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1.  Stenting for Peripheral Artery Disease of the Lower Extremities 
Executive Summary
Background
Objective
In January 2010, the Medical Advisory Secretariat received an application from University Health Network to provide an evidentiary platform on stenting as a treatment management for peripheral artery disease. The purpose of this health technology assessment is to examine the effectiveness of primary stenting as a treatment management for peripheral artery disease of the lower extremities.
Clinical Need: Condition and Target Population
Peripheral artery disease (PAD) is a progressive disease occurring as a result of plaque accumulation (atherosclerosis) in the arterial system that carries blood to the extremities (arms and legs) as well as vital organs. The vessels that are most affected by PAD are the arteries of the lower extremities, the aorta, the visceral arterial branches, the carotid arteries and the arteries of the upper limbs. In the lower extremities, PAD affects three major arterial segments i) aortic-iliac, ii) femoro-popliteal (FP) and iii) infra-popliteal (primarily tibial) arteries. The disease is commonly classified clinically as asymptomatic claudication, rest pain and critical ischemia.
Although the prevalence of PAD in Canada is not known, it is estimated that 800,000 Canadians have PAD. The 2007 Trans Atlantic Intersociety Consensus (TASC) II Working Group for the Management of Peripheral Disease estimated that the prevalence of PAD in Europe and North America to be 27 million, of whom 88,000 are hospitalizations involving lower extremities. A higher prevalence of PAD among elderly individuals has been reported to range from 12% to 29%. The National Health and Nutrition Examination Survey (NHANES) estimated that the prevalence of PAD is 14.5% among individuals 70 years of age and over.
Modifiable and non-modifiable risk factors associated with PAD include advanced age, male gender, family history, smoking, diabetes, hypertension and hyperlipidemia. PAD is a strong predictor of myocardial infarction (MI), stroke and cardiovascular death. Annually, approximately 10% of ischemic cardiovascular and cerebrovascular events can be attributed to the progression of PAD. Compared with patients without PAD, the 10-year risk of all-cause mortality is 3-fold higher in patients with PAD with 4-5 times greater risk of dying from cardiovascular event. The risk of coronary heart disease is 6 times greater and increases 15-fold in patients with advanced or severe PAD. Among subjects with diabetes, the risk of PAD is often severe and associated with extensive arterial calcification. In these patients the risk of PAD increases two to four fold. The results of the Canadian public survey of knowledge of PAD demonstrated that Canadians are unaware of the morbidity and mortality associated with PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.
The diagnosis of PAD is difficult as most patients remain asymptomatic for many years. Symptoms do not present until there is at least 50% narrowing of an artery. In the general population, only 10% of persons with PAD have classic symptoms of claudication, 40% do not complain of leg pain, while the remaining 50% have a variety of leg symptoms different from classic claudication. The severity of symptoms depends on the degree of stenosis. The need to intervene is more urgent in patients with limb threatening ischemia as manifested by night pain, rest pain, ischemic ulcers or gangrene. Without successful revascularization those with critical ischemia have a limb loss (amputation) rate of 80-90% in one year.
Diagnosis of PAD is generally non-invasive and can be performed in the physician offices or on an outpatient basis in a hospital. Most common diagnostic procedure include: 1) Ankle Brachial Index (ABI), a ratio of the blood pressure readings between the highest ankle pressure and the highest brachial (arm) pressure; and 2) Doppler ultrasonography, a diagnostic imaging procedure that uses a combination of ultrasound and wave form recordings to evaluate arterial flow in blood vessels. The value of the ABI can provide an assessment of the severity of the disease. Other non invasive imaging techniques include: Computed Tomography (CT) and Magnetic Resonance Angiography (MRA). Definitive diagnosis of PAD can be made by an invasive catheter based angiography procedure which shows the roadmap of the arteries, depicting the exact location and length of the stenosis / occlusion. Angiography is the standard method against which all other imaging procedures are compared for accuracy.
More than 70% of the patients diagnosed with PAD remain stable or improve with conservative management of pharmacologic agents and life style modifications. Significant PAD symptoms are well known to negatively influence an individual quality of life. For those who do not improve, revascularization methods either invasive or non-invasive can be used to restore peripheral circulation.
Technology Under Review
A Stent is a wire mesh “scaffold” that is permanently implanted in the artery to keep the artery open and can be combined with angioplasty to treat PAD. There are two types of stents: i) balloon-expandable and ii) self expandable stents and are available in varying length. The former uses an angioplasty balloon to expand and set the stent within the arterial segment. Recently, drug-eluting stents have been developed and these types of stents release small amounts of medication intended to reduce neointimal hyperplasia, which can cause re-stenosis at the stent site. Endovascular stenting avoids the problem of early elastic recoil, residual stenosis and flow limiting dissection after balloon angioplasty.
Research Questions
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting more effective than percutaneous transluminal angioplasty (PTA) in improving patency?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting provide immediate success compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting associated with less complications compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting compared to PTA reduce the rate of re-intervention?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion) is primary stenting more effective than PTA in improving clinical and hemodynamic success?
Are drug eluting stents more effective than bare stents in improving patency, reducing rates of re-interventions or complications?
Research Methods
Literature Search
A literature search was performed on February 2, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports from 1950 to January Week 3, 2010
Comparative randomized controlled trials (RCTs), systematic reviews and meta-analyses of RCTs
Proven diagnosis of PAD of the lower extremities in all patients.
Adult patients at least 18 years of age.
Stent as at least one treatment arm.
Patency, re-stenosis, re-intervention, technical success, hemodynamic (ABI) and clinical improvement and complications as at least an outcome.
Exclusion Criteria
Non-randomized studies
Observational studies (cohort or retrospective studies) and case report
Feasibility studies
Studies that have evaluated stent but not as a primary intervention
Outcomes of Interest
The primary outcome measure was patency. Secondary measures included technical success, re-intervention, complications, hemodynamic (ankle brachial pressure index, treadmill walking distance) and clinical success or improvement according to Rutherford scale. It was anticipated, a priori, that there would be substantial differences among trials regarding the method of examination and definitions of patency or re-stenosis. Where studies reported only re-stenosis rates, patency rates were calculated as 1 minus re-stenosis rates.
