesterol ratio increased, and HDL cholesterol concentration decreased with increasing cotinine concentration among both non-smokers and active smokers. There were step changes in the relationship between tobacco exposure and cardiovascular biomarkers at the interface of non-smokers exposed to SHS and active smokers. Non-smokers with high exposure to SHS had lower cotinine concentrations than light active smokers but comparable concentrations of CRP (p=0.709), HDL cholesterol (p=0.931) and the TC/HDL cholesterol ratio (p=0.405). Fibrinogen concentration was less clear-cut and only increased in moderate and heavy active smokers. The second study in this chapter explored the association between self-reported levels of SHS exposure and telomere shortening per annum using a subgroup of participants from the SFHS. Of the 1,303 non-smokers, telomere length decreased more rapidly with increasing age among participants with high level of SHS exposure, compared with both those with no exposure (adjusted coefficient -0.006, 95% CI -0.008- -0.004) (high vs no SHS: p=0.010) or low exposure (adjusted coefficient -0.005, 95% CI -0.007- -0.003) (high vs low SHS: p=0.005). In summary, there is now substantial evidence of an association between active cigarette smoking and PAD.
This thesis adds to the limited existing evidence on SHS as an independent risk factor for PAD. There was an overall association between exposure to SHS and PAD, with suggestion of a dose-response relationship. However, the association varied by age category. Individuals aged <60 were more strongly associated with the prevalence of IC. SHS was significantly associated with incident PAD only in men. This thesis further demonstrates that exposure to SHS carries a disproportionately higher cardiovascular risk than active smoking for a given level of smoke exposure. Telomere shortening per year of age may be an intermediate step between SHS and CVD including PAD. This also supports the association between SHS exposure and the atherosclerosis-related biomarkers, which play an important role in the pathophysiology of PAD. Further research is needed in the future to better understand the association between SHS and PAD, and the underlying mechanisms. The research in this thesis supports the need to protect the general public from exposure to SHS.

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Siggberg, Ida. "Lipid Markers in Men and Women with Peripheral Arterial Disease." Thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-93344.

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Introduction Lipoprotein(a) (Lp(a)) and oxidized LDL (oxLDL) are circulating lipoproteins known to promote development of atherosclerosis. LDL can be oxidized in several ways, including enzymatic oxidation by myeloperoxidase (MPO). The knowledge regarding these biomarkers in men and women with different presentations of peripheral arterial disease (PAD) is scarce. Aim To investigate sex differences in plasma levels of MPO, Lp(a) and oxLDL in patients undergoing open vascular surgery. A secondary aim was to elucidate how indication for surgery, risk factors and comorbidity influenced the levels of lipid markers. Methods A multicenter observational study done within the framework of an ongoing study targeting atherosclerosis, where lipids and inflammation are studied in patients undergoing open vascular surgery for either PAD (intermittent claudication (IC) or critical limb ischemia (CLI)) or carotid artery stenosis, having an ankle brachial pressure index <0.9 or >1.4. Participants were included 2019-2020, with blood samples collected immediately before surgery. Results A total of 30 men and 26 women were included. The indication for surgery was CLI (50.0%), IC (30.4%) and carotid stenosis (19.6%). Women and men displayed similar levels of Lp(a), MPO and oxLDL. Lp(a) was lower among CLI patients as compared to IC in univariate (P=0.038) but not in multivariate analysis. Oxidized LDL levels and LDL, Lp(a) and cholesterol correlated significantly. Conclusions There were no statistically significant differences in lipid markers between sexes. Levels of Lp(a) differed between the surgical indication groups and were lowest among the more severely diseased patients (CLI). Our findings need further evaluation in larger cohorts, taking effects of lipid-lowering therapies into consideration.

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Stoffers, Henri Elise Johannes Hubertus. "Peripheral arterial occlusive disease prevalence and diagnostic management in general practice /." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1995. http://arno.unimaas.nl/show.cgi?fid=7926.

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25

Dickinson, Karen Joanna. "The regulation of platelet function in patients with peripheral arterial disease." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598024.

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Platelets play an important role in the pathogenesis of atherothrombosis and, as such, measuring platelet dysfunction in patients with peripheral arterial disease (PAD) may be a useful prognostic marker for future cardiovascular events. Detecting increased platelet activity but also reduced platelet inhibition is important in the management of these patients. Prediction of cardiovascular risk could allow tailored anti-platelet regimens in high risk groups. Dissection of platelet function in patients with PAD could allow cardiovascular risk stratification and the aim of this thesis was to develop methods to allow 'platelet profiling' in patients with PAD to determine an individual's platelet reactivity. Platelet fibrinogen binding and platelet-leukocyte interactions were determined using flow cytometry. The mechanism of platelet inhibition by nitric oxide (NO) was elucidated further using various inhibitors of the nitric oxide signalling pathway, measurement of cGMP levels and Western blotting for vasodilator stimulated phosphoprotein. In addition, the cytokine profile of these patients was determined, with particular reference to those chemokines important in platelet leukocyte interactions. , Patients with peripheral arterial disease exhibited largely unchanged basal platelet activity (as measured by platelet-leukocyte aggregates and platelet fibrinogen binding), but significantly increased response to the agonist, adenosine diphosphate (ADP). Platelet inhibition in response to NO was reduced in patients with critical limb ischaemia (CLI). In patients with CLI, further work using modulators of the NO pathway demonstrated that the reduced platelet inhibition by NO may be attributable to abnormal protein kinase G (PKG) function. In addition, a global reduction in plasma chemokine levels was seen with increasing disease severity in PAD, including RANTES, MCP-1α and IL-10. This suggests a potential humoral or platelet factor present in patients with PAD causing this change and questions the traditional Th/Th-type cytokine dichotomy in favour of a more integrated cytokine network system. If these observations correlate with clinical outcomes this profiling tool will have important clinical value. This could have therapeutic implications e.g. dual anti-platelet therapy for high risk patients with PAD. Furthermore it would be interesting to study the effect of c1opidogrel and cilostazol or dipyridamole in combined approach to reducing platelet activation (P2Y12 antagonism) and increasing platelet inhibition (phosphodiesterase, PDE inhibition). New therapeutic ideas could be tested, directed by a patients 'profile' in order to combat this platelet hyperactivity in an attempt to reduce the significant cardiovascular morbidity and mortality associated with PAD.

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Cunningham, Margaret. "Psychological factors associated with walking in patients with Peripheral Arterial Disease." Thesis, University of Stirling, 2010. http://hdl.handle.net/1893/3040.

