No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Humoral predictors of ankle-brachial index in patients with peripheral arterial disease and controls
Abstract
Introduction:
Peripheral arterial disease (PAD) is a common condition due to atherosclerosis with high prevalence in population over 55 years. Although its pathophysiology is well recognized, the role of inflammatory markers is still not fully known.
Objectives:
The aim of the study was to assess the relation of C-reactive protein (CRP), tumor necrosis factors-alpha (TNF-alpha) and interleukin-6 (IL-6) to ankle-brachial index (ABI) and metabolic variables in patients with PAD. The second aim was to find the most significant humoral predictor of ABI.
Patients and methods:
The study groups consisted of 55 patients (36 men and 19 women) diagnosed with PAD (age 63.65 ± 6.11 years) and 34 control subjects (7 men, 27 women) of average age 59.88 ± 6.10 years with ABI > 0.9. Blood samples were analyzed for glycaemia, lipid profile and inflammatory markers (CRP, TNF-alpha and IL-6).
Results:
A significantly higher serum total cholesterol (p = 0.04), triglycerides (p = 0.005) and lower HDL cholesterol (p < 0.0001) were found in the PAD group as compared to controls. Patients with PAD had significantly higher serum glucose (p = 0.008), CRP (p = 0.0044), IL-6 (p < 0.0001) and TNF-α (p < 0.0001) in comparison to controls. In a multiple linear regression analysis among variables log IL-6 and log HDL cholesterol were most significantly related to ABI (LW 4.75 for log IL-6, LW 4.016 for log HDL cholesterol, respectively, p < 0.01) in all subjects.
Conclusions:
We conclude that among traditional and humoral risk factors IL-6 is the strongest predictor of ABI. HDL cholesterol is also significant and strong predictor of decreased ABI and could be a potential biomarker of PAD in patients using lipid lowering drugs (Tab. 1, Ref. 31).
... Some researchers believe IL-6 is more specific to vascular inflammation than CRP [134]. Previous studies have found higher IL-6 levels associated with the incidence of PAD and PAD severity [135][136][137][138][139]. Supporting the role of IL-6 in PAD diagnosis and risk stratification, Chen et al. found that patients with a higher grade of CT-derived peripheral artery stenosis had higher IL-6 levels than those with lower stenosis grades (Table 2) [140]. ...
... C-reactive protein, a well-established marker of systemic inflammation, is the most studied molecular marker for PAD diagnosis and prognosis. Circulating CRP levels are increased in PAD patients compared to healthy subjects and are associated with PAD severity [135,[150][151][152][153]. Elevated CRP levels in PAD patients are associated with an increased risk of major adverse cardiovascular events (MACE) and mortality [154,155]. ...
... In 2020, Bueno et al. found that symptomatic carotid artery disease patients had higher 18 F-FDG uptake and circulating CRP than asymptomatic patients, but a direct correlation between 18 F-FDG uptake and CRP levels was not presented [157]. Other inflammation-indicating biomarkers, such as IL-8, pentraxin-3 (PTX-3), neutrophil gelatinase-associated lipocalin (NGAL), calprotectin, or tumor necrosis factor (TNF)-α, have also shown their potential in PAD diagnosis, among which PTX-3 and TNF-α were also associated with PAD severity [133,135,143,151]. Future studies are still needed to illustrate the relationship between these inflammatory markers and imaging markers of PAD. ...
Peripheral artery disease (PAD) is a common and debilitating condition characterized by the narrowing of the limb arteries, primarily due to atherosclerosis. Non-invasive multi-modality imaging approaches using computed tomography (CT), magnetic resonance imaging (MRI), and nuclear imaging have emerged as valuable tools for assessing PAD atheromatous plaques and vessel walls. This review provides an overview of these different imaging techniques, their advantages, limitations, and recent advancements. In addition, this review highlights the importance of molecular markers, including those related to inflammation, endothelial dysfunction, and oxidative stress, in PAD pathophysiology. The potential of integrating molecular and imaging markers for an improved understanding of PAD is also discussed. Despite the promise of this integrative approach, there remain several challenges, including technical limitations in imaging modalities and the need for novel molecular marker discovery and validation. Addressing these challenges and embracing future directions in the field will be essential for maximizing the potential of molecular and imaging markers for improving PAD patient outcomes.
... Early in 2001, Ridker PM et al. reported the use of CRP as a potential marker of incident PAD [19], which was later confirmed by other authors [14,20]. In addition, several prospective studies have reported increased levels of CRP in PAD patients compared to controls [14,[21][22][23][24] and an association with PAD severity and ABI [25][26][27]. CRP has also been proposed as a marker of worse outcome considering major CV events (stroke and myocardial infarction), major amputation/revascularization and mortality in high risk PAD patients [14,23,28], although it has been suggested that CRP might be more useful for short-term risk prediction rather than for long-term evaluation [29,30]. ...
... The impact of other inflammatory biomarkers for PAD diagnosis and prognosis has been also evaluated ( Table 1). For instance, IL-6, IL-8, pentraxin-3, neutrophil gelatinaseassociated lipocalin (NGAL), calprotectin or tumor necrosis factor (TNF)-α were significantly higher in PAD patients compared with healthy controls [14,[21][22][23][24]33,34], and some of these candidates; IL-6, TNF-α, and pentraxin-3 were associated to PAD severity, assessed either by ABI or clinical scales [21,23,52]. Among those pro-inflammatory markers, IL-6 stands out as a prominent predictor of functional outcomes. ...
... The impact of other inflammatory biomarkers for PAD diagnosis and prognosis has been also evaluated ( Table 1). For instance, IL-6, IL-8, pentraxin-3, neutrophil gelatinaseassociated lipocalin (NGAL), calprotectin or tumor necrosis factor (TNF)-α were significantly higher in PAD patients compared with healthy controls [14,[21][22][23][24]33,34], and some of these candidates; IL-6, TNF-α, and pentraxin-3 were associated to PAD severity, assessed either by ABI or clinical scales [21,23,52]. Among those pro-inflammatory markers, IL-6 stands out as a prominent predictor of functional outcomes. ...