Statistical Analysis
Odds ratios (for binary outcomes) or mean difference (for continuous outcomes) with 95% confidence intervals (CI) were calculated for each endpoint. An intention to treat principle (ITT) was used, with the total number of patients randomized to each study arm as the denominator for each proportion. Sensitivity analysis was performed using per protocol approach. A pooled odds ratio (POR) or mean difference for each endpoint was then calculated for all trials reporting that endpoint using a fixed effects model. PORs were calculated for comparisons of primary stenting versus PTA or other alternative procedures. Level of significance was set at alpha=0.05. Homogeneity was assessed using the chi-square test, I2 and by visual inspection of forest plots. If heterogeneity was encountered within groups (P < 0.10), a random effects model was used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, these analyses were repeated within subgroups of patients defined by time of outcome assessment to evaluate sustainability of treatment benefit. Results were pooled based on the diseased artery and stent type.
Summary of Findings
Balloon-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, there is no significant difference in patency between primary stenting using balloon-expandable bare metal stents and PTA at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 1.26 (0.74, 2.13); 12 months 0.95 (0.66, 1.38); and 24 months 0.72 (0.34. 1.55).
There is no significant difference in clinical improvement, re-interventions, peri and post operative complications, mortality and amputations between primary stenting using balloon-expandable bare stents and PTA in patients with superficial femoral artery. The pooled OR and their corresponding 95% CI are clinical improvement 0.85 (0.50, 1.42); ankle brachial index 0.01 (-0.02, 0.04) re-intervention 0.83 (0.26, 2.65); complications 0.73 (0.43, 1.22); all cause mortality 1.08 (0.59, 1.97) and amputation rates 0.41 (0.14, 1.18).
Self-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, primary stenting using self-expandable bare metal stents is associated with significant improvement in patency at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 2.35 (1.06, 5.23); 12 months 1.54 (1.01, 2.35); and 24 months 2.18 (1.00. 4.78). However, the benefit of primary stenting is not observed for clinical improvement, re-interventions, peri and post operative complications, mortality and amputation in patients with superficial femoral artery disease. The pooled OR and their corresponding 95% CI are clinical improvement 0.61 (0.37, 1.01); ankle brachial index 0.01 (-0.06, 0.08) re-intervention 0.60 (0.36, 1.02); complications 1.60 (0.53, 4.85); all cause mortality 3.84 (0.74, 19.22) and amputation rates 1.96 (0.20, 18.86).
Balloon expandable stents vs PTA in iliac artery occlusive disease
Based on moderate quality of evidence, despite immediate technical success, 12.23 (7.17, 20.88), primary stenting is not associated with significant improvement in patency, clinical status, treadmill walking distance and reduction in re-intervention, complications, cardiovascular events, all cause mortality, QoL and amputation rates in patients with intermittent claudication caused by iliac artery occlusive disease. The pooled OR and their corresponding 95% CI are: patency 1.03 (0.56, 1.87); clinical improvement 1.08 (0.60, 1.94); walking distance 3.00 (12.96, 18.96); re-intervention 1.16 (0.71, 1.90); complications 0.56 (0.20, 1.53); all cause mortality 0.89 (0.47, 1.71); QoL 0.40 (-4.42, 5.52); cardiovascular event 1.16 (0.56, 2.40) and amputation rates 0.37 (0.11, 1.23). To date no RCTs are available evaluating self-expandable stents in the common or external iliac artery stenosis or occlusion.
Drug-eluting stent vs balloon-expandable bare metal stents in crural arteries
Based on a very low quality of evidence, at 6 months of follow-up, sirolimus drug-eluting stents are associated with a reduction in target vessel revascularization and re-stenosis rates in patients with atherosclerotic lesions of crural (tibial) arteries compared with balloon-expandable bare metal stent. The OR and their corresponding 95% CI are: re-stenosis 0.09 (0.03, 0.28) and TVR 0.15 (0.05, 0.47) in patients with atherosclerotic lesions of the crural arteries at 6 months follow-up. Both types of stents offer similar immediate success. Limitations of this study include: short follow-up period, small sample and no assessment of mortality as an outcome. Further research is needed to confirm its effect and safety.
PMCID: PMC3377569  PMID: 23074395
2.  Fetuin-A Levels Are Increased in Patients With Type 2 Diabetes and Peripheral Arterial Disease 
Diabetes Care  2010;34(1):156-161.
OBJECTIVE
Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD).
RESEARCH DESIGN AND METHODS
We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes–PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes–non-PAD) were examined.
RESULTS
Type 2 diabetes–PAD subjects (399 ± 155 μg/ml) had significantly higher fetuin-A levels than type 2 diabetes–non-PAD subjects (247 ± 42; P < 0.001). In NGM-PAD subjects (376 ± 144), fetuin-A was significantly higher than in type 2 diabetes–non-PAD subjects (P < 0.001). Type 2 diabetes–PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes–PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1–3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0–1.7, P = 0.039) for the prevalence of myocardial infarction.
CONCLUSIONS
In contrast to previous findings, fetuin-A was higher in type 2 diabetes–PAD patients than in type 2 diabetes–non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes–non-PAD patients. In type 2 diabetes–PAD patients, fetuin-A was inversely associated with mediasclerosis—the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease.
doi:10.2337/dc10-0788
PMCID: PMC3005446  PMID: 20929991
3.  Link between Peripheral Artery Disease and Heart Rate Variability in Hemodialysis Patients 
PLoS ONE  2015;10(8):e0120459.
Peripheral artery disease (PAD) and low heart rate variability (HRV) are highly prevalent in hemodialysis patients, and both are associated with increased cardiovascular morbidity and mortality. This study aims to examine the suggested relationship between PAD and HRV, and the relationship of parameters before and after hemodialysis. This study enrolled 161 maintenance hemodialysis patients. PAD was defined as ABI < 0.9 in either leg. HRV was performed to assess changes before and after hemodialysis. The change in HRV (△HRV) was defined as post-hemodialysis HRV minus pre-hemodialysis HRV. Patients’ clinical parameters were collected from the dialysis records. All HRV parameters except high frequency (HF) % were lower in patients with PAD than patients without PAD, though not achieving significant level. In patients without PAD, HF (P = 0.013), low frequency (LF) % (P = 0.028) and LF/HF (P = 0.034) were significantly elevated after hemodialysis, whereas no significant HRV parameters change was noted in patients with PAD. Serum intact parathyroid hormone was independently associated with △HF (β = -0.970, P = 0.032) and △LF% (β = -12.609, P = 0.049). Uric acid level (β = -0.154, P = 0.027) was negatively associated with △LF/HF in patients without PAD. Our results demonstrated that some of the HRV parameters were significantly increased after hemodialysis in patients without PAD, but not in patients with PAD, reflecting a state of impaired sympatho-vagal equilibrium. Severity of secondary hyperparathyroidism and hyperuricemia contributed to lesser HRV parameters increase after hemodialysis in patients without PAD.
doi:10.1371/journal.pone.0120459
PMCID: PMC4523171  PMID: 26237669
4.  Prevalence and risk factors associated with peripheral artery disease in elderly patients undergoing peritoneal dialysis 
Background
Rapid growth of the elderly peritoneal dialysis (PD) population is posing a special challenge for renal teams. Peripheral artery disease (PAD) has been reported to be an independent predictor of cardiovascular and all-cause mortality in hemodialysis patients. However, the prevalence and associated risk factors for PAD in elderly PD patients have not yet been fully investigated.
