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      A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease

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          Abstract

          Peripheral artery disease (PAD) is due to the blockage of the arteries supplying blood to the lower limbs usually secondary to atherosclerosis. The most severe clinical manifestation of PAD is critical limb ischemia (CLI), which is associated with a risk of limb loss and mortality due to cardiovascular events. Currently CLI is mainly treated by surgical or endovascular revascularization, with few other treatments in routine clinical practice. There are a number of problems with current PAD management strategies, such as the difficulty in selecting the appropriate treatments for individual patients. Many patients undergo repeated attempts at revascularization surgery, but ultimately require an amputation. There is great interest in developing new methods to identify patients who are unlikely to benefit from revascularization and to improve management of patients unsuitable for surgery. Circulating biomarkers that predict the progression of PAD and the response to therapies could assist in the management of patients. This review provides an overview of the pathophysiology of PAD and examines the association between circulating biomarkers and PAD presence, severity and prognosis. While some currently identified circulating markers show promise, further larger studies focused on the clinical value of the biomarkers over existing risk predictors are needed.

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          Peripheral arterial disease detection, awareness, and treatment in primary care.

          Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis that is common and is associated with an increased risk of death and ischemic events, yet may be underdiagnosed in primary care practice. To assess the feasibility of detecting PAD in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics. The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a multicenter, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States in June-October 1999. A total of 6979 patients aged 70 years or older or aged 50 through 69 years with history of cigarette smoking or diabetes were evaluated by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was 0.90 or less, if it was documented in the medical record, or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease. Frequency of detection of PAD; physician and patient awareness of PAD diagnosis; treatment intensity in PAD patients compared with treatment of other forms of CVD and with patients without clinical evidence of atherosclerosis. PAD was detected in 1865 patients (29%); 825 of these (44%) had PAD only, without evidence of CVD. Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Among patients with PAD, classic claudication was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis risk factor profiles compared with those who had CVD. Smoking behavior was more frequently treated in patients with new (53%) and prior PAD (51%) only than in those with CVD only (35%; P <.001). Hypertension was treated less frequently in new (84%) and prior PAD (88%) only vs CVD only (95%; P <.001) and hyperlipidemia was treated less frequently in new (44%) and prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications were prescribed less often in patients with new (33%) and prior PAD (54%) only vs CVD only (71%, P<.001). Treatment intensity for diabetes and use of hormone replacement therapy in women were similar across all groups. Prevalence of PAD in primary care practices is high, yet physician awareness of the PAD diagnosis is relatively low. A simple ABI measurement identified a large number of patients with previously unrecognized PAD. Atherosclerosis risk factors were very prevalent in PAD patients, but these patients received less intensive treatment for lipid disorders and hypertension and were prescribed antiplatelet therapy less frequently than were patients with CVD. These results demonstrate that underdiagnosis of PAD in primary care practice may be a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD.
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            Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000.

            Peripheral arterial disease (PAD) is associated with significant morbidity and mortality and is an important marker of subclinical coronary heart disease. However, estimates of PAD prevalence in the general US population have varied widely. We analyzed data from 2174 participants aged 40 years and older from the 1999-2000 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial index <0.90 in either leg. The prevalence of PAD among adults aged 40 years and over in the United States was 4.3% (95% CI 3.1% to 5.5%), which corresponds to approximately 5 million individuals (95% CI 4 to 7 million). Among those aged 70 years or over, the prevalence was 14.5% (95% CI 10.8% to 18.2%). In age- and gender-adjusted logistic regression analyses, black race/ethnicity (OR 2.83, 95% CI 1.48 to 5.42) current smoking (OR 4.46, 95% CI 2.25 to 8.84), diabetes (OR 2.71, 95% CI 1.03 to 7.12), hypertension (OR 1.75, 95% CI 0.97 to 3.13), hypercholesterolemia (OR 1.68, 95% CI 1.09 to 2.57), and low kidney function (OR 2.00, 95% CI 1.08 to 3.70) were positively associated with prevalent PAD. More than 95% of persons with PAD had 1 or more cardiovascular disease risk factors. Elevated fibrinogen and C-reactive protein levels were also associated with PAD. This study provides nationally representative prevalence estimates of PAD in the United States, revealing that PAD affects more than 5 million adults. PAD prevalence increases dramatically with age and disproportionately affects blacks. The vast majority of individuals with PAD have 1 or more cardiovascular disease risk factors that should be targeted for therapy.
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              Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.

              In persons with diabetes, chronic hyperglycemia (assessed by glycosylated hemoglobin level) is related to the development of microvascular disease; however, the relation of glycosylated hemoglobin to macrovascular disease is less clear. To conduct a meta-analysis of observational studies of the association between glycosylated hemoglobin and cardiovascular disease in diabetic persons. Search of the MEDLINE database by using Medical Subject Heading search terms and key words related to glycosylated hemoglobin, diabetes, and cardiovascular disease. Prospective cohort studies with data on glycosylated hemoglobin levels and incident cardiovascular disease. Relative risk estimates were derived or abstracted from each cohort study that met the inclusion criteria. Adjusted relative risk estimates for glycosylated hemoglobin (total glycosylated hemoglobin, hemoglobin A1, or hemoglobin A1c levels) and cardiovascular disease events (coronary heart disease and stroke) were pooled by using random-effects models. Three studies involved persons with type 1 diabetes (n = 1688), and 10 studies involved persons with type 2 diabetes (n = 7435). The pooled relative risk for cardiovascular disease was 1.18; this represented a 1-percentage point increase in glycosylated hemoglobin level (95% CI, 1.10 to 1.26) in persons with type 2 diabetes. Results in persons with type 1 diabetes were similar but had a wider CI (pooled relative risk, 1.15 [CI, 0.92 to 1.43]). This review largely reflects the limitations of the literature. Important concerns were residual confounding, the possibility of publication bias, the small number of studies, and the heterogeneity of study results. Pending confirmation from large, ongoing clinical trials, this analysis shows that observational studies are consistent with limited clinical trial data and suggests that chronic hyperglycemia is associated with an increased risk for cardiovascular disease in persons with diabetes.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                18 May 2015
                May 2015
                : 16
                : 5
                : 11294-11322
                Affiliations
                [1 ]The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine & Dentistry, James Cook University, Townsville, QLD 4811, Australia; E-Mails: smriti.krishna@ 123456jcu.edu.au (S.M.K.); joseph.moxon@ 123456jcu.edu.au (J.V.M.)
                [2 ]Department of Vascular and Endovascular Surgery, the Townsville Hospital, Townsville, QLD 4810, Australia
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: jonathan.golledge@ 123456jcu.edu.au ; Tel.: +61-7-4796-1417; Fax: +61-7-4796-1401.
                Article
                ijms-16-11294
                10.3390/ijms160511294
                4463701
                25993296
                75ec1a65-11b1-485b-b298-262b0bf206da
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 February 2015
                : 08 April 2015
                Categories
                Review

                Molecular biology
                peripheral artery disease,critical limb ischemia,biomarkers,angiogenesis,arteriogenesis

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