Peripheral arterial disease (PAD) of the lower extremities is a chronic illness predominantly of atherosclerotic aetiology, associated to traditional cardiovascular (CV) risk factors. It is one of the most prevalent CV conditions worldwide in subjects >65 years, estimated to increase greatly with the aging of the population, becoming a severe socioeconomic problem in the future. The narrowing and thrombotic occlusion of the lower limb arteries impairs the walking function as the disease progresses, increasing the risk of CV events (myocardial infarction and stroke), amputation and death. Despite its poor prognosis, PAD patients are scarcely identified until the disease is advanced, highlighting the need for reliable biomarkers for PAD patient stratification, that might also contribute to define more personalized medical treatments. In this review, we will discuss the usefulness of inflammatory molecules, matrix metalloproteinases (MMPs), and cardiac damage markers, as well as novel components of the liquid biopsy, extracellular vesicles (EVs), and non-coding RNAs for lower limb PAD identification, stratification, and outcome assessment. We will also explore the potential of machine learning methods to build prediction models to refine PAD assessment. In this line, the usefulness of multimarker approaches to evaluate this complex multifactorial disease will be also discussed.
... Levels of markers like Il-6, IL-8, TNF-α, pentraxin-3, and calprotectin were reported to be increased in PAD patients compared to the control group [27]. In addition, IL-6 and TNF-α were also associated with the severity of PAD evaluated by clinical scales and by the ankle-brachial index (ABI) [29][30][31]. Overall, the pathomechanism of the development and progression of diabetic lower limb ulcers involves the role that IL-6 and TNF-α play in stimulating inflammation, oxidative stress, and impaired wound healing. In diabetic patients with peripheral neuropathy, these cytokines can further increase the risk of developing foot ulcers due to the loss of protective sensation and impaired neurovascular function. ...
Inflammation is involved in the pathomechanism of vascular diseases. Pro-inflammatory cytokines are important in perioperative monitoring. The aim of the study was the perioperative assessment of biochemical tests and inflammatory markers in patients with vasculopathy, focusing on the identification of subjects prone to complications. The study was performed between 2020 and 2023 at the Clinical County Hospital in Târgu Mureș on enrolled diabetic and non-diabetic patients with vasculopathy and lower limb surgery (amputation or necrectomy). Pre- and postoperative inflammatory markers, biochemical, and hematological tests (n = 62) were performed. Positive correlation was found between preoperative C-reactive protein (CRP) and interleukin-6 (IL-6) levels, and between preoperative triglyceridemia and glycemia/cholesterolemia. Positive correlation was present between pre- and postoperative values of IL-6, tumor necrosis factor-alfa (TNF-α), CRP, and fibrinogen. Preoperative TNF-α values positively correlated with malondialdehyde (MDA) levels, postoperative TNF-α values with transaminase enzymes. Diabetic patients presented higher IL-6 results compared to non-diabetic subjects. We can conclude that dynamic assessment of inflammatory markers is appropriate for monitoring perioperative course. Half of the subjects presented moderately increased preoperative IL-6 levels, and one quarter had critically high values, which might predict prolonged hospitalization. The assessment of oxidative stress, inflammatory markers and biochemical parameters enables the identification of patients prone to complications, so they can benefit from more complex management.
... The levels of IL-6 and IL-8 are significantly higher in PAD patients 13,24-29 . IL-6 is linked to PAD severity 25,27,30 . In comparison to normal individual groups, PAD have been found to have higher levels of circulating soluble intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) 13,26,28,29,31,32 . ...
The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation. The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy. Therefore, current study is aimed to evaluate the inflammatory and endothelial dysfunction markers with their correlation to biomarkers that can help for in-time diagnosis and efficient prognosis of developing diabetes-associated PAD. Enzyme-linked immunosorbent assay was used to evaluate the interlukin-6, interlukin-8, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) in PAD with diabetes group, diabetic group and healthy individual group while biomarkers were measured by kit method. It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16). The overall means for the parameters, IL-6, IL-8, ICAM, VCAM, urea, S/creatinine, CK-MB, AST, ALT, cholesterol, triglyceride, HDL, LDL, PT, aPTT, INR, HbA1C, and CRP within all groups were significantly (P < 0.05) different from each other. Therefore, it was concluded that the change in IL-6, IL-8, ICAM and VCAM can serve as an accurate diagnostic indicator and successful treatment.
Background:
Inflammatory responses mediated by adipocytokines may affect both atherosclerosis development and progression, as well as the risk of in-stent restenosis. The aim of this study was to determine the relationships between blood leptin, adiponectin and tumor necrosis factor-alpha (TNF-alpha) concentrations and the 1-year outcome of superficial femoral artery (SFA) stenting.
Methods:
Blood concentrations of leptin, adiponectin and TNF-alpha were determined in 70 patients undergoing SFA stenting due to intermittent claudication and in 40 patients undergoing carotid artery stenting (CAS). All subjects were followed up for at least 1 year in relation to the occurrence of clinically driven target lesion revascularization (TLR) or a major adverse cardiovascular event (MACE).
Results:
Patients undergoing SFA stenting and CAS had similar blood adipocytokine concentrations. Patients with diabetes mellitus presented a higher leptin concentration, lower adiponectin-to-leptin ratio, and lower blood adiponectin concentration indexed to fat mass (FM) and to visceral adiposity score (VAS). In Kaplan-Meier analysis, blood concentration of TNF-alpha indexed to FM and to VAS was higher in patients who underwent TLR and MACE. However, in multifactorial analysis, the severity of atherosclerosis lesions in the femoropopliteal vascular region, estimated in relation to TASC-II classification, was the only predictor of TLR.