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Objectives This thesis aimed to explore psychological factors associated with walking behaviour in patients with Peripheral Arterial Disease, within the framework of Leventhal et al’s (1998) Common-sense Model of Self-regulation of Health and Illness. The objective was to identify psychological factors which could be modified to increase walking behaviour in these patients. Method A series of three studies were conducted to achieve these aims. The first study was an exploratory qualitative study, to explore the illness and treatment beliefs and walking behaviour of patients with intermittent claudication. The second study was a cross-sectional postal questionnaire to a cohort of patients with intermittent claudication, which tested the influence of the psychological factors identified in the qualitative study, in a larger sample. The final study was a randomised controlled trial of a brief psychological intervention designed to modify the illness and walking beliefs of patients with intermittent claudication, in order to increase walking behaviour. Results Beliefs about intermittent claudication, and beliefs about walking were both found to be associated with walking behaviour in the qualitative study. The results from the cross-sectional postal questionnaire confirmed this relationship – taken as a set, illness and walking beliefs accurately predicted adherence to minimum walking levels for 93.4% of the sample. The brief psychological intervention successfully modified illness and treatment beliefs and increased walking behaviour in patients newly diagnosed with intermittent claudication. Conclusion This thesis highlights the importance of illness and walking beliefs to the walking behaviour of patients with intermittent claudication. The thesis has added to the body of knowledge about intermittent claudication, and the findings of this thesis have implications for the treatment of patients with intermittent claudication within the health service. Theoretical and clinical implications of this research are discussed.

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Khan, Shaukat Nawaz. "Risk factor stratification of peripheral arterial disease in the United Kingdom." Thesis, University of Newcastle Upon Tyne, 2005. http://hdl.handle.net/10443/223.

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Objective: To document the patient characteristics, primary care and hospital management and QoL in patients with intermittent claudication in the United Kingdom. Also to determine the appropriate use of prophylactic therapy, to determine markers of high and low risk and to suggest approaches to optimise the management of peripheral arterial disease. Methods: 474 patients were recruited from 23 centres across the United Kingdom. Data was collected at baseline and at six months and risk factors profile was analysed. Results: Symptomatic disease is more prevalent in men and those above 60. A high proportion of patients were hypertensive and control of blood pressure was not optimal. Use of antiplatelet agents and lipid lowering therapy was less than satisfactory though it improved following hospital referral. Life style modification advice was patchy and not uniform and intensive support for such programmes was lacking. Majority of patients improved not only on clinical parameters but also their QoL over a six month period. 35% underwent peripheral imaging and 7.8% had an interventional procedure. 14% had a vascular event over six months. Low ABPI, high systolic pressure and prior CHD were significantly associated with development of all vascular events. Conclusions: Use of appropriate therapy to reduce the risk factor profile is less than optimal. There is a need for uniform national guidelines for appropriate management of peripheral arterial disease patients in the United Kingdom.

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Bennett, Philip Christopher. "Peripheral arterial disease amongst minority ethnic groups in the United Kingdom." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4726/.

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Peripheral arterial disease (PAD), a common manifestation of atherosclerosis, is an important healthcare problem with considerable morbidity and mortality. Intermittent claudication (IC) is the commonest symptomatic manifestation of this disease. This thesis investigates the prevalence of PAD in South Asians (people originating from India, Pakistan and Bangladesh) and Blacks (Black African, Black Caribbean) and makes ethnic comparisons of its associations with traditional cardiovascular risk factors, inflammatory and haemostatic biomarkers and markers of angiogenesis in these ethnic groups. This thesis also makes associations between common carotid intima media thickness, a marker of pre-clinical atherosclerosis, traditional cardiovascular risk factors and novel biomarkers. Furthermore this thesis validates translated versions of the Edinburgh Claudication Questionnaire into Punjabi and Urdu.

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Wästgård, Rebecka. "Peripheral arterial disease (PAD) - A descriptive cost study with gender analyses." Thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-48543.

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Yu, S. R. "Cytoprotective mechanisms of erythropoietin and erythropoietin derivatives in peripheral arterial disease." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1458006/.

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A third of patients with critical limb ischaemia (CLI) eventually require amputation. Inconsistencies between successful revascularisation and functional outcomes exist, and underlying musculopathy in CLI patients has been identified. Erythropoietin (EPO) has tissue-protective effects in response to ischaemic injury, but its clinical use is often precluded by thromboembolic side effects. Non-haematopoietic EPO-derivatives have been designed to retain only tissueprotective functions of EPO. We hypothesised that ARA-290 (EPO-derivative) may have tissue-protective potential that could represent a novel therapeutic adjunct in patients with CLI. The effect of EPO and ARA-290 in mediating cytoprotection in an in vitro simulated ischaemia model of skeletal muscle was assessed firstly in the immortalised murine C2C12 myoblast cell line and subsequently in skeletal myoblasts isolated from CLI and control donors. In human and murine cells, simulated ischaemia alone demonstrated a detrimental effect on cell function and survival. Addition of EPO or ARA-290 demonstrated significant improvements in function and survival and utilised JAK2/STAT3, PI3k/Akt and NF!B signalling molecules. Isolation of human skeletal myoblasts from CLI patients has not previously been described. Comparison of CLI and control myoblasts elucidated significant differences in their function and survival under both normoxic and simulated ischaemic conditions. CLI myoblasts and myotubes exhibited increased proliferative capacity but reduced migratory and contractile function and importantly a reduced susceptibility to a second ischaemic-insult compared with control myoblasts and myotubes. Evaluation of several variations in the hindlimb ischaemia model allowed the creation of a model which closely recapitulated the muscular pathology observed in human CLI patients. ARA-290 demonstrated improved functional, histological and perfusion outcomes compared to EPO or vehicle-control treated animals. These studies demonstrate the potential of ARA-290 to protect tissues and cells from ischaemic-injury and encourages the development of novel pharmacological therapies for use in patients with “no option” CLI or severe functional deficit.

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Rockley, Mark. "Intraoperative Physiologic Monitoring During Endovascular Revascularization for Atherosclerotic Peripheral Arterial Disease." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41149.

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Peripheral vascular disease (PVD) is defined by insufficient blood flow to limbs and can result in pain, gangrene, and amputation. Minimally invasive angioplasty treatments for PVD are common but suffer from high failure rates. We conducted three studies: 1) a systematic review to describe methods of intraoperative blood flow assessment; 2) a retrospective cohort study to describe the correlation between outpatient blood flow assessment and clinical outcomes; and 3) a prospective observational study to describe the reliability and association between intraoperative blood flow assessment and clinical outcomes. While limb blood flow is routinely assessed before and after interventions, intraoperative assessment has not been well described. Postoperative blood flow assessments are strongly correlated with clinical outcomes. Intraoperative blood flow assessment is feasible and strongly correlated with clinical outcomes. Intraoperative blood flow assessment may be a useful tool to guide intraoperative decision making.

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Smith, Felicity Barbara. "Role of fibrinogen and fibrin D-dimer in peripheral arterial disease." Thesis, University of Glasgow, 1998. http://theses.gla.ac.uk/30947/.