Methods
A total of 69 elderly PD patients were included in the present study. PAD was defined as either an ankle-brachial index < 0.9 or a history of intermittent claudication, lower-limb amputation, foot ulcers, or gangrene. On enrollment, clinical and biochemical characteristics were collected.
Results
The overall prevalence of PAD was 31.9%. Compared with non-PAD patients, PAD patients were significantly older and more likely to be female and have longer PD duration and lower diastolic blood pressure (P < 0.001, = 0.002, 0.018, and 0.007, respectively). Serum albumin level (P < 0.001) and residual renal Kt/V value (P < 0.001) were significantly lower, but the serum C-reactive protein level (P = 0.005) was significantly higher, in PAD patients compared with non-PAD patients. Logistic regression analysis showed that serum albumin level (odds ratio = 1.485, P = 0.040) and residual renal Kt/V value (odds ratio = 1.725, P = 0.016) were independently associated with PAD.
Conclusion
A high prevalence of PAD appeared among elderly PD patients in Macao. Serum albumin level and residual renal Kt/V value were independently related to PAD.
doi:10.2147/VHRM.S37008
PMCID: PMC3480278  PMID: 23112578
ankle-brachial index; atherosclerosis; elderly; peripheral artery disease; peritoneal dialysis
5.  Peripheral Artery Disease, Gender, and Depression in the Heart and Soul Study 
Journal of vascular surgery  2014;60(2):396-403.
Background
Despite the high prevalence of peripheral artery disease (PAD) in women, risk factors for PAD in women are not well understood.
Methods
Gender-specific risk factors for PAD were examined in a prospective cohort study of 1024 patients (184 women and 840 men) with stable coronary artery disease who were recruited between 2000 to 2002. Logistic regression models were used to evaluate associations between traditional and non-traditional risk factors and PAD in both men and women.
Results
11% of women and 13% of men were found to have PAD. Women with PAD had a similar prevalence of traditional risk factors (hypertension, hyperlipidemia, and smoking) compared to women without PAD. Women with PAD were significantly more likely to suffer from depression than women without PAD. Men with PAD were more likely to have hypertension, diabetes mellitus, a history of smoking, a worse lipid profile and higher levels of inflammatory biomarkers compared to men without PAD. In a multivariate model, depression was the only significant factor associated with PAD in women while smoking and elevated fibrinogen were independently associated with PAD in men.
Conclusions
The current findings suggest gender differences in risk factors for the development of PAD. Further research is needed to understand the role of depression in PAD.
doi:10.1016/j.jvs.2014.02.013
PMCID: PMC4199228  PMID: 24661811
6.  Prevalence of peripheral arterial disease in high-risk patients using ankle-brachial index in general practice: a cross-sectional study 
Aims:
The deleterious nature of peripheral arterial disease (PAD) is compounded by a status of underdiagnosed and undertreated disease. We evaluated the prevalence and predictive factors of PAD in high-risk patients using the ankle-brachial index (ABI).
Methods:
The ABI was measured by general practitioners in France (May 2005–February 2006) in 5679 adults aged 55 years or older and considered at high risk. The primary outcome was prevalence of PAD (ABI strictly below 0.90).
Results:
In all, 21.3% patients had signs or symptoms suggestive of PAD, 42.1% had previous history of atherothrombotic disease and 36.6% had two or more cardiovascular risk factors. Prevalence of PAD was 27.8% overall, ranging from 10.4% in patients with cardiovascular risk factors only to approximately 38% in each other subgroup. Prevalence differed depending on the localization of atherothrombotic events: it was 57.1–75.0% in patients with past history of symptomatic PAD; 24.6–31.1% in those who had experienced cerebrovascular and/or coronary events. Regarding the classical cardiovascular risk factors, PAD was more frequent when smoking and hypercholesterolemia history were reported. PAD prevalence was also higher in patients with history of abdominal aortic aneurysm, renal hypertension or atherothrombotic event. Intermittent claudication, lack of one pulse in the lower limbs, smoking, diabetes and renovascular hypertension were the main factors predictive of low ABI.
Conclusions:
Given the elevated prevalence of PAD in high-risk patients and easiness of diagnosis using ABI in primary care, undoubtedly better awareness would help preserve individual cardiovascular health and achieve public health goals.
doi:10.1111/j.1742-1241.2008.01953.x
PMCID: PMC2705819  PMID: 19125994
7.  Prevalence of peripheral arterial disease in patients at non-high cardiovascular risk. Rationale and design of the PANDORA study 
Background
Lower extremity peripheral arterial disease (PAD) is a marker of widespread atherosclerosis. Individuals with PAD, most of whom do not show typical PAD symptoms ('asymptomatic' patients), are at increased risk of cardiovascular ischaemic events. American College of Cardiology/American Heart Association guidelines recommend that individuals with asymptomatic lower extremity PAD should be identified by measurement of ankle-brachial index (ABI). However, despite its associated risk, PAD remains under-recognised by clinicians and the general population and office-based ABI detection is still poorly-known and under-used in clinical practice. The Prevalence of peripheral Arterial disease in patients with a non-high cardiovascular disease risk, with No overt vascular Diseases nOR diAbetes mellitus (PANDORA) study has a primary aim of assessing the prevalence of lower extremity PAD through ABI measurement, in patients at non-high cardiovascular risk, with no overt cardiovascular diseases (including symptomatic PAD), or diabetes mellitus. Secondary objectives include documenting the prevalence and treatment of cardiovascular risk factors and the characteristics of both patients and physicians as possible determinants for PAD under-diagnosis.
Methods/Design
PANDORA is a non-interventional, cross-sectional, pan-European study. It includes approximately 1,000 primary care participating sites, across six European countries (Belgium, France, Greece, Italy, The Netherlands, Switzerland). Investigator and patient questionnaires will be used to collect both right and left ABI values at rest, presence of cardiovascular disease risk factors, current pharmacological treatment, and determinants for PAD under-diagnosis.
Discussion
The PANDORA study will provide important data to estimate the prevalence of asymptomatic PAD in a population otherwise classified at low or intermediate risk on the basis of current risk scores in a primary care setting.