Conclusions:
Circulating adipocytokines did not distinguish patients with different clinical manifestations of atherosclerosis. Higher ratios of TNF-alpha-to-FM and to VAS before SFA stenting were related to TLR and MACE occurrence. Dysregulation in adipocytokine secretion may be a potential mediator of a pro-atherogenic action of diabetes mellitus in patients with peripheral artery disease.
Background
Strong evidence implicates inflammation in the development of atherosclerotic heart disease but less is known about peripheral arterial disease (PAD). Our objective was to test the hypothesis that a composite index of inflammatory burden is associated with PAD. Methods
Cross-sectional analysis of a randomly-selected group of 903 community-dwelling men in the MrOS cohort recruited between 2000 and 2002. Using blood samples, we measured seven cytokines and related these levels to prevalent PAD (ankle-brachial index (ABI) <0.9) both individually and as part of an “inflammatory burden score” (a composite sum of the number of pro-inflammatory cytokines in the highest quartile). ResultsOverall, 6.75% of men had ABI <0.9. The odds of prevalent PAD were higher in men with the highest quartile (Q4) levels of interleukin-6 multivariable (MV) adjusted (odds ratio (OR) =3.95 (95% CI, 1.4–11.3), tumor necrosis factor alpha OR = 4.44 (95% confidence interval (CI), 1.5–12.8), and C-reactive protein OR = 3.63 (95% CI, 1.4–9.4) compared to men in Q1. The magnitude of the association of these cytokines with PAD was similar to the effect of being 10 years older, OR = 2.41 (95% CI, 1.16–3.7). These significant effects persisted after additional MV adjustment for smoking except for CRP. Men with the highest inflammatory burden score (≥3) had 3.6 (95% CI, 1.5–8.7) increased odds of PAD, p trend = 0.03. After smoking adjustment the linear trend was borderline statistically significant (p trend = 0.10). Conclusion
Inflammatory burden is associated with prevalent PAD, an association similar to aging 10 years. The inflammatory effects of smoking contributes to the underlying association between inflammation and PAD.
Previous research analyzed the level of plasma inflammatory markers in patients with coronary disease, but very few studies have evaluated these markers in patients with peripheral arterial disease (PAD). The objective of this study was to investigate the plasma levels of inflammatory markers in patients with PAD and in healthy controls. The following plasma levels of biomarkers were measured in 80 patients with PAD (mean age 68 ± 5 years) and in 72 healthy participants (mean age 67 ± 6 years): interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), L-selectin (LS), neopterin (N), P-selectin (PS), E-selectin (ES), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and matrix metalloproteinase 2 (MMP-2), and 9 (MMP-9). Significantly higher levels of IL-6 (P < .001), TNF-α (P < .0001), ES (P < .0001), LS (P < .0001), PS (P < .0001), ICAM-1 (P < .001), VCAM-1 (P < .001), N (P < .001), MMP-2 (P < .001), and MMP-9 (P < .005) were found in the patients with PAD. Patients with PAD show a inflammation marker profile different from that of control participants. Reducing the high plasma levels of inflammatory markers could be a new therapeutic approach both for the prevention and the treatment of PAD.
. The level of systemic inflammation as measured by circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6) is linked to an increased risk for cardiovascular diseases (CVD) and cancer.
Methods
. We recruited 154 current and former smokers between 40 and 80 years of age with 25 or more pack-years of smoking history to study the relationship between inflammatory markers (CRP and IL-6) and smoking status.
Results
. Our results show that male smokers had significantly higher levels of serum IL-6 compared to male former smokers. We did not find any gender specific differences for smoking and CRP levels but the IL-6 levels were slightly lower in females compared to males. Additionally, our results show that CRP is significantly associated with IL-6 regardless of smoking status. Modelling indicates that the significant predictors of CRP levels were biomarkers of the metabolic syndrome while the significant predictors of IL-6 levels were age and plasma triglycerides among former smokers and the numbers of smoked packs of cigarettes per year among smokers.
Conclusions
. In conclusion, our study showed that CRP levels were not associated with markers of smoking intensity. However, IL-6 levels were significantly associated with smoking especially among current smokers.
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.
Background
Peripheral artery disease (PAD) is associated with impaired mobility and a high rate of mortality. The aim of this systematic review was to investigate whether reduced lower extremity performance was associated with an increased incidence of cardiovascular and all‐cause mortality in people with PAD.
Methods and Results
A systematic search of the MEDLINE, EMBASE, SCOPUS, Web of Science, and Cochrane Library databases was conducted. Studies assessing the association between measures of lower extremity performance and cardiovascular or all‐cause mortality in PAD patients were included. A meta‐analysis was conducted combining data from commonly assessed performance tests. The 10 identified studies assessed lower extremity performance by strength tests, treadmill walking performance, 6‐minute walk, walking velocity, and walking impairment questionnaire (WIQ). A meta‐analysis revealed that shorter maximum walking distance was associated with increased 5‐year cardiovascular (unadjusted RR=2.54, 95% CI 1.86 to 3.47, P<10−5, n=1577, fixed effects) and all‐cause mortality (unadjusted RR=2.23 95% CI 1.85 to 2.69, P<10−5, n=1710, fixed effects). Slower 4‐metre walking velocity, a lower WIQ stair‐climbing score, and poor hip extension, knee flexion, and plantar flexion strength were also associated with increased mortality. No significant associations were found for hip flexion strength, WIQ distance score, or WIQ speed score with mortality.
Conclusions
A number of lower extremity performance measures are prognostic markers for mortality in PAD and may be useful clinical tools for identifying patients at higher risk of death. Further studies are needed to determine whether interventions that improve measures of lower extremity performance reduce mortality.