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This thesis is composed of two studies. The principal aim of the first study, the Sites of Atheroma Study, was to determine whether plasma fibrinogen, fibrin D-dimer and other haemostatic factors (von Willebrand Factor and plasminogen activator inhibitor - type I) were related to the angiographic site and severity of atherosclerosis in the arteries of the lower limb. The principal aim of the second study, the Prognostic Study of Intermittent Claudication, was to determine whether plasma fibrinogen, fibrin D-dimer and other haemostatic factors (von Willebrand Factor and tissue plasminogen activator), were related to the future incidence of atherothrombotic events, and deterioration of peripheral arterial disease in subjects with intermittent claudication. The study samples in both studies consisted of men and women with ischaemic symptoms in the lower limb referred to the Peripheral Vascular Clinic, Royal Infirmary of Edinburgh. In the Sites of Atheroma Study, 192 patients referred for angiography were categorised by site and severity of peripheral atherosclerosis using the Bollinger angiographic scoring system. A clinical examination was conducted on each patient including the administration of a questionnaire and taking of a blood sample for the measurement of haemostatic factors. In the Prognostic Study, 607 patients with intermittent claudication who had had a comprehensive examination at baseline, including measurement of haemostatic factors, were followed up over six years to determine the incidence of fatal and non-fatal ischaemic heart disease and stroke and deterioration of peripheral arterial disease. Follow-up data were obtained from hospital records, general practitioners, self-administered questionnaires, the Information and Statistics division of the Common Services Agency and the Scottish National Health Service Central Registry. Results from the Sites of Atheroma Study indicated that 34 (17.7%) patients had predominantly aorto-iliac disease, 85 (44.3%) had femoro-popliteal disease and 73 (38.0%) had dual-site disease. There were no significant differences in the mean levels of the haemostatic factors between patients with disease affecting different sites. An independent relationship was found between nephelometric fibrinogen and between fibrin D-dimer and disease severity only in the femoro-popliteal arteries. On multiple regression, fibrinogen remained independently associated with disease severity in the femoro-popliteal arteries, when life-time smoking or current smoking were taken into account. There was no influence of current smoking on the association between fibrin D-dimer and disease severity but, on inclusion of life-time smoking, the association became non-significant. In the Prognostic Study of Intermittent Claudication, a total of 210 (34.6%) patients died during the six year follow-up period. Of these 90 (42.9%) died from ischaemic heart disease, 29 (13.8%) from stroke and 27 (12.9%) from other vascular causes, including cardiac arrhythmias and ruptured aneurysm. Ninety three (15.3%) patients had a non-fatal myocardial infarction and 79 (13.0%) had a fatal or non-fatal stroke. Forty five (7.4%) patients underwent investigations for peripheral arterial disease and 64 (10.5%) patients progressed to severe chronic leg ischaemia. A total of 203 (33.4%) patients did not have a vascular event or show any deterioration of limb ischaemia. Baseline median levels of plasma fibrinogen, fibrin D-dimer and von Willebrand Factor were significantly higher in patients who died from ischaemic heart disease compared to those who had no vascular events. Tissue plasminogen activator antigen levels were significantly elevated in patients who suffered a stroke. All the relationships between the haemostatic factors and vascular events became weaker and statistically non-significant in analysis adjusting for cardiovascular risk factors and baseline ischaemic heart disease. von Willebrand Factor levels were significantly raised in claudicants who developed severe chronic leg ischaemia (rest pain, ulceration and gangrene). In multivariate analyses adjusting for life-time smoking, fibrinogen became significantly associated with the risk of vascular intervention, and von Willebrand Factor was associated with the risk of severe chronic leg ischaemia. In conclusion, these results indicate that there may be a stronger relationship between chronic smoking and increased fibrin turnover than coagulation in symptomatic peripheral arterial disease. Increased coagulation and fibrinolytic activity may also contribute to thrombosis or progression of atherosclerosis in the coronary and cerebral arteries in claudicants. The effect that fibrinogen, fibrin D-dimer and other haemostatic factors may have on the progression of peripheral arterial disease was mostly independent of cigarette smoking.

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Woodburn, Kenneth Robert. "Blood rheology and thrombotic mediators in peripheral arterial disease and revascularisation surgery." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/20877.

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Rheological parameters and levels of plasma fibrinogen, cross-linked fibrin degradation products (FDP's), von Willebrand Factor antigen (vWF), factor VII, and Plasminogen Activator Inhibitor (P.A.I.), were found to be altered in 219 patients with occlusive arterial disease undergoing revascularisation procedures, when compared with an age-matched random population sample. Elevated levels of some of these potential thrombotic mediators are associated with the angiographic severity of arterial disease on univariate analysis, while multivariate analysis indicates that log (FDP) is independently related to disease severity, and other thrombotic mediators show a trend towards significant independent association. Surgical relief of critical limb ischaemia in 82 of these patients returned the alterations in blood rheology to control levels, but plasma fibrinogen, vWF, P.A.I., and FDP levels remained significantly higher than in the population controls. Percutaneous angioplasty in 40 cases was associated with transient alterations in vWF and t.P.A. levels in arterial blood that may be a consequence of endothelial injury, and with a significant elevation in cross-linked FDP levels 3 months after successful angioplasty. This alteration in fibrin turnover may be related to restenosis following angioplasty. Elevated pre-operative plasma fibrinogen, vWF, and FDP's, were associated with graft occlusion and patient death on univariate analysis of 186 consecutive infra-inguinal bypass grafts, while multivariate analysis indicates that pre-operative plasma von Willebrand Factor levels (p < 0.001), systolic ankle pressure (p < 0.01), female sex (p = 0.03), and limb sepsis (p = 0.01), are all independently predictive of graft occlusion and patient death within 1 year following surgery.

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Tzoulaki, Ioanna. "Inflammation and haemostasis in the development and progression of peripheral atherosclerotic disease." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/2148.

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Peripheral arterial disease (PAD) defines atherosclerotic disease of the arteries to the legs. PAD begins early in life and remains asymptomatic over long periods. The ankle brachial index (ABI) is an important diagnostic test which can identify asymptomatic individuals and serve as a good marker of the underlying peripheral and systemic atherosclerosis. Recent advances in vascular biology proposed a role of inflammatory and haemostatic mechanisms in atherosclerotic disease. Although inflammatory and haemostatic markers have been associated with coronary atherosclerosis in large scale epidemiological studies their role in PAD development is not well established and for many markers unknown. Also, their relationship with the progression of early asymptomatic disease has not been studied before. The aim of this thesis was to examine 12 markers of inflammation and haemostasis in relation to peripheral atherosclerotic progression and incident PAD. The Edinburgh Artery Study was used for this analysis. This is a population based cohort study of 1,592 men and women recruited in 1987. ABI was measured at baseline and at two follow up examinations which were conducted after 5 and after 12 years. Also, subjects were followed up for cardiovascular events for 17 years. Conventional cardiovascular risk factors, C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin, fibrinogen, D-dimer, tissue plasminogen activator (t-PA), vonWillebrand factor (vWF), factor VII, fibrinopeptide A (FpA) and prothrombin fragments 1+2 (F1+2) were measured at baseline. Valid ABI measurements were available for 1,582 subjects at baseline, for 1,081 subjects at the 5 year follow up and for 816 subjects at the 12 year follow up. The population showed a progression in atherosclerotic disease assessed by the mean ABI decline over time. The mean change in ABI was -0.04 (0.18) after 5 years and -0.06 (0.19) after 12 years. From inflammatory markers, CRP (p <0.01), IL-6 (p <0.001) and ICAM-1 (p <0.01) were associated with atherosclerotic progression after 12 years, independently of baseline ABI and of conventional cardiovascular risk factors. Also, from haemostatic markers, fibrinogen (p =0.05) and D-dimer (p ≤ 0.05) were significantly associated with atherosclerotic progression independently of baseline ABI and cardiovascular risk factors. Moreover, subjects with higher levels of both D-dimer and IL-6 at baseline had the greatest ABI decline. Also, IL-6 showed the stronger independent effect on atherosclerotic progression and retained statistical significance after adjustments for all inflammatory markers and for fibrinogen and D-dimer. Approximately 26% of the baseline population developed at least one event of major CVD and 14% of the baseline population developed symptomatic PAD after 17 years of follow up. Inflammatory markers, CRP and IL-6 showed modest associations with PAD which lost statistical significance in the multivariable model. On the other hand, these markers were associated with incident major CVD with hazard ratios (95% CI) 1.6 (1.2, 2.3) and 1.8 (1.3, 2.6) respectively (top vs. bottom tertile) in the multivariable model. ICAM-1 showed weak associations with incident CVD, however, was significantly associated with PAD with hazard ratio (95% CI) 1.8 (1.2, 2.7) (top vs. bottom tertile) after adjustments for cardiovascular risk factors and CVD at baseline. Haemostatic markers, fibrinogen and D-dimer were associated with 2.2 (95% CI: 1.5, 3.2) and 1.7 (1.2, 2.6) increase in the risk of PAD development and 1.8 (1.3, 2.3) and 1.6 (1.2, 2.1) increase in the risk of CVD independently of cardiovascular risk factors and history of CVD at baseline, respectively. This analysis showed a major role of inflammatory markers, CRP, IL-6 and ICAM-1 in atherosclerotic development and progression. In addition, fibrinogen and D-dimer, but not other haemostatic factors, were associated with progressive and incident peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation. Most importantly, the majority of the reported associations were not explained by increased levels of cardiovascular risk factors or pre-existing clinical or subclinical arterial disease. Thus these markers are more likely to have a causal than a consequential role in atherosclerotic disease.