Trial registration number
Clinical Trials.gov Identifier: NCT00689377.
doi:10.1186/1471-2261-10-35
PMCID: PMC2927475  PMID: 20687927
8.  Presence of Peripheral Arterial Disease Predicts Loss of Residual Renal Function in Incident CAPD Patients 
♦ Background: Accelerated cardiovascular disease (CVD), including peripheral arterial disease (PAD), is very common in patients with end-stage renal disease. Residual renal function (RRF) is a strong predictor of patient survival that is suggested to be linked to the degree of CVD. However, the relationship between PAD and decline in RRF has not previously been measured.
♦ Methods: We studied incident continuous ambulatory peritoneal dialysis patients from Peking University Third Hospital. An ankle brachial index of less than 0.9 was used to diagnose PAD. Residual renal function (RRF) was determined as the mean of 24-hour urea and creatinine clearances (glomerular filtration rate). The Cox proportional hazards model was used to identify factors predicting loss of RRF.
♦ Results: The study included 86 patients (age: 61 ± 14 years; men: 51%), 23 of whom had PAD at baseline. Mean follow-up was 19 months (median: 18 months; range: 6 – 30 months). In univariate analysis, baseline PAD, peritonitis during follow-up, inflammation (C-reactive protein), serum uric acid, Ca×P, and serum phosphate were all significantly associated with a greater-than-50% decrease in RRF during follow-up. In multivariate analysis, only baseline PAD, Ca×P, and peritonitis were independently associated with a decline in RRF.
♦ Conclusions: Our study suggests that PAD may be a clinically important marker of CVD predicting the loss of RRF. It remains to be determined whether interventions aimed at decreasing PAD may also improve renal vascular status and thus slow the rate of RRF decline.
doi:10.3747/pdi.2010.00109
PMCID: PMC3525373  PMID: 21532004
Ankle brachial index; end-stage renal disease; cardiovascular disease; inflammation; nutrition; atherosclerosis
9.  Abdominal Obesity is Associated with Peripheral Artery Disease in Hemodialysis Patients 
PLoS ONE  2013;8(6):e67555.
Background
Peripheral arterial disease (PAD) is a leading cause of morbidity in hemodialysis (HD) patients. Recent evidence suggests that abdominal obesity (AO) may play a role in PAD. However, the association between AO and PAD has not been thoroughly studied in HD patients.
Methods
The present cross-sectional study aimed to examine the relationship between AO and PAD in a cohort of 204 chronic HD patients. The ankle brachial index (ABI) was used as an estimate of the presence of PAD. Plasma adiponectin levels, interleukin-6 (IL-6) levels, high sensitivity C-reactive protein (hs-CRP) levels, asymmetric dimethylarginine (ADMA) levels, and lipid profiles were measured. Logistic regression was used to estimate the association between the presence of PAD and AO as well as other potential risk factors.
Results
The metabolic risk factors and all individual traits, including elevated ln-transformed hs-CRP, were found to be significant (P<0.05) more frequently in HD patients with AO than that in control subjects. Patients with AO had a higher prevalence of PAD than the control individuals, with a mean ABI of 0.96±0.23 and 1.08±0.16 (P<0.0001) and PAD prevalence of 26.9% and 10.8% (P = 0.003), respectively. By multivariate analysis, AO (odds ratio [OR], 4.532; 95% CI, 1.765–11.639; P = 0.002), elevated serum ln-transformed ADMA (OR, 5.535; 95% CI, 1.323–23.155; P = 0.019), and ln-transformed IL-6 (OR, 1.567; 95% CI, 1.033–2.378; P = 0.035) were independent predictors of the presence of PAD.
Conclusions
HD patients with AO exhibited a cluster of metabolic risk factors and lower ABI. AO, elevated serum ln-transformed ADMA, and ln-transformed IL-6 were independent predictors of the presence of PAD.
doi:10.1371/journal.pone.0067555
PMCID: PMC3695898  PMID: 23840739
10.  The Prevalence of Peripheral Arterial Disease in Korean Patients with Type 2 Diabetes Mellitus Attending a University Hospital 
Diabetes & Metabolism Journal  2011;35(5):543-550.
Background
Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis and is associated with significant morbidity and mortality. Diabetes is known to increase the risk of PAD two- to four-fold. The prevalence of PAD in Korean diabetic patients has not been established. In this study, we investigated the prevalence of PAD in Korean patients with type 2 diabetes attending a large university hospital and analyzed the factors associated with PAD.
Methods
A total of 2,002 patients with type 2 diabetes who underwent ankle-brachial index (ABI) measurement in an outpatient clinic were enrolled. PAD was defined as an ABI ≤0.9. Clinical characteristics of 64 patients with PAD were compared with those of 192 age- and sex-matched control patients without PAD.
Results
Of the 2,002 type 2 diabetic patients, 64 (3.2%) were diagnosed as having PAD. PAD was associated with higher prevalences of retinopathy, nephropathy, neuropathy, cerebrovascular and coronary artery disease. Patients with PAD had higher systolic blood pressure and serum triglyceride level and reported higher pack-years of smoking. Multivariate analysis showed that the presence of micro- and macrovascular complications and high systolic blood pressure are factors independently associated with PAD.
Conclusion
The prevalence of PAD in diabetic patients was 3.2%, suggesting that the prevalence in Korean diabetic patients is lower than that of patients in Western countries.
doi:10.4093/dmj.2011.35.5.543
PMCID: PMC3221031  PMID: 22111047
Diabetes mellitus, type 2; Peripheral arterial disease; Prevalence; Risk factors
11.  Plasma S100A12 Levels and Peripheral Arterial Disease in End-Stage Renal Disease 
Nephron Extra  2011;1(1):242-250.
Background
S100A12 is an endogenous ligand of the receptor for advanced glycation end products (RAGE). Plasma S100A12 levels are high in end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (HD). Peripheral arterial disease (PAD) is common in HD patients and is associated with increased cardiovascular morbidity and mortality rates in this population. To date, however, no study has specifically assessed the relationship between plasma S100A12 and PAD in HD patients.
Methods
We conducted a cross-sectional study of 152 HD patients in our affiliated hospital. We investigated PAD history and patient characteristics and quantified plasma S100A12 levels in all participants.
Results
HD patients with PAD (n = 26; 21.9 [13.6–33.4] ng/ml) showed significantly higher plasma S100A12 levels than HD patients without PAD (n = 126; 11.8 [7.5–17.6]ng/ml; p < 0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR] 5.71; 95% confidence interval [CI] 1.29–25.3; p = 0.022) was identified as an independent factor associated with PAD prevalence. Another factor associated with PAD prevalence was the ankle-brachial index (OR 0.54; 95% CI 0.40–0.74; p < 0.001).