Low-grade systemic inflammation plays an important role in the pathogenesis and natural history of chronic obstructive pulmonary disease (COPD) and peripheral arterial disease (PAD). The aim of the study was to analyze plasma concentrations of selected markers of inflammation in patients suffering from PAD with or without coexistent COPD.
Thirty patients (6 women) with advanced PAD (at least IIb stage according to Fontaine scale) hospitalized due to critical limb ischemia were examined. In all patients spirometry was performed to confirm or exclude COPD. Plasma concentration of IL-6, IL-8 and TNF-α was measured using ELISA method. Statistical analysis was performed according to COPD status and according to smoking status independently.
In the whole group of patients with PAD, COPD was recognized in 14 cases (for the first time in 10 cases). All patients were smokers (46.7% current, 53.3% ex-smokers). We found a significant correlation between FEV1%N (percent of norm of first second expiratory volume) and the number of years of smoking (r = -0.39; p < 0.05). We found similar concentrations of IL-6 (2.54 pg/ml vs. 2.31 pg/ml), IL-8 (8.55 pg/ml vs. 8.14 pg/ml, TNF-α (0.72 pg/ml vs. 1.75 pg/ml) in the COPD(+) group in comparison to the COPD(-) group (differences were not significant). We observed significant positive correlations (p < 0.05) between concentrations of measured markers and significant negative correlations between pain free walking distance and these markers.
Our study confirmed coexistence of PAD with COPD. The character of inflammation is similar in these smoking-related diseases.
Peripheral artery disease (PAD), which consists of partial or complete obstruction of the arteries in the lower limbs, is one of the most common manifestations of atherosclerosis, affecting ≈27 million individuals in Europe and North America.1 Its main symptomatic expression, intermittent claudication, was first described by the French veterinarian Bouley2 in a horse affected by progressive limping and lameness consequent to a fibrous clot that occluded the femoral arteries of the posterior limbs. In humans, this condition was noted by Brodie3 in 1846, but it was Charcot4 who in 1858 clearly defined and described the syndrome (and used the term “intermittent claudication”).3,4 Reproducibly elicited by walking-induced muscle ischemia and consistently relieved by rest that allows reperfusion of the affected limb, intermittent claudication may be considered “leg effort angina.” Indeed, for a long time, treatment was aimed exclusively at relieving leg symptoms and improving the functional status of affected individuals. However, in the 1950s, Stammers5 and Allen et al6 independently observed that patients with claudication were at high mortality risk. Subsequent prospective studies confirmed that patients with PAD rarely progress to limb loss but that the presence of PAD is a powerful and independent predictor of cardiac and cerebral ischemic events.7,–,11 However, this increased risk appears to be poorly related to classic risk factors, suggesting that once PAD is established, subsequent cardiovascular risk is related to the severity and extent of the underlying atherosclerotic disease and possibly other factors.7,–,11
It is well established that hypertension, smoking, diabetes mellitus, and hypercholesterolemia play a major role in the initiation and development of atherosclerosis and its clinical manifestations, although the prognostic potency of each of these factors in atherogenesis differs in the …
Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic inflammation. The aim of our study was to assess whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 6 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 6 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFa) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-I were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were signifi cantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001).
These results confi rm that white blood cell activation is characteristic of systemic atherosclerosis and that these inflammation markers increase in conditions of hemodynamic stress.
Peripheral arterial disease (PAD) is usually taken to mean arterial occlusive disease because of arteriosclerosis, impeding the blood flow to the lower extremity. Of course, it is important to keep in mind that a broader definition of PAD would include all noncoronary arterial disease, including carotid artery disease. Furthermore, there are many disorders that can cause arterial occlusive disease other than arteriosclerosis although it is by far the most common. These disorders can be due to pathobiology intrinsic to the vessel wall, as in vasculitis, thromboangiitis obliterans, or fibromuscular dysplasia; or secondary to extrinsic pathology as in compression syndromes, such as popliteal artery entrapment. Embolic disease (such as that due to atheroembolism from a diseased aorta, or cardiogenic thrombus) or dissection of the aorta, may cause occlusion of peripheral arteries. In addition, the broad scope of PADs includes nonocclusive arterial disease, such as aneurysms, traumatic or congenital arteriovenous fistulas or malformations, and vascular tumors. However, for the purposes of this compendium, we focus on atherosclerotic arterial occlusive disease that impairs blood flow to the lower extremities.
Defined in this way, PAD is the most common disease that is most commonly overlooked. Although it is unusual for PAD to manifest in those aged 65 years, and ≈20% of individuals aged >80 years.1 Regrettably, most of these individuals are not diagnosed, as documented in the PARTNERS (PAD Awareness, Risk, and Treatment: New Resources for Survival) screening study.2 As a consequence, individuals with PAD are less likely than those with coronary artery disease to receive optimal medical therapy (OMT). This is a tragic situation because OMT saves life and limb. In their comprehensive and lucid review of medical therapy, Creager and Bonaca 3 point out …
New data on the epidemiology of peripheral artery disease (PAD) are available, and they should be integrated with previous data. We provide an updated, integrated overview of the epidemiology of PAD, a focused literature review was conducted on the epidemiology of PAD. The PAD results were grouped into symptoms, diagnosis, prevalence, and incidence both in the United States and globally, risk factors, progression, coprevalence with other atherosclerotic disease, and association with incident cardiovascular morbidity and mortality. The most common symptom of PAD is intermittent claudication, but noninvasive measures, such as the ankle-brachial index, show that asymptomatic PAD is several times more common in the population than intermittent claudication. PAD prevalence and incidence are both sharply age-related, rising >10% among patients in their 60s and 70s. With aging of the global population, it seems likely that PAD will be increasingly common in the future. Prevalence seems to be higher among men than women for more severe or symptomatic disease. The major risk factors for PAD are similar to those for coronary and cerebrovascular disease, with some differences in the relative importance of factors. Smoking is a particularly strong risk factor for PAD, as is diabetes mellitus, and several newer risk markers have shown independent associations with PAD. PAD is strongly associated with concomitant coronary and cerebrovascular diseases. After adjustment for known cardiovascular disease risk factors, PAD is associated with an increased risk of incident coronary and cerebrovascular disease morbidity and mortality.