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Kock, Marcus Cornelius Johannes Maria. "Diagnostic imaging of peripheral arterial disease with multi-detector row computed tomography angiography." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10509.

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Lee, Kui-Joo. "The detection of double product break point in individuals with peripheral arterial disease." Virtual Press, 2000. http://liblink.bsu.edu/uhtbin/catkey/1178340.

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Peripheral arterial disease (PAD) is a common manifestation of stenoses and occlusions of the arteries of the lower extremities. Clinically, PAD is an important effect on functional ability, and quality of life because symptomatic patients are typically able to walk less than one to three blocks before rest is required.The double product break point (DPBP), also defined as the oxygen consumption at which the first portion of nonlinear increase in rate pressure product (systolic blood pressure X heart rate) begins has been identified to determine the anaerobic threshold during exercise test. The purpose of this study was to determine whether the DPBP could be detected in patients with PAD during a symptom-limited GXT on the motor-driven treadmill. Six male subjects (68.2 ± 6.5 yrs) with history of diagnosis of PAD participated in this study. Double product (DP) was assessed every 15 seconds during the test via the Kyokko Bussan CM-4001 automated blood pressure unit. The DPBP and VT were determined visually by three blinded observers. The mean values of Peak V02 and maximal heart rate were 19.4 ± 5.8 (ml/kg/min) and 130 ± 13 (bpm), respectively. In 4 of the six exercise tests in the present study, the DPBP and the VT were determined. The mean V02 at the DPBP and the VT were 15.7 ± 2.6 ml/kg/min and 14.2 ± 0.6 ml/kg/min, corresponding to 73 ± 7.2 and 74.5 ± 5.4 % respectively. In 3 of the six exercise tests both of the DPBP and VT were determined. The Mean V02 at the DPBP and VT were 14.6 ± 1.8 and 14.3 ± 0.7, respectively. The difference of the mean VO2 at the VT and DPBP was -.0.33 ml/kg/min.In conclusion, the results of the present study suggest that the DPBP can be identified and used as a useful marker to determine the functional performance in PAD patients. Walking time or distance measurement depends on the patient's perception of the pain. Thus, this study provides an objective way to appraise the functional performance and therapeutic results obtained from the exercise training in PAD patients, and provides a reference for exercise prescription for this population.
School of Physical Education

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O'Donnell, M. E. "The Effects of Cilostazol on Inflammatory Response in Patients With Peripheral Arterial Disease." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501396.

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Robertson, Alan. "Allopurinol as a possible oxygen sparing agent during exercise in peripheral arterial disease." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/6d3e342c-d2fb-4cec-b678-082d1fb2e067.

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Patients with peripheral arterial disease (PAD) can only walk so far before they get leg pain (intermittent claudication) and have to stop. They are also at risk in the future of needing amputation of one of their limbs. Allopurinol is a new possible treatment for this condition as it has been shown in coronary arterial disease to prolong exercise before angina pain occurs. This is thought to be because allopurinol can both prevent oxygen wastage in tissues and prevent the formation of harmful oxidative stress. We hypothesised that allopurinol could prolong the time to leg pain in participants with PAD. In a double-blind, randomised controlled clinical trial 50 participants with PAD were randomised to receive either allopurinol 300mg twice daily or placebo for six months. The primary outcome was change in exercise capacity on treadmill testing at six months. Secondary outcomes were six-minute walking distance, Walking Impairment Questionnaire, SF-36 QoL questionnaire, flow-mediated dilatation and oxidised LDL. Outcome measures were repeated mid-study and at end of study. The mean age of participants was 68.4 years (SD 1.2) with 39/50 (78%) male. Only five participants withdrew in the course of the study, two in the active group and three in the placebo group. There was a significant reduction in uric acid levels in those on active treatment of 52.1% (p<0.001), but no significant change in either the pain-free or the maximum distance they were able to walk. Other measures of exercise capacity, blood vessel function and the participants’ own assessment of their health and walking ability also did not change during the course of the study. In summary, although allopurinol has been shown to be of benefit in a number of other diseases, in this study there was no evidence of any improvement following treatment in patients with peripheral arterial disease.

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Price, Jacqueline Frances. "Glucose intolerance and steroid sex hormones in the aetiology of peripheral arterial disease." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/23158.

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The prevalence of peripheral arterial disease is known to be higher in subjects with diabetes mellitus or impaired glucose tolerance compared with non-diabetic subjects. The objective of study 1 was to determine whether this could be explained by differing levels of 'traditional' risk factors, such as smoking, hypertension, dyslipidaemia and obesity. Methods: 1,592 men and women aged 55-74 years were selected at random from the age-sex registers of 11 general practices throughout Edinburgh, Scotland. Subjects underwent a comprehensive medical examination, including assessment for peripheral arterial disease (positive intermittent claudication questionnaire or major asymptomatic disease on non-invasive testing), a glucose tolerance test and measurement of cardiovascular risk factors (including smoking, blood pressure, body mass index and serum lipids and lipoproteins). Results: 288 subjects (18.7%) were found to have diabetes or impaired glucose tolerance (IGT). The prevalence of peripheral arterial disease was greater in subjects with diabetes or IGT (20.6%) compared to those with normal glucose tolerance (12.5%) (age and sex adjusted OR 1.45; 95% CI 1.03, 2.04). In subjects with diabetes or IGT, mean levels of smoking, systolic blood pressure and serum triglycerides were significantly higher in subjects with peripheral arterial disease than in those without disease (p£0.05). In general, levels of cardiovascular risk factors were higher in subjects with diabetes or IGT compared with normal glucose tolerant subjects; this included systolic blood pressure and triglycerides, but not smoking. In multivariate analysis, subjects with diabetes or IGT no longer had a significantly higher risk of peripheral arterial disease after adjusting separately for systolic blood pressure (OR 1.22, 95% CI 0.85, 1.73) or serum triglycerides (OR 1.26 95% CI 0.89, 1.79). Simultaneous adjustment for both risk factors reduced the odds of disease further to 1.11 (95% CI 0.78, 1.58). Conclusions: Raised levels of serum triglycerides and systolic blood pressure in subjects with diabetes or IGT may explain a major portion of their increased risk of peripheral arterial disease. The objectives of study 2 were to determine whether, in non-diabetic men and women from the general population, there was an association between peripheral arterial disease and (i) plasma insulin levels or (ii) endogenous steroid sex hormones.