Conclusion
These results suggest that plasma S100A12 levels are strongly associated with PAD prevalence in ESRD patients undergoing HD.
doi:10.1159/000335198
PMCID: PMC3290833  PMID: 22470398
S100A12; Peripheral arterial disease; Chronic kidney disease; Receptor for advanced glycation end products
12.  Prevalence of lower extremity Peripheral artery disease among adult diabetes patients in Southwestern Uganda 
Background
Peripheral artery disease (PAD) is a major complication of atherosclerosis. PAD can be diagnosed with low-cost diagnostic techniques and is associated with significant morbidity and mortality. While the major epidemiologic risk factors for PAD have been established in the western world, data from resource-poor countries are limited. We performed a cross-sectional study to determine the prevalence and correlates of PAD among patients with diabetes at Mbarara Referral Hospital in southwestern Uganda.
Methods
We consecutively enrolled diabetes patients aged 50 years or greater presenting to the outpatient clinic. We collected blood for fasting lipid profile, HIV serology, and glycosylated hemoglobin, measured blood pressure and ankle brachial index, and administered the Edinburgh Claudication Questionnaire (ECQ). We also surveyed patients for other PAD risk factors. We used logistic regression to determine correlates of PAD.
Results
We enrolled 229 diabetes patients. The median age of 60 years (IQR 55–66), and 146 (63.7%) were female. Fifty five patients (24%) had PAD (ABI of ≤ 0.9). Of these, 48 /55 (87.27%) had mild PAD (ABI 0.71-0.9) while 7/55 (12.73%) had moderate to severe PAD (ABI < 0.7). Amongst those with PAD, 24/55 (43.64%) reported claudication by the ECQ. Correlates of PAD included female sex (AOR 2.25, 95% CI 1.06 - 4.77, p = 0.034), current high blood pressure (AOR 2.59, 95% CI 1.25-5.33, p = 0.01), and being on a sulfonylurea–glibenclamide (AOR 3.47, 95% CI 1.55 - 7.76, p = 0.002).
Conclusion
PAD was common in diabetic patients in southwestern Uganda. Given its low cost and ease of measurement, ABI deserves further assessment as a screening tool for both PAD and long term cardiovascular risk amongst diabetics in this region.
doi:10.1186/1471-2261-14-75
PMCID: PMC4057935  PMID: 24913468
13.  Associations of Diabetes Mellitus and Other Cardiovascular Disease Risk Factors with Decline in the Ankle Brachial Index 
Objectives
We compared associations of diabetes mellitus (DM) and other cardiovascular disease (CVD) risk factors with decline in the ankle brachial index (ABI) over four years in participants with and without peripheral artery disease (PAD).
Methods
Five hundred sixty-six participants, 300 with PAD, were followed prospectively for four years.
Results
Mean (SD) baseline ABI values were 0.70 (0.13) for participants with both PAD and DM, 0.67 (0.14) for participants with only PAD, 1.10 (0.13) for participants with only DM, and 1.10 (0.10) for participants with neither PAD nor DM. After adjusting for age, gender, and baseline ABI, corresponding ABI change from baseline to 4-year follow-up were -0.02, -0.04, +0.05, and +0.05 respectively. Compared to participants with neither PAD nor DM, participants with only PAD showed significantly more ABI decline (P < .01), while the decline in participants with both PAD and DM was borderline non-significant (P = .06). After adjustments for baseline ABI, age, gender, African-American ethnicity, and other cardiovascular disease (CVD) risk factors; independent factors associated with ABI decline in participants with PAD in the lower ABI leg were older age and elevated D-dimer. DM was not related to ABI decline.
Conclusions
Despite being an important risk factor for PAD, DM was not independently associated with ABI decline. This could reflect the effect of DM promoting both PAD and lower extremity arterial stiffness, resulting in a small decline in the ABI over time. In conclusion, ABI change over time in persons with diabetes may not accurately reflect underlying atherosclerosis.
doi:10.1177/1358863X14554033
PMCID: PMC4515111  PMID: 25358555
Peripheral artery disease; Ankle brachial index; Diabetes
14.  Association Between Depression and Peripheral Artery Disease: Insights From the Heart and Soul Study 
Background
Depression is known to increase the risk of coronary artery disease, but few studies have evaluated the association between depression and peripheral artery disease (PAD). We examined the association of depression with PAD and evaluated potential mediators of this association.
Methods and Results
We used data from the Heart and Soul Study, a prospective cohort of 1024 men and women with coronary artery disease recruited in 2000–2002 and followed for a mean of 7.2±2.6 years. Depressive symptoms were assessed with the validated 9-item Patient Health Questionnaire. Prevalent PAD at baseline was determined by self-report. Prospective PAD events were adjudicated on the basis of review of medical records. We used logistic regression and Cox proportional-hazards models to estimate the independent associations of depressive symptoms with prevalent PAD and subsequent PAD events. At baseline, 199 patients (19%) had depressive symptoms (Patient Health Questionnaire ≥10). Prevalent PAD was reported by 12% of patients with depression and 7% of those without depression (base model adjusted for age and sex: odds ratio 1.79, 95% confidence interval 1.06–3.04, P=0.03; full model adjusted for comorbidities, medications, PAD risk factors, inflammation, and health behaviors: odds ratio 1.59, 95% confidence interval 0.90–2.83, P=0.11). During follow-up, PAD events occurred in 7% of patients with depression and 5% of those without depression (base model adjusted for age and sex: hazard ratio 2.09, 95% confidence interval 1.09–4.00, P=0.03; full model adjusted for comorbidities, medications, PAD risk factors, inflammation, and health behaviors: hazard ratio 1.33, 95% confidence interval 0.65–2.71, P=0.44). Factors explaining >5% of the association between depression and incident PAD events included race/ethnicity, diabetes, congestive heart failure, high-density lipoprotein, triglyceride levels, serum creatinine, inflammation, smoking, and levels of physical activity.
Conclusions
Depressive symptoms were associated with a greater risk of PAD. Because the association was explained partly by modifiable risk factors, our findings suggest that more aggressive treatment of these risk factors could reduce the excess risk of PAD associated with depression. (J Am Heart Assoc. 2012;1:e002667 doi: 10.1161/JAHA.112.002667.)
doi:10.1161/JAHA.112.002667
PMCID: PMC3487348  PMID: 23130170
depression; peripheral artery disease; risk factors
15.  Angiotensin Receptor Blockers Decrease the Risk of Major Adverse Cardiovascular Events in Patients with End-Stage Renal Disease on Maintenance Dialysis: A Nationwide Matched-Cohort Study 
PLoS ONE  2015;10(10):e0140633.