© 2015 American Heart Association, Inc.
Inflammatory activity may influence results of percutaneous transluminal angioplasty (PTA). The purpose of this study was to evaluate the relationship between: 1) Proinflammatory markers [interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor- α (TNF-α) and high sensitive C-reactive protein (CRP)]; 2) Type 1 T helper cell marker [interleukin-12 (IL-12)]; 3) Type 2 T helper cell marker [transforming growth factor-β (TGF-β)] and in-stent restenosis, six months after femoral PTA with stent implantation.
We performed a single-center prospective study with 26 patients with peripheral artery disease (PAD) requiring percutaneous transluminal angioplasty (PTA) and stenting. As control, we studied 26 patients who were submitted to diagnostic angiography. Serum samples were collected before stent implantation, 24 hours and six months after the procedure. To detect restenosis, a new angiography was obtained at six months.
Restenosis was observed in ten (38.5%) patients who underwent PTA and stenting.. There was a trend to increased levels of IL-6, TNF-α, TGF-β and IL-12 24 hours after PTA and stenting compared to pre-treatment. IL-8 levels showed a statistically significant reduction 24 hours after vs pre-treatment (P<.05), 6 months vs pre-treatment and 6 months vs 24 hours (P<.01). There was no statistical difference between cytokines levels when comparing restenosis and no restenosis groups. CRP levels were already high at pre-treatment.
No inflammatory marker was independently identified as risk factor for in-stent restenosis, six months after femoral percutaneous transluminal angioplasty with stent implantation. The question that remains is whether acute phase reactants will be clinically useful to predict the individual risk for in-stent restenosis.
Copyright © 2015 Elsevier Inc. All rights reserved.
Background:
The associations of triglyceride (TG) to high-density lipoprotein cholesterol ratio (HDL‑C) and total cholesterol (TC) to HDL‑C ratio and low ankle brachial index (ABI) were seldom investigated.
Patients and methods:
A population based cross-sectional survey was conducted and 2982 participants 60 years and over were recruited. TG, TC, HDL‑C, and low-density lipoprotein cholesterol (LDL-C) were assessed in all participants. Low ABI was defined as ABI ≤ 0.9 in either leg. Multiple logistic regression models were applied to study the association between TG/HDL‑C ratio, TC/HDL‑C ratio and low ABI.
Results:
The TG/HDL‑C ratios for those with ABI > 0.9 and ABI ≤ 0.9 were 1.28 ± 1.20 and 1.48 ± 1.13 (P < 0.0001), while the TC/HDL‑C ratios were 3.96 ± 1.09 and 4.32 ± 1.15 (P < 0.0001), respectively. After adjusting for age, gender, body mass index, obesity, current drinking, physical activity, hypertension, diabetes, lipid-lowering drugs, and cardiovascular disease history, the odds ratios (ORs) with 95 % confidence intervals (CIs) of low ABI for TG/HDL‑C ratio and TC/HDL‑C ratio were 1.10 (0.96, 1.26) and 1.34 (1.14, 1.59) in non-smokers. When TC was further adjusted, the ORs (95 % CIs) were 1.40 (0.79, 2.52) and 1.53 (1.21, 1.93) for TG/HDL‑C ratio and TC/HDL‑C ratio, respectively. Non-linear relationships were detected between TG/HDL‑C ratio and TC/HDL‑C ratio and low ABI in both smokers and non-smokers.
Conclusions:
TC/HDL‑C ratio was significantly associated with low ABI in non-smokers and the association was independent of TC, TG, HDL‑C, and LDL-C. TC/HDL‑C might be considered as a potential biomarker for early peripheral arterial disease screening.
Background-The associations of low (<0.90) and high (>1.40) ankle brachial index (ABI) with risk of all-cause and cardiovascular disease (CVD) mortality have not been examined in a population-based setting. Methods and Results-We examined all-cause and CVD mortality in relation to low and high ABI in 4393 American Indians in the Strong Heart Study. Participants had bilateral ABI measurements at baseline and were followed up for 8.3±2.2 years (36 589 person-years). Cox regression was used to quantify mortality rates among participants with high and low ABI relative to those with normal ABI (0.90 ≤ ABI ≤ 1.40). Death from all causes occurred in 1022 participants (23.3%; 27. 9 deaths per 1000 person-years), and of these, 272 (26.6%; 7.4 deaths per 1000 person-years) were attributable to CVD. Low ABI was present in 216 participants (4.9%), and high ABI occurred in 404 (9.2%). Diabetes, albuminuria, and hypertension occurred with greater frequency among persons with low (60.2%, 44.4%, and 50.1%) and high (67.8%, 49.9%, and 45.1%) ABI compared with those with normal ABI (44.4%, 26.9%, and 36.5%), respectively (P<0.0001). Adjusted risk estimates for all-cause mortality were 1.69 (1.34 to 2.14) for low and 1. 77 (1.48 to 2.13) for high ABI, and estimates for CVD mortality were 2.52 (1.74 to 3.64) for low and 2.09 (1.49 to 2.94) for high ABI. Conclusions-The association between high ABI and mortality was similar to that of low ABI and mortality, highlighting a U-shaped association between this noninvasive measure of peripheral arterial disease and mortality risk. Our data suggest that the upper limit of normal ABI should not exceed 1.40.