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Sanderson, Brad E. "Supervised stationary cycling versus supervised treadmill-walking for periperal arterial disease /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18988.pdf.

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Burdess, Anne. "Role of inflammation and platelet activation in the adverse cardiovascular outcomes of patients undergoing surgery for critical limb ischaemia." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9539.

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Increased platelet activation and inflammation play a key role in atherothrombosis. Patients with peripheral arterial disease are at increased risk of adverse cardiovascular events, particularly at the time of surgery. We postulated that the increase in peri-operative cardiovascular events is mediated by increased platelet activation and inflammation. We hypothesized that peri-operative dual anti-platelet therapy would improve biomarkers of atherothrombosis without causing unacceptable bleeding in patients undergoing surgery for critical limb ischaemia (CLI). Prior to interventional study, I validated a sensitive flow cytometric technique for the reproducible assessment of in vivo platelet activation in patients with peripheral arterial disease. Thirty patients with stable claudication, attended on two occasions to permit within-day and between-day comparisons. A variety of platelet activation markers were compared to the gold standard of platelet–monocyte aggregation. Platelet-monocyte aggregation demonstrated comparable within-day (mean difference ± co-efficient of reproducibility; 0.9±15.4%) and between-day reproducibility (2.0±12.4%). Plateletmonocyte aggregates correlated well with other platelet activation markers (P selectin r=0.30; Platelet CD40L r=0.41; Platelet microparticles r=0.27; P≤0.026) and monocyte activation markers (monocyte CD40 r=0.27;monocyte CD11b r=0.47; P≤0.026). In a cross sectional study, I demonstrated that resting in vivo platelet activation and inflammation was increased in patients with CLI in comparison to healthy controls, patients with stable claudication and those undergoing treatment for acute coronary syndromes. In addition, platelet activation and inflammation throughout the peri-operative period was markedly increased in CLI patients compared with non-vascular patients undergoing arthroplasty, and exceeded the rise attributable to the stress of surgery itself. In a prospective double-blind randomised controlled trial, 108 patients undergoing infra-inguinal revascularisation or amputation for CLI were maintained on aspirin (75 mg daily) and randomised to clopidogrel (600 mg prior to surgery, and 75 mg daily for 3 days; n=50) or matched placebo (n=58). Peri-operative in vivo platelet activation and inflammation, cardiac-Troponin I (c-TnI) release and bleeding outcomes were recorded. Clopidogrel reduced markers of platelet activation and inflammation before surgery and throughout the post-operative period. Overall, there were 18 troponin-positive events (16.7%), with half of the troponin rises (9) occurring prior to surgery. Patients with postoperative elevations in c-Tn I had significantly greater levels of pre-operative platelet-monocyte aggregation, monocyte CD40, IL-6 and hsCRP. However, despite reducing platelet and inflammatory markers, clopidogrel did not have a direct effect on peri-operative c-Tn I. There was no increase in major life-threatening or minor bleeding, although blood transfusions and wound haematomas were significantly increased. Using sensitive and validated methodologies, I have provided a detailed examination of in vivo platelet activation and inflammation in high-risk vascular surgical patients. This approach has provided the first objective assessment of the risks and benefits of intensive peri-operative anti-platelet therapy in this patient group. Dual anti-platelet therapy reduced biomarkers of atherothrombosis without causing unacceptable bleeding. However, large-scale clinical trials would be required to confirm whether these reductions translate into improvements in clinical outcome.

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Youssef, Fahed. "The effects of lipid lowering treatment on the arterial wall and renal function in patients with peripheral arterial disease." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1446282/.

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Background: Peripheral arterial disease (PAD) is common condition and associated with an increased vascular risk and impaired renal function. Studies have shown a reduction in vascular risk following lipid lowering with a statin in patients with PAD, which may be attributed to a decrease in intima media thickness (IMT) and regression of atherosclerosis. Aims: To study the effect of lipid lowering treatment with statin on patients with peripheral arterial disease. This included monitoring carotid and femoral IMT, renal function and distribution of the enodthelin-1 (ET-1) and its receptors in the arterial wall of patients with advanced PAD.;Materials and Methods: Duplex ultrasound was used to measure the arterial IMT and renal function and renal blood flow (RBF) indices in hyperlipidaemic claudicants before and after short-term atorvastatin treatment. Radioimmunoassay and immunostaining were applied to study ET-1 receptors in segments of popliteal arteries obtained from amputated legs.;Results: There was regression in the carotid and femoral IMT and an improvement in both serum creatinine and urate levels after eight weeks of atorvastatin 20 mg/day (n=25). This improvement in renal function was confirmed after treatment with a different statin (simvastatin) (n=103). Cystatin C, a more sensitive marker, decreased in addition to creatinine and urate in a prospective study (18 patients) after two months of atorvastatin treatment. However, the RBF indices did not change. The distribution of ET-1 receptors in the popliteal arteries from both normo- and hyperlipidaemic patients with advanced PAD (n=12) was also documented.;Conclusions: I am presenting evidence that statin can cause early regression in the IMT and protect renal function. This treatment may also reduce the inflammatory markers in atherosclerotic popliteal arteries.

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Graeber, Brendon Lewis. "Increase in Peripheral Arterial Tone Predicts Myocardial Ischemia Induced by Mental Stress." Yale University, 2006. http://ymtdl.med.yale.edu/theses/available/etd-06272006-121029/.