Background
Major adverse cardiovascular events (MACE) cause the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD) on maintenance Hemodialysis (HD) or peritoneal dialysis (PD). Many randomized-controlled trials (RCTs) have proved that angiotensin receptor blockers (ARBs) can reduce the risk of MACE in the people with normal or impaired kidney function without dialysis. This study seeks to clarify whether ARBs therapy could also attenuate this risk in patients with ESRD on maintenance dialysis.
Materials and Methods
The National Health Research Institute provided a database of one million random subjects for the study. A random sample was taken of 1800 patients ≥18 years y/o with ESRD on dialysis without a history of MACE and use of ARBs within 6-months prior to enrollment. Cox proportional hazard regression analysis was used to identify the risk factors and compute the hazard ratios accompanying 95% confidence intervals.
Results
In these 1800 patients, 1061 had never used ARBs, while 224 had used them for 1–90 days, and 515 had used them for more than 90 days. We found that ARBs significantly decrease the incidences of acute myocardial infarctions (AMI), coronary artery diseases (CAD) requiring coronary stent or percutaneous transluminal coronary angioplasty (PTCA), peripheral artery disease (PAD) requiring percutaneous transluminal angioplasty (PTA), and acute stroke. Cumulative prescription days of ARBs beyond 365–760 days or more were found to be negatively correlated with incidence of MACEs. For patients with dual comorbidity (i.e., mellitus and hyperlipidemia), 91–365 cumulative prescription days might also attenuate the risk.
Conclusions
For patients on maintenance dialysis, the use of ARBs could significantly attenuate the risk of major cardiovascular events: AMI, acute stroke, and PAD requiring PTA.
doi:10.1371/journal.pone.0140633
PMCID: PMC4619342  PMID: 26488749
16.  Elevated osteoprotegerin is associated with abnormal ankle brachial indices in patients infected with HIV: a cross-sectional study 
Background
Patients infected with HIV have an increased risk for accelerated atherosclerosis. Elevated levels of osteoprotegerin, an inflammatory cytokine receptor, have been associated with a high incidence of cardiovascular disease (including peripheral arterial disease, or PAD), acute coronary syndrome, and cardiovascular mortality. The objective of this study was to determine whether PAD is prevalent in an HIV-infected population, and to identify an association with HIV-specific and traditional cardiovascular risk factors, as well as levels of osteoprotegerin.
Methods
One hundred and two patients infected with HIV were recruited in a cross-sectional study. To identify the prevalence of PAD, ankle-brachial indices (ABIs) were measured. Four standard ABI categories were utilized: ≤ 0.90 (definite PAD); 0.91-0.99 (borderline); 1.00-1.30 (normal); and >1.30 (high). Medical history and laboratory measurements were obtained to determine possible risk factors associated with PAD in HIV-infected patients.
Results
The prevalence of PAD (ABI ≤ 0.90) in a young HIV-infected population (mean age: 48 years) was 11%. Traditional cardiovascular risk factors, including advanced age and previous cardiovascular history, as well as elevated C-reactive protein levels, were associated with PAD. Compared with patients with normal ABIs, patients with high ABIs had significantly elevated levels of osteoprotegerin [1428.9 (713.1) pg/ml vs. 3088.6 (3565.9) pg/ml, respectively, p = 0.03].
Conclusions
There is a high prevalence of PAD in young HIV-infected patients. A number of traditional cardiovascular risk factors and increased osteoprotegerin concentrations are associated with abnormal ABIs. Thus, early screening and aggressive medical management for PAD may be warranted in HIV-infected patients.
doi:10.1186/1758-2652-13-12
PMCID: PMC2859852  PMID: 20307322
17.  Peripheral Arterial Disease in Patients Presenting with Acute Coronary Syndrome in Six Middle Eastern Countries 
To describe prevalence and impact of peripheral arterial disease (PAD) in patients with acute coronary syndrome (ACS), data were collected over 5 months from 6 Middle Eastern countries. Patients were divided into 2 groups (with and without PAD). Out of 6705 consecutive ACS patients, PAD was reported in 177 patients. In comparison to non-PAD, PAD patients were older and more likely to have cardiovascular risk factors. They were more likely to have high Killip class, high GRACE risk score, and non-ST elevation ACS (NSTEACS) at presentation. Thrombolytics, antiplatelet use, and coronary intervention were comparable in both groups. When presented with ST-elevation myocardial infarction (STEMI), patients with PAD had worse outcomes, while in NSTEACS; PAD was associated with higher rate of heart failure in comparison to non-PAD patients. In diabetics, PAD was associated with 2-fold increase in mortality when compared to non-PAD (P = 0.028). After adjustment, PAD was associated with high mortality in STEMI (adjusted OR 2.6; 95% CI 1.23–5.65, P = 0.01). Prevalence of PAD in ACS in the Gulf region is low. Patients with PAD and ACS constitute a high risk group and require more attention. PAD in patients with STEMI is an independent predictor of in-hospital death.
doi:10.1155/2011/815902
PMCID: PMC3246760  PMID: 22220279
18.  Peripheral Artery Disease and Chronic Kidney Disease: Clinical Synergy to Improve Outcomes 
Persons with chronic kidney disease (CKD) are at a higher risk of developing peripheral artery disease (PAD) and its adverse health outcomes than individuals in the general population who have normal renal function. Classic atherosclerosis risk factors care (e.g., age, smoking, diabetes, hypertension and hyperlipidemia) are common in CKD patients, but CKD also imposes additional unique risk factors that promote arterial disease (e.g., chronic inflammation, hypoalbuminemia and a pro-calcific state). Current nephrology clinical practice is adversely impacted by PAD diagnostic challenges, the complexities of managing two serious comorbid diseases, delayed vascular specialist referral, and slow PAD treatment initiation in CKD patients. Persons with CKD are less likely to be provided recommended ‘optimal’ PAD care. The knowledge that both limb and mortality outcomes are significantly worse in CKD patients, especially those on dialysis, is not a biologic fact, but can serve as a care delivery call to action. Nephrologists can facilitate positive change. This manuscript proposes that patients with PAD and CKD be strategically co-managed by care teams that encompass the skills to create and use evidence-based care pathways. This proposed collaborative multidisciplinary approach will include vascular medicine specialists, nephrologists, wound specialists and mid-level providers. Just as clinical care quality metrics have served as the base for ESRD and acute MI quality improvement, it is time that such quality outcomes metrics be initiated for the large PAD-CKD population. This new system will identify and resolve key gaps in the current care model so that clinical outcomes improve within a cost-effective care frame for this vulnerable population.
doi:10.1053/j.ackd.2014.07.005
PMCID: PMC4254470  PMID: 25443571
Peripheral artery disease; kidney disease; clinical outcomes; collaborative care; multi-disciplinary teams
19.  THE RELATIONSHIP BETWEEN SEX HORMONES, SEX HORMONE BINDING GLOBULIN AND PERIPHERAL ARTERY DISEASE IN OLDER PERSONS 
Atherosclerosis  2012;225(2):469-474.