Circulating levels of C-reactive protein (CRP) are associated with an increased risk of coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). Observational and experimental evidence suggest that CRP might differentially predict fatal and nonfatal cardiovascular events. Here, we sought to determine the predictive value of CRP for fatal and nonfatal CAD, stroke, or PAD.
CRP levels were measured in 18 450 apparently healthy participants in the EPIC-Norfolk cohort. Cox proportional hazards models were used to quantify the association between CRP levels and fatal and nonfatal CAD events, strokes, and PAD events. Bootstrapping was applied to test for significant differences between the risk of fatal and nonfatal events. During 208 485 person-years at risk, 2915 CAD events, 361 strokes, and 657 PAD events occurred. CRP was associated with fatal and nonfatal CAD events and nonfatal PAD events. When adding CRP to predictive risk models for fatal and nonfatal events corrected for known cardiovascular risk factors, the net reclassification index was 2.1% for fatal and 1.9% for nonfatal events. Multivariate adjusted hazard ratios for fatal CAD events (hazard ratio, 1.36; 95% confidence interval, 1.27-1.46) differed significantly (mean difference, 13%; 95% confidence interval, 5.1%-21.9%; P<0.001) from the multivariate adjusted hazard ratio for nonfatal CAD events (hazard ratio, 1.21; 95% confidence interval, 1.15-1.26).
In the EPIC-Norfolk cohort, CRP was associated with fatal and nonfatal CAD events, as well as nonfatal PAD events. Adding CRP to risk stratification models resulted in a small improvement in classification for both fatal and nonfatal events. Importantly, CRP was significantly more strongly associated with fatal CAD events than with nonfatal CAD events.
We compared plasma apolipoprotein profiles in subjects with peripheral artery disease (PAD) treated with statin medications (n = 21), subjects with PAD who are untreated with statins (n = 18), and control subjects (n = 70). Subjects were assessed on plasma apolipoproteins, medical history, physical examination, ankle-brachial index, and exercise performance using a treadmill test. The percentage of subjects with an abnormal value of apolipoprotein B (ApoB) (≥ 95 mg/dL) was 53% in the PAD group untreated with statins, 29% in the treated PAD group, and 13% in the controls (p < 0.001). The PAD group untreated with statins had higher values for ApoB (p < 0.001), triglycerides (p < 0.01), low-density lipoprotein (LDL)-cholesterol / high-density lipoprotein (HDL)-cholesterol ratio (p < 0.05), and glucose (p < 0.01) than the control group. In contrast, when the statin-treated PAD group was compared with controls, none of the variables were different except that the treated PAD group had lower LDL-cholesterol (p < 0.01) and higher glucose (p < 0.01). Furthermore, the PAD group treated with statins had lower ApoB (p < 0.01), triglycerides (p < 0.001), LDL-cholesterol (p < 0.05), LDL-cholesterol / HDL-cholesterol ratio (p < 0.05), and non-HDL-cholesterol (p < 0.05) than the untreated PAD group. In conclusion, subjects with PAD who are untreated with statin medications have higher levels of ApoB than controls, whereas subjects treated with statins have a more favorable risk profile, characterized by lower ApoB, LDL-C, LDL-C / HDL-C ratio, and non-HDL-C concentrations. Statin therapy may be efficacious for improving apolipoprotein profiles in subjects with PAD and intermittent claudication.
Impact of multiple cardiovascular (CV) risk factors on the intima-media thickness (IMT) of femoral and carotid artery segments measured simultaneously has not been studied in asymptomatic adults. This study examined the impact of multiple CV risk factors on the IMT in asymptomatic adults.
Femoral and carotid IMT were measured by B-mode ultrasonography in 1080 asymptomatic subjects (aged 24-43 years) of the Bogalusa Heart Study.
In multivariate analyses, systolic blood pressure, age, male, total cholesterol/HDL cholesterol ratio and smoking were common independent predictor variables for the femoral and carotid IMT. Systolic blood pressure followed by age were the major determinant risk factors for the IMT of all arterial segments except carotid bulb for which age was the major predictor. The independent variables listed explained 11% of the variability in femoral IMT, 28% in common carotid, 18% in carotid bulb, 10% in internal carotid and 27% in composite carotid segments. Mean IMT increased with increasing number of risk factors in all arterial segments; p for trend=0.003 for femoral and 0.001 for all carotid segments.
The observed deleterious trend of increasing IMT of the femoral and different segments of the carotid artery with increasing number of CV risk factors provide evidence of silent systemic atherosclerosis in asymptomatic young adults. These findings underscore the importance of multiple for risk factors profiling in early life. Studies of the femoral and carotid IMT may be helpful along with measurements of risk factors for evaluation of asymptomatic atherosclerotic disease.
The aim of this study was to determine whether persistently high levels of interleukin-6 (IL-6) or soluble vascular adhesion molecule-1 (sVCAM-1) are associated with faster functional decline compared to fluctuating or persistently low biomarker levels in 255 participants with peripheral arterial disease. Participants underwent baseline and ≥2 annual follow-up measures of IL-6 and sVCAM-1. Participants were categorized as follows: category 1, annual levels of IL-6 (or sVCAM-1) were in the lowest tertile for ≥3 study visits; category 3, annual levels of IL-6 (or sVCAM-1) were in the highest tertile for ≥3 visits. Category 2 levels of IL-6 (or sVCAM-1) did not meet criteria for group 1 or 3. Six-minute walking distance, fastest paced 4-m walking velocity, and the Short Physical Performance Battery were measured annually. Results were adjusted for age, gender, race, co-morbidities, statin use, physical activity, the ankle-brachial index, and other confounders. Across IL-6 categories, average annual decreases in 6-minute walking distance were -21.4 feet in category 1, -49.2 feet in category 2, and -76.8 feet in category 3 (p for trend = 0.013), and average annual decreases in Short Physical Performance Battery score were -0.18, -0.45, and -0.62, respectively (p for trend = 0.022). Similar associations of IL-6 categories with decrease in fastest paced walking velocity were observed (p for trend = 0.034). There were no significant associations of sVCAM-1 categories with functional decline. In conclusion, in participants with peripheral arterial disease, persistently high IL-6 levels are associated with faster functional decline compared to those with fluctuating or persistently low IL-6 levels.