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Mental stress ischemia (MSI) is associated with poor prognosis for coronary artery disease (CAD) and is amenable to treatment, yet no easily administered test exists to diagnose it. Given the known increase in systemic vascular tone in response to stress, we studied the ability of peripheral arterial tonometry (PAT), a noninvasive functional measure of arterial tone, to predict those vulnerable to MSI. Seventy-seven patients with chronic stable CAD were subjected to mental stress with concomitant assessment of myocardial perfusion and pulse wave amplitude. Nuclear perfusion imaging was used to document MSI, and PAT was used to measure pulse wave and microarterial tone. A ratio of PAT measurements during stress to those before stress was used to characterize vascular responses. Serum catecholamines and endothelin-1 (ET-1) were simultaneously measured. Subjects who experienced MSI had a lower average PAT ratio than those who did not (0.76 ¡À 0.04 vs. 0.91 ¡À 0.05, P = 0.03). A receiver operating characteristics curve for PAT ratio predicting MSI had an area under the curve of 0.613 (standard error, 0.065, one-sided P = 0.04). Maxima of sensitivity and specificity were observed at a threshold of 0.78 to define an abnormal PAT ratio. Cross-tabulation of groups above and below this threshold with groups of subjects with and without MSI showed a significant predictive relationship between PAT ratio and MSI (P = 0.03). Subjects at or below this threshold (¡Ü0.78) displayed a significant increase in norepinephrine levels during mental stress (235 pg/ml at baseline, 259 pg/ml during mental stress, P = 0.007). Subjects above this threshold (>0.78) displayed a significant decline in their ET-1 levels 24 hours after mental stress (1.15 pg/ml after mental stress, 0.93 pg/ml 24 hours later, P = 0.01), while those at or below threshold had a continued increase. PAT ratio is a complex functional measure of peripheral arterial tone that significantly predicts the occurrence of MSI. It may have clinical value as an easily administered screening test for MSI.

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Chaparala, Ramakrishna P. C. "The role of humoral and cellular mediators in the progression of peripheral arterial disease." Thesis, University of Leeds, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578621.

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Traditional risk factors for peripheral arterial disease (PAD) include smoking, hypertension, advanced age, diabetes and heart disease. These do not fully explain the differential nature of disease progression. Inflammatory and immunological factors have been increasingly implicated as active mediators of atherosclerotic disorders, including PAD. In particular, an imbalance between Thl and Th2 responses is thought to promote the progression of the atherosclerotic process. The extent of this imbalance in PAD is poorly understood. The aim of this study was therefore to examine the involvement of cytokines, anti- endothelial antibodies (AEA) such as anti-cardiolipin(a-CL) and anti-Bz-Glycoproteinl antibodiestanti-Bz-Gl'I) and antibodies to heat shock protein60 (aI?-ti-HSP60) as mediators of Thl and Th2 responses in the pathophysiology of this vascular disorder. Materials and Methods Patients included age-matched controls, stable claudicants (SC), critical limb ischaemics (Cl). Plasma baseline cytokine profiles, AEA and anti-HSP60 were analysed. Whole blood was stimulated with lipopolysaccharide (LPS) and analysed for interlukins by fluid-phase multiplex immunoassay. AEA and anti-HSP60 levels were determined by enzyme-linked immunosorbent assay. Data were analysed by Kruskall-Wallis tests and Mann-Whitney-U tests post hoc. 3 Results: Significantly higher levels of IL-6 were found in Cl compared to SC, which in turn were higher than in the Control group. IL-lO and IL-13 levels were higher in PAD subgroups (SC and Cl) versus control although there was no significant difference between PAD subgroups. AEA and anti-HSP60 levels tended to be higher in association with increasing PAD severity. However, while Cl Anti-B2-GPI levels were higher than in Control there was no significant difference in anti-CL levels. Anti-HSP60 was different in each of the three groups Clc-SCc-Control. Following an in vitro LPS challenge, unstandardized IL-8 and IL-13 production was higher in PAD patients compared to controls after 6h of incubation. However when these levels were standardized against the white cell count this effect was not seen. Conclusions: In conclusion, this study does not support either Thl or Th2 cytokines as being predominant in PAD (i.e., representing a Thl:Th2 imbalance), although inflammatory burden is more pronounced in severe manifestations of the disease. A minor degree of inflammatory hyper-responsiveness associated with cultured whole blood from SC and Cl patients appeared to relate to leukocytosis rather than being attributable to an inherent inflammatory dysfunction per se. The profile of all the mediators studied were however, seen to be influenced by disease severity.

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Davie-Smith, Fiona. "Factors influencing quality of life after lower extremity amputation for peripheral arterial occlusive disease." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8465/.

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Recent literature suggests that 84% of lower extremity amputations (LEAs) are due to peripheral arterial occlusive disease (PAOD), and half of those will have diabetes. Only 40% will go on to rehabilitate with a prosthetic limb and the remainder will be wheelchair dependent. Until now, the majority of research has focused on the short-term clinical outcomes in this population e.g. prosthetic fitting, morbidity and mortality rates. There is a dearth of research into the long-term impact of a LEA on the individual’s quality of life (QoL), especially in those with PAOD with or without diabetes. Aim This thesis aims to determine which factors influence QoL after an LEA due to PAOD in the presence or absence of diabetes. Methods A prospective review of medical case notes and other relevant documentation was conducted on all patients who underwent a major lower extremity amputation for PAOD in NHS Greater Glasgow and Clyde in Scotland, between 1st March 2014 and 28th February 2015. Patients who consented to follow-up completed the EQ-5D-5L QoL measure, Reintegration into Normal Living (RNLI) and the Prosthetic Limb Users Survey of Mobility (PLUS-M), 6 and 12 months after LEA. Semi-structured interviews were conducted on 15 participants who completed follow up questionnaires to explore their views and experiences of living with a LEA and to understand which factors influence their QoL. Results There were 171 participants with a LEA in one year and their mean age was 66.2 years, 75% were males and 53% had diabetes. Over two thirds of the cohort lived in the two most deprived areas in Glasgow. From the follow up questionnaires (n=101) participation, measured by the RNLI had the greatest influence on QoL six and twelve months after LEA. Limb fitting positively influenced QoL, however, level of mobility was poor for all levels of LEA and there was a positive association between mobility (PLUS-M) and QoL. Mortality was seven times greater in those who were not limb fitted. Face-to-face interviews identified five broad themes that influenced QoL: the prosthesis; experience of pain; social support/isolation; sense of self/identity and interactions with others with an amputation. Conclusion Quality of Life was influenced by several factors, primarily participation, which was improved if limb-fitted. Those of male gender, younger age and diagnosed with diabetes were more likely to have a prosthesis fitted. While having a prosthesis did not determine QoL per se, those with greater levels of mobility were more likely to be able to participate, feel less isolated and require less social support which afforded them greater levels of QoL. Conversely, those who were wheelchair dependent or had poorer levels of prosthetic mobility reported lower levels of QoL; which was associated with dependence on social support, feelings of isolation and changes in the way they felt about themselves.

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Marimuthu, Rekha. "Study of Monocytes in Diabetic Foot Ulcer (DFU) patients with Peripheral Arterial Disease (PAD)." Thesis, The University of Sydney, 2018. https://hdl.handle.net/2123/21374.