Objective
The prevalence of peripheral artery disease (PAD) increases with aging and is higher in persons with metabolic syndrome and diabetes. PAD is associated with adverse outcomes, including frailty and disability. The protective effect of testosterone and sex hormone binding globulin (SHBG) for diabetes in men suggests that the biological activity of sex hormones may affect PAD, especially in older populations.
Methods
Nine hundred and twenty-one elderly subjects with data on SHBG, testosterone (T), estradiol (E2) were selected from InCHIANTI study. PAD was defined as an Ankle-Brachial Index (ABI) <0.90. Logistic regression models adjusted for age (Model 1), age, BMI, insulin, interleukin-6, physical activity, smoking, chronic diseases including metabolic syndrome (Model 2), and a final model including also sex hormones (Model 3) were performed to test the relationship between SHBG, sex hormones and PAD.
Results
The mean age (± SD) of the 419 men and 502 women was 75.0 ± 6.8 years (Sixty two participants (41 men, 21 women) had ABI<0.90. Men with PAD had SHBG levels lower than men without PAD (p=0.03). SHBG was negatively and independently associated with PAD in men (p=0.028). but not in women. The relationship was however attenuated after adjusting for sex hormones (p=0.07). The E2 was not significantly associated with PAD in both men and women. In women, but not in men, T was positively associated with PAD, even after adjusting for multiple confounders, including E2 (p=0.01).
Conclusions
Low SHBG and high T levels are significantly and independently associated with the presence of PAD in older men and women, respectively.
doi:10.1016/j.atherosclerosis.2012.09.014
PMCID: PMC4050374  PMID: 23102785
SHBG; sex hormones; PAD; older persons
20.  Low Lifetime Recreational Activity is a Risk Factor for Peripheral Arterial Disease 
Background
The relationship between lifetime physical activity and the risk of developing peripheral arterial disease (PAD) is not known.
Methods
We studied 1381 patients referred for elective coronary angiography in a point prevalence analysis. PAD was defined as ankle-brachial index (ABI) < 0.9 at the time or a history of revascularization of the lower extremities regardless of ABI measure. We used a validated physical activity questionnaire to retrospectively measure each patient's lifetime recreational activity (LRA). Multivariate and logistic regression analyses were used to assess the independent association of LRA to ABI and the presence of PAD.
Results
PAD was present in 19% (n=258) of all subjects. Subjects reporting no regular LRA had greater diastolic BP and were more likely to be female. They had lower average ABI, and a higher proportion had PAD (25.6%). In a regression model including traditional risk factors and LRA, multivariate analysis showed that age (p <0.001), female gender (p <0.001), systolic blood pressure (p =0.014), fasting glucose (p <0.001), serum triglycerides (p =0.02) and cumulative pack years (p <0.001) were independent negative predictors of ABI, and LRA was a positive predictor of ABI (p <0.001). History of sedentary lifestyle independently increased the odds ratio for PAD (OR =1.46; 95% CI, 1.0112.103) when assessed by logistic regression. Intriguingly, there is a correlation between physical activity and gender, such that women with low lifetime recreational activity are at greatest risk.
Conclusion
Recalled lifetime recreational activity is positively correlated to ABI and associated with PAD. Whereas the mechanism for this effect is not clear, LRA may be a useful clinical screening tool for PAD risk and strategies to increase adult recreational activity may reduce the burden of PAD later in life.
doi:10.1016/j.jvs.2011.02.052
PMCID: PMC3152670  PMID: 21664093
Intermittent claudication; exercise; vascular disease; atherosclerosis
21.  Lower Extremity Nerve Function in Patients With Lower Extremity Ischemia 
Archives of internal medicine  2006;166(18):1986-1992.
Background
We determined whether lower extremity ischemia, as measured by the ankle brachial index (ABI), is associated with impaired lower extremity nerve function.
Methods
Participants included 478 persons with peripheral arterial disease (PAD) identified from noninvasive vascular laboratories and 292 persons without PAD identified from a general medicine practice and noninvasive vascular laboratories. Peripheral arterial disease was defined as an ABI lower than 0.90 (mild PAD: ABI, 0.70 to <0.90; moderate PAD: ABI, 0.50 to <0.70; and severe PAD: ABI, <0.50). The ABI and electrophysiologic measures of the peroneal, sural, and ulnar nerves were obtained.
Results
Among 546 participants without diabetes, PAD participants had significantly impaired peripheral nerve function in the upper and lower extremities compared with non-PAD participants. After adjusting for age, sex, race, smoking, height, body mass index, recruitment source, alcohol use, disk disease, spinal stenosis, cardiac disease, and cerebrovascular disease, these associations were not statistically significant. After adjusting for confounders among nondiabetic participants, those with severe PAD (ABI, <0.50) had poorer peroneal nerve conduction velocity (NCV) compared with participants without PAD (42.6 vs 44.8 m/s; P=.003) and poorer peroneal NCV compared with participants with mild PAD (42.6 vs 45.0 m/s; P=.001) or moderate PAD (42.6 vs 44.1 m/s; P=.03). Among 224 participants with diabetes, after adjusting for confounders, PAD was associated with poorer peroneal NCV (40.8 vs 43.5 m/s; P=.01), sural nerve amplitude (3.1 vs 4.8 μV; P=.045), and ulnar NCV (47.6 vs 50.2 m/s; P=.03) compared with those without PAD.
Conclusions
Our findings suggest that leg ischemia impairs peroneal nerve function. This association is less strong in patients with diabetes, perhaps because of the overriding influence of diabetes on peripheral nerve function. Clinicians should consider screening for PAD in patients with idiopathic peroneal nerve dysfunction. Peripheral arterial disease–associated nerve dysfunction may contribute to PAD-associated functional impairment.
doi:10.1001/archinte.166.18.1986
PMCID: PMC2645651  PMID: 17030832
22.  High Prevalence of Peripheral Arterial Disease in Korean Patients with Coronary or Cerebrovascular Disease 
Journal of Korean Medical Science  2012;27(6):625-629.