We evaluated whether carotid intima-media thickness (CIMT) and the presence or absence of plaque improved coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF).
Traditional CHD risk prediction schemes need further improvement as the majority of the CHD events occur in the "low" and "intermediate" risk groups. On an ultrasound scan, CIMT and presence of plaque are associated with CHD, and therefore could potentially help improve CHD risk prediction.
Risk prediction models (overall, and in men and women) considered included TRF only, TRF plus CIMT, TRF plus plaque, and TRF plus CIMT plus plaque. Model predictivity was determined by calculating the area under the receiver-operating characteristic curve (AUC) adjusted for optimism. Cox proportional hazards models were used to estimate 10-year CHD risk for each model, and the number of subjects reclassified was determined. Observed events were compared with expected events, and the net reclassification index was calculated.
Of 13,145 eligible subjects (5,682 men, 7,463 women), approximately 23% were reclassified by adding CIMT plus plaque information. Overall, the CIMT plus TRF plus plaque model provided the most improvement in AUC, which increased from 0.742 (TRF only) to 0.755 (95% confidence interval for the difference in adjusted AUC: 0.008 to 0.017) in the overall sample. Similarly, the CIMT plus TRF plus plaque model had the best net reclassification index of 9.9% in the overall population. Sex-specific analyses are presented in the manuscript.
Adding plaque and CIMT to TRF improves CHD risk prediction in the ARIC (Atherosclerosis Risk In Communities) study.
Emerging evidence suggests that different inflammatory biomarkers operate through distinct biologic mechanisms. We hypothesized that the relation to peripheral arterial disease (PAD) varies for individual markers.
In a community-based sample we measured 12 biomarkers including plasma CD40 ligand, fibrinogen, lipoprotein-associated phospholipase-A2 mass and activity, osteoprotegerin, P-selectin, and tumor necrosis factor receptor 2 (TNFR2); and serum C-reactive protein, intracellular adhesion molecule-1, interleukin-6, monocyte chemoattractant protein-1, and myeloperoxidase in Framingham Offspring Study participants (n=2800, 53% women, mean age 61 years). We examined the cross-sectional relation of the biomarker panel to PAD using (1) a global test of significance to determine whether at least one of 12 biomarkers was related to PAD using the TEST statement in the LOGISTIC procedure in SAS and (2) stepwise multivariable logistic regression with forward selection of markers with separate models for (1) ankle-brachial index (ABI) category (<0.9, 0.9-1.0, >1.0) and (2) presence of clinical PAD (intermittent claudication or lower extremity revascularization).
The group of inflammatory biomarkers were significantly related to both ABI and clinical PAD (p=0.01 and p=0.02, respectively, multi-marker adjusted global significance test). Multivariable forward elimination regression retained interleukin-6 and TNFR2 as significantly associated with PAD. For one standard deviation change in interleukin-6 and TNFR2 concentrations, there was a 1.21 (p=0.005) and 1.19 (p=0.009) increased odds of a change in ABI level respectively. Similar results were observed for clinical PAD.
Interleukin-6 and TNFR2 were significantly associated with PAD independent of established risk factors and each other, suggesting that each marker represents a distinct biologic pathway.
To examine whether insulin resistance was associated with ultrasound-assessed measures of atherosclerosis in men with varying degrees of obesity.
A random selection of subjects from the general population were divided into quintiles of a body mass index/blood glucose score that was shown to be a valid and reproducible index of the degree of insulin sensitivity as assessed by the clamp technique. Every fourth man in quintiles 1 and 5 and every 20th man in quintiles 2-4 (in total, 104 men) were selected for an ultrasound examination of the carotid and femoral arteries and a euglycaemic hyperinsulinaemic clamp examination, adjusted for fat-free mass.
A university hospital.
A total of 104 clinically healthy 58-year-old men of Swedish ancestry.
The mean common carotid artery intima-media thickness (IMT), but not the common femoral IMT, correlated significantly with glucose infusion rate (GIR) (r = - 0.20, P < 0.05), systolic blood pressure (r = 0.20, P < 0.05), pulse pressure (r = 0.23 P < 0.01), heart rate (r = 0.20, P < 0.05), HDL cholesterol (r = - 0.18, P < 0.05), log triglycerides (r = 0.28, P < 0.01), apoA1 (r = - 0.20, P < 0.05), apoB (r = 0.21, P < 0.05), LDL particle size (r = - 0.22, P < 0.05) and plasma insulin (r = 0.20, P < 0.05). In a multiple regression, common carotid IMT was independently associated with log triglycerides (beta = 0.25, P = 0.012) and pulse pressure (beta = 0.21, P = 0.031) (R2 = 8.7%, P = 0.005)
Insulin sensitivity, measured with the gold standard euglycaemic hyperinsulinaemic clamp method, showed similar associations with ultrasound-assessed measures of atherosclerosis in the carotid arteries as established cardiovascular risk factors, but only triglycerides and pulse pressure contributed independently to the variability in the common carotid intima-media thickness.
Several novel risk factors for atherosclerosis have recently been proposed, but few comparative data exist to guide clinical use of these emerging biomarkers.
To compare the predictive value of 11 lipid and nonlipid biomarkers as risk factors for development of symptomatic peripheral arterial disease (PAD).