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Diabetic foot ulcers (DFUs) are one common and severe complication of diabetes, showing impaired wound healing. Peripheral arterial disease (PAD), which is common in diabetes, increases the severity of DFUs leading to delayed or unsuccessful healing. Prolonged inflammation is one of the likely contributors to this, with an imbalance in macrophage phenotypes seen in diabetes. Monocytes, precursors to macrophages, express M1/M2 macrophage markers indicating monocyte skewing to a particular macrophage phenotype begins in the circulation. Whether the presence of DFU is associated with monocyte M1-skewing and the presence of PAD further influences this is not known. The main aim of this study was to investigate the effect of PAD on the inflammatory profile of circulating monocytes and ulcer macrophages in DFU patients, as well as determining whether monocyte/macrophage profile relates to healing parameters. Blood and ulcer biopsy samples were collected from DFU patients with and without PAD. Whole blood flow cytometry was used to determine monocyte subset proportions and M1-skewing, which was also compared with historical data from healthy controls. Immunohistochemistry was used to detect M1/M2 ulcer macrophages. DFU patients in general had a higher proportion of intermediate monocytes than controls (p=0.042) and DFU/PAD had more intermediates than DFU/NoPAD (p=0.02), suggesting PAD worsens this imbalance. M1-skewing of monocytes was higher in DFU/PAD patients than DFU/NoPAD group (p=0.046) in addition to strong M1 skewing in DFU patients in general (p<0.001). DFU/PAD patients had more M1 macrophages in their ulcers than DFU/NoPAD patients (p=0.04) and their M1/M2 ratio correlated positively with ulcer cross-sectional area (p=0.01). This study highlighted the enhanced inflammatory profile in DFU patients, particularly those complicated with PAD. These monocyte and macrophage alterations, may contribute to the delay in wound healing typical of this group.

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Ninomiya, John Koichi. "Non-invasive measures of peripheral arterial disease as predictors of coronary heart and cerebrovascular disease morbidity and mortality /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3189029.

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Hywood, Jack. "Assessment of the angiogenic potential of induced endothelial cells derived from patients with peripheral arterial disease." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23658.

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Peripheral arterial disease (PAD) and coronary artery disease (CAD) are major causes of mortality and morbidity globally [1–4]. While endovascular or surgical revascularisation procedures represent the gold standard therapy for severe atherosclerotic disease a substantial subset of patients are unsuitable for these interventions due to pre-existing morbidity or an extremely calcified vasculature [2, 5–10]. Furthermore, restenosis of vessels represents a not uncommon outcome of these procedures [11]. As such, there is a significant patient population refractory to existing medical and surgical treatments. Novel therapies are required to improve outcomes for this challenging subset of patients. Therapeutic angiogenesis, also referred to as neovascularisation, refers to the in- duction of a pro-angiogenic state in affected tissue to stimulate and augment vessel formation [12]. With increasing knowledge regarding the growth factors and the dynamics involved in vessel formation therapeutic angiogenesis represents a possible approach in treating these patients. While multiple approaches exist for altering the local growth factor concentrations in tissues with poor vascular supply, cellular therapies are a particularly promising strategy for therapeutic angiogenesis [13]. Pro-angiogenic cells are theoretically capable of providing a long-term source of growth factors and even integrating into an expanding vasculature. While endogenous cell types such as mesenchymal stem cells and endothelial progenitor cells are pro-angiogenic, there is growing interest in the capacity of endothelial-like cells derived via reprogramming techniques for therapeutic angiogenesis. The promise of reprogrammed endothelial-like cells lies in the capacity for production of large numbers of efficacious patient-derived autologous cells. Such patient-derived cells would theoretically have reduced immunogenicity upon transplantation back into the patient [14–16]. Endothelial-like cells produced from induced pluripotent stem cells (iPSCs) have been demonstrated to be pro-angiogenic in pre-clinical models [17–20]. Recently, dermal fibroblasts have been transdifferentiated to endothelial-like cells, referred to as induced endothelial cells (iECs) [21–24]. Multiple studies have found that iECs also possess pro-angiogenic properties, augmenting the restoration of blood flow in pre-clinical murine models of PAD [20–23]. The potential benefits of direct transdifferentiation of somatic cells to iECs over reprogramming to full pluripotency to produce endothelial-like cells include potentially reducing production times, increased efficiency, and reduced tumourigenic risk [15, 16, 20, 25]. Existing results demonstrating the pro-angiogenic nature of iECs have used neonatal fibroblasts as the somatic cell type undergoing transdifferentiation [20]. As such, it has not yet been determined whether the pro-angiogenic effects will be replicated in iECs generated from patients with atherosclerotic disease. These patients typically have a high burden of atherosclerotic risk factors including advanced age, smoking, diabetes, hypertension, and hyperlipidaemia, among others. There exists the capacity for these risk factors to influence the epigenetic signature of somatic fibroblasts de- rived from these patients, and for this epigenetic signature to either act as a barrier to transdifferentiation, or perhaps be carried through the transdifferentiation process and impact on iEC phenotype. In addition, recent pro-angiogenic results have been produced using iECs derived using lentiviral vector induced over-expression of the relevant transcription factors [20]. Use of viral vectors that integrate into somatic cell DNA makes reprogrammed cells incompatible with clinical use [20, 24]. Non-integrating factors, such as synthetic modified mRNA, have been used successfully in reprogramming to pluripotency and transdifferentiation and offer a means of producing clinical grade cells [26–30]. The objectives of the work presented within this thesis were to determine whether dermal fibroblasts obtained from PAD patients could be transdifferentiated into iECs using modified mRNA, and to establish whether they replicate the pro- angiogenic properties found in neonatal-derived iECs likewise produced using modified mRNA. We commenced by determining whether fibroblasts from PAD patients could be transdifferentiated into iECs using an existing protocol. We first established patient specific fibroblast cell lines from PAD patients. This was accomplished by taking full thickness skin biopsies from patients undergoing endarterectomies, with skin samples taken from the site of incision. Patients had an array of cardiovascular risk factors consistent with their advanced atherosclerotic disease. We employed a protocol previously used to transdifferentiate neonatal fibroblasts using modified mRNA to up-regulate the transcription factors ETV2, FLI1, GATA2 and KLF4. We successfully transdifferentiated patient-derived fibroblasts to iECs, inducing morphological changes consistent with conversion to endothelial-like cells and establishing a CD31+ population of cells that was sorted from CD31- cells at the completion of the transdifferentiation proto- col. In addition, we applied this protocol to a line of neonatal fibroblasts to establish a neonatal-derived iEC line to act as a control against which to compare the patient- derived iECs in in vitro and in vivo studies. Having established both neonatal and patient-derived iEC lines we proceeded to assess the phenotype of these cell lines with an array of in vitro assays. Both neonatal and patient-derived iEC lines expressed endothelial cell surface markers CD31 and CD144. Neonatal-derived iECs demonstrated tubulogenesis, while the capacity for tubulogenesis was heterogeneous across patient-derived iEC lines. Both neonatal and patient-derived iECs bound the endothelial cell marker UEA 1 lectin, and demonstrated uptake, though limited, of acetylated low density lipoprotein. Both neonatal and patient-derived iECs demonstrated positive trends in their migration towards VEGF though these were not statistically significant. In addition, we compared the cytokine secretion profiles for each cell line for a selection of pro-angiogenic cytokines. Of particular note, we found that patient-derived iECs consistently secreted more VEGF than neonatal-derived iECs. These findings demonstrated that patient-derived and neonatal-derived iECs have similar endothelial-like properties, but that patient specific differences between the patient-derived iEC lines exist. We continued by comparing the capacity for patient-derived and neonatal-derived iEC lines to promote angiogenesis in vivo. The neonatal-derived iEC line and three patient-derived iEC lines were used in a murine model of peripheral arterial disease. In the first such test of neonatal-derived iECs generated using the above-mentioned protocol we established that intramuscular injection of these cells immediately post excision of the femoral vessels led to improved perfusion at days 8-14 post-surgery. These results closely match those of a previous in vivo study using iECs generated with lentiviral vectors [20]. Of the three patient-derived iECs lines investigated, we found that two of these lines produced a similar improvement in perfusion, with improvement noted at 4 and 8 days post-surgery, respectively. The third patient-derived iEC line demonstrated no improvement in perfusion in comparison to control at any time point. These results indicated that the pro-angiogenic capacity of iECs demonstrated in previous pre-clinical studies are replicated in iECs generated using modified mRNA, and that iECs produced from peripheral arterial disease patients have the capacity to induce a similar degree of improvement in perfusion. However, the lack of a response associated with one patient-derived iEC line highlighted the capacity for heterogeneity between patient-derived iEC lines. This study shows that iECs can be successfully generated from patients with severe peripheral arterial disease and that these cells have the capacity to replicate the pro-angiogenic qualities of neonatal-derived iECs. However, the heterogeneity between patient-derived iEC lines highlights the possibility that not all patient-derived iECs will behave identically. This heterogeneity may arise possibly through genetic differences between patients, but also potentially as a result of epigenetic differences that accrue in somatic fibroblasts as a result of a patient’s exposure to atherosclerotic dis- ease risk factors including, notably, advanced age. As a result, the effectiveness of individual patient-derived iEC lines for therapeutic angiogenesis may be dependent on patient-specific factors. These findings support continued investigation of iECs as a potential cellular therapy for peripheral arterial disease, but highlight the need to further investigate the link between patient-specific factors and iEC efficacy.