This prospective study surveyed the prevalence of peripheral arterial disease (PAD) in Korean patients with coronary arterial disease (CAD) or cerebrovascular disorder (CVD). From March 2010, 576 hospitalized patients in cardiovascular or stroke center were enrolled as the study group. Ankle-brachial index (ABI) was measured and the cut-off point for diagnosing PAD was ≤ 0.9 at rest. A total of 424 hospitalized patients in the Department of Surgery and aged ≥ 50 yr was enrolled as the control group. The prevalence of PAD was significantly higher in the study group than the control group (7.6% vs 1.7%; P < 0.001). To analyze the relationship of other vascular diseases and PAD, the patients were regrouped; group A (no CAD or CVD), group B (CAD only), group C (CVD only), and group D (CAD and CVD). Compared with group A, those with other vascular diseases (group B, C, D) had significantly higher prevalence of PAD, diabetes, dyslipidemia, renal insufficiency and claudication. The trend that patients with CAD or CVD are at risk of PAD is observed in this cross-sectional study in Koreans. Routine ABI measurement is recommended in these high-risk groups for early detection and proper management of PAD.
doi:10.3346/jkms.2012.27.6.625
PMCID: PMC3369448  PMID: 22690093
Ankle-Brachial Index; Peripheral Arterial Disease; Prevalence; Coronary Artery Disease; Cerebrovascular Disorder
23.  Relationship between Kidney Disease and Endothelial Function in Peripheral Artery Disease 
Journal of vascular surgery  2014;60(6):1605-1611.
Objective
We have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as increased morbidity and mortality in patients undergoing vascular procedures, determining factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired endothelial function (EF) in patients with PAD.
Methods
This was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled into the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation (FMD) was performed to assess EF. Kidney function was characterized by eGFR using the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants.
Results
97 patients with intermittent claudication participated in this study. Mean age was 69 ± 8 years, 97% were male, and 77% were Caucasian. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%) and diabetes mellitus (38%). Mean ABI was 0.73 ± 0.14 and mean FMD was 7.0% ± 3.8, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 ml/min/1.73m2, β: 0.12; CI: 0.05, 0.20; P = .001). After multivariable regression adjusting for age, race, log TNF-α, hypertension, dyslipidemia, and diabetes, eGFR remained significantly associated with EF (P = .033).
Conclusions
In patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process.
doi:10.1016/j.jvs.2014.08.105
PMCID: PMC4254442  PMID: 25441679
24.  Risk Factors and Incidence for Peripheral Arterial Disease in Patients with Typical Lumbar Spinal Stenosis 
Korean Journal of Spine  2014;11(3):183-187.
Objective
Intermittent claudication (IC) is a typical symptom of peripheral arterial disease (PAD) and lumbar spinal stenosis (LSS). In order to prevent misdiagnosis of vascular disease, it is important to know the incidence of and risk factors for PAD in patients with LSS. Therefore, the aim of our study was to evaluate the incidence of and risk factors for PAD in patients with typical and severe LSS who underwent spinal surgical treatment.
Methods
The occurrence of PAD was examined retrospectively in 171 consecutive patients with LSS and severe IC who underwent surgical treatment at our hospital from June 2012 to June 2013. Data were collected on background characteristics (sex, age) and known risk factors for PAD, such as hypertension, diabetes mellitus, smoking, hyperlipidemia, stroke, and ischemic heart disease.
Results
Of the 171 patients enrolled, 7 had an abnormal ankle-brachial index (ABI). Computed tomography angiography (CTA) was performed in these patients, and a final diagnosis of PAD was established for all 7 patients. The incidence of PAD in all patients with LSS was 4.1%(7 of 171). Stroke and ischemic heart disease were significantly more common in the LSSPAD group compared with the LSS group. Multiple logistic regression analyses with a forced-entry method revealed that age and stroke (p<0.05) were independent risk factors for PAD.
Conclusion
To prevent misdiagnosis of fatal PAD, we recommend ABI be assessed in patients with LSS and history of stroke.
doi:10.14245/kjs.2014.11.3.183
PMCID: PMC4206957  PMID: 25346766
Peripheral arterial disease; Ankle brachial pressure index; Lumbar spinal stenosis
25.  Arterial spin labeling MRI reproducibly measures peak-exercise calf muscle perfusion in healthy volunteers and patients with peripheral arterial disease 
JACC. Cardiovascular imaging  2012;5(12):1224-1230.
Objectives
We hypothesized that arterial spin labeling (ASL) magnetic resonance imaging (MRI) at 3 Tesla (T) would be a reliable non-contrast technique for measuring peak exercise calf muscle blood flow in both healthy volunteers and patients with peripheral arterial disease (PAD) and will discriminate between these groups.
Background
Prior work demonstrated the utility of first-pass gadolinium-enhanced calf muscle perfusion MRI in patients with PAD. However, patients with PAD often have advanced renal disease and cannot receive gadolinium.
Methods
PAD patients had claudication and an ankle brachial index 0.4–0.9. Age-matched normal subjects (NL) had no PAD risk factors and were symptom-free with exercise. All performed supine plantar flexion exercise in a 3T MRI scanner using a pedal ergometer until exhaustion or limiting symptoms and were imaged at peak exercise with 15 averaged ASL images. Peak perfusion was measured from ASL blood flow images by placing a region of interest in the calf muscle region with the greatest signal intensity. Perfusion was compared between PAD and NL and repeat testing was performed in 12 subjects (5 NL, 7 PAD) for assessment of reproducibility.
Results
Peak exercise calf perfusion (mean±SD) of 15 NL (age 54±9 years) was higher than in 15 PAD (age 64±5 years, ABI 0.70±0.14) (80±23mL/min-100g vs. 49±16mL/min-100g, p<0.001). Five NL performed exercise matched to PAD and again demonstrated higher perfusion (84±25mL/min-100g, p<0.002). As a measure of reproducibility, intra-class correlation coefficient between repeated studies was 0.87 (95% CI 0.61–0.96). Inter-observer reproducibility was 0.96 (95% CI 0.84–0.99).
Conclusions
ASL is a reproducible non-contrast technique for quantifying peak exercise blood flow in calf muscle. Independent of exercise time, ASL discriminates between NL and PAD. This technique may prove useful for clinical trials of therapies for improving muscle perfusion, especially in patients unable to receive gadolinium.
doi:10.1016/j.jcmg.2012.03.022
PMCID: PMC3531823  PMID: 23236972
Peripheral arterial disease; Magnetic resonance imaging; Perfusion; Arterial spin labeling

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