Nested case-control study using plasma samples collected at baseline from a prospective cohort of 14 916 initially healthy US male physicians aged 40 to 84 years, of whom 140 subsequently developed symptomatic PAD (cases); 140 age- and smoking status-matched men who remained free of vascular disease during an average 9-year follow-up period were randomly selected as controls.
Incident PAD, as determined by baseline total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol-HDL-C ratio, triglycerides, homocysteine, C-reactive protein (CRP), lipoprotein(a), fibrinogen, and apolipoproteins (apo) A-I and B-100.
In univariate analyses, plasma levels of total cholesterol (P<.001), LDL-C (P =.001), triglycerides (P =.001), apo B-100 (P =.001), fibrinogen (P =.02), CRP (P =.006), and the total cholesterol-HDL-C ratio (P<.001) were all significantly higher at baseline among men who subsequently developed PAD compared with those who did not, while levels of HDL-C (P =.009) and apo A-I (P =.05) were lower. Nonsignificant baseline elevations of lipoprotein(a) (P =.40) and homocysteine (P =.90) were observed. In multivariable analyses, the total cholesterol-HDL-C ratio was the strongest lipid predictor of risk (relative risk [RR] for those in the highest vs lowest quartile, 3.9; 95% confidence interval [CI], 1.7-8.6), while CRP was the strongest nonlipid predictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In assessing joint effects, addition of CRP to standard lipid screening significantly improved risk prediction models based on lipid screening alone (P<.001).
Of 11 atherothrombotic biomarkers assessed at baseline, the total cholesterol-HDL-C ratio and CRP were the strongest independent predictors of development of peripheral arterial disease. C-reactive protein provided additive prognostic information over standard lipid measures.
Peripheral vascular disease (PVD) is a common condition often associated with cardiovascular risk factors and events. With the aid of B-mode ultrasound scanning, evidence is emerging that these risk factors and events are significantly related to an increased carotid and femoral intima-media thickness (IMT). More importantly, treatment of these risk factors is associated with a decrease or a diminished progression of the IMT, paralleled by a reduction in cardiovascular events and an improvement in the symptoms associated with PVD. This evidence is particularly strong for lipid lowering therapy. Additional predictors of cardiovascular risk like the IMT, could now influence the decision to intervene with medication.
We tested the hypothesis that a combination of measurements of different aspects of atherosclerosis, including burden of atherosclerosis and levels of inflammation, would contain more predictive information than either alone in an outpatient population. We enrolled 110 patients (62 +/- 15 years of age) who were referred to the noninvasive vascular laboratory for sequential Doppler pressure measurements of the lower extremities. We measured ankle-brachial index (ABI) and serum markers of inflammation and followed subjects for a mean of 2.25 years. Fifty subjects did not have peripheral arterial disease (PAD; ABI > or =0.9), whereas 60 did (ABI <0.9). Markers of inflammation, including C-reactive protein (3.83 +/- 0.9 vs 2.11 +/- 1.1, p = 0.019), were higher in subjects who had PAD. During follow-up, 42% developed an event (myocardial infarction, stroke, unplanned coronary or lower extremity revascularization, or death). Decreasing ABI (chi-square 7.3, p = 0.026) and increasing C-reactive protein (chi-square 22.1, p <0.001) increased the risk of an event. Risk increased sixfold between the lowest and highest groups for all events and fourfold for hard events (myocardial infarction, stroke, and death) using both C-reactive protein and ABI. In conclusion, patients who have PAD and increased inflammation are at highest risk for adverse cardiovascular outcomes. Characterizing atherosclerosis on the basis of these parameters provides important prognostic information.
Recently, markers of inflammation, haemostasis, and blood rheology have received much attention as risk factors for coronary heart disease and stroke. However, their role in peripheral arterial disease (PAD) is not well established and some of them, including the pro-inflammatory cytokine interleukin-6 (IL-6), have not been examined before in prospective epidemiological studies.
In the Edinburgh Artery Study, we studied the development of PAD in the general population and evaluated 17 potential blood markers as predictors of incident PAD. At baseline (1987), 1519 men and women free of PAD aged 55-74 were recruited. After 17 years, 208 subjects had developed symptomatic PAD. In analysis adjusted for cardiovascular risk factors and baseline cardiovascular disease (CVD), only C-reactive protein, fibrinogen, lipoprotein (a), and haematocrit [hazard ratio (95% CI) corresponding to an increase equal to the inter-tertile range 1.30 (1.08, 1.56), 1.16 (1.05, 1.17), 1.22 (1.04, 1.44), 1.22 (1.08, 1.38)] were significantly (P < 0.01) associated with PAD. However, these markers provided very little prognostic information for incident PAD to that obtained by cardiovascular risk factors and the ankle brachial index. Other markers including IL-6, intracellular adhesion molecule 1, d-dimer, tissue plasminogen activator antigen, and plasma and blood viscosities showed weak associations, which were considerably attenuated when CVD risk factors were accounted for.
Our prospective data showed that several inflammatory, haemostatic, and rheological markers are associated with incident PAD; however, their clinical utility is likely to be limited. Future research is necessary to validate the importance of these biomarkers explicitly on PAD and to address the causality of the reported associations.
IL-6 and hsCRP plasma levels in subjects with diabetic foot and possible correlation with clinical variables: A multicenter study
- J Ahmad
- M Zubair
- A Malik
- M Siddiqui
- S K Wngnoo
- Cathepsind
Ahmad J, Zubair M, Malik A, Siddiqui M, Wngnoo SK. CathepsinD, adiponectin, TNF-alpha, IL-6 and hsCRP plasma levels in subjects with
diabetic foot and possible correlation with clinical variables: A multicenter
study. Foot 2012; 22: 194-199.
A Prediction Model for the Peripheral Arterial Disease Using NHANES Data
- Y Zhang
- J Huang
- P Wang
Zhang Y, Huang J