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Wright, Gary Allan. "Prevalence of left ventricular hypertrophy in peripheral arterial disease and its relation to blood pressure." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/d0f29144-6cbc-4838-bb86-315088fc024f.

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Objectives: To assess the prevalence of left ventricular hypertrophy (LVH) inpatients with newly diagnosed peripheral arterial disease (PAD). Methods: Consecutive patients referred for the first time for assessment of PAD with a history of intermittent claudication and ankle brachial pressure of index of ≤0.9 were recruited. All subjects underwent a full echocardiogram, office blood pressure and 24 hour ambulatory blood pressure monitoring. Results: Out of 350 subjects screened, left ventricular mass measurements were available on 227 (65%). The prevalence of LVH indexed to body surface area was 50%. In a multiple regression model the factors independently related to LVH were age, sex and history of diabetes. There was no relation between presence of LVH and 24 hour blood pressure. Conclusion: LVH is prevalent in patients with PAD and is not associated with 24 hour blood pressure.

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Basile, Ilaria <1979&gt. "Peripheral arterial disease and diabetes: effects on endothelial progenitor cell differentiation and nitric oxide metabolism." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2008. http://amsdottorato.unibo.it/978/1/Tesi_Basile_Ilaria.pdf.

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In the recent years it is emerged that peripheral arterial disease (PAD) has become a growing health problem in Western countries. This is a progressive manifestation of atherothrombotic vascular disease, which results into the narrowing of the blood vessels of the lower limbs and, as final consequence, in critical leg ischemia. PAD often occurs along with other cardiovascular risk factors, including diabetes mellitus (DM), low-grade inflammation, hypertension, and lipid disorders. Patients with DM have an increased risk of developing PAD, and that risk increases with the duration of DM. Moreover, there is a growing population of patients identified with insulin resistance (IR), impaired glucose tolerance, and obesity, a pathological condition known as “metabolic syndrome”, which presents increased cardiovascular risk. Atherosclerosis is the earliest symptom of PAD and is a dynamic and progressive disease arising from the combination of endothelial dysfunction and inflammation. Endothelial dysfunction is a broad term that implies diminished production or availability of nitric oxide (NO) and/or an imbalance in the relative contribution of endothelium-derived relaxing factors. The secretion of these agents is considerably reduced in association with the major risks of atherosclerosis, especially hyperglycaemia and diabetes, and a reduced vascular repair has been observed in response to wound healing and to ischemia. Neovascularization does not only rely on the proliferation of local endothelial cells, but also involves bone marrow-derived stem cells, referred to as endothelial progenitor cells (EPCs), since they exhibit endothelial surface markers and properties. They can promote postnatal vasculogenesis by homing to, differentiating into an endothelial phenotype, proliferating and incorporating into new vessels. Consequently, EPCs are critical to endothelium maintenance and repair and their dysfunction contributes to vascular disease. The aim of this study has been the characterization of EPCs from healthy peripheral blood, in terms of proliferation, differentiation and function. Given the importance of NO in neovascularization and homing process, it has been investigated the expression of NO synthase (NOS) isoforms, eNOS, nNOS and iNOS, and the effects of their inhibition on EPC function. Moreover, it has been examined the expression of NADPH oxidase (Nox) isoforms which are the principal source of ROS in the cell. In fact, a number of evidences showed the correlation between ROS and NO metabolism, since oxidative stress causes NOS inactivation via enzyme uncoupling. In particular, it has been studied the expression of Nox2 and Nox4, constitutively expressed in endothelium, and Nox1. The second part of this research was focused on the study of EPCs under pathological conditions. Firstly, EPCs isolated from healthy subject were cultured in a hyperglycaemic medium, in order to evaluate the effects of high glucose concentration on EPCs. Secondly, EPCs were isolated from the peripheral blood of patients affected with PAD, both diabetic or not, and it was assessed their capacity to proliferate, differentiate, and to participate to neovasculogenesis. Furthermore, it was investigated the expression of NOS and Nox in these cells. Mononuclear cells isolated from peripheral blood of healthy patients, if cultured under differentiating conditions, differentiate into EPCs. These cells are not able to form capillary-like structures ex novo, but participate to vasculogenesis by incorporation into the new vessels formed by mature endothelial cells, such as HUVECs. With respect to NOS expression, these cells have high levels of iNOS, the inducible isoform of NOS, 3-4 fold higher than in HUVECs. While the endothelial isoform, eNOS, is poorly expressed in EPCs. The higher iNOS expression could be a form of compensation of lower eNOS levels. Under hyperglycaemic conditions, both iNOS and eNOS expression are enhanced compared to control EPCs, as resulted from experimental studies in animal models. In patients affected with PAD, the EPCs may act in different ways. Non-diabetic patients and diabetic patients with a higher vascular damage, evidenced by a higher number of circulating endothelial cells (CECs), show a reduced proliferation and ability to participate to vasculogenesis. On the other hand, diabetic patients with lower CEC number have proliferative and vasculogenic capacity more similar to healthy EPCs. eNOS levels in both patient types are equivalent to those of control, while iNOS expression is enhanced. Interestingly, nNOS is not detected in diabetic patients, analogously to other cell types in diabetics, which show a reduced or no nNOS expression. Concerning Nox expression, EPCs present higher levels of both Nox1 and Nox2, in comparison with HUVECs, while Nox4 is poorly expressed, probably because of uncompleted differentiation into an endothelial phenotype. Nox1 is more expressed in PAD patients, diabetic or not, than in controls, suggesting an increased ROS production. Nox2, instead, is lower in patients than in controls. Being Nox2 involved in cellular response to VEGF, its reduced expression can be referable to impaired vasculogenic potential of PAD patients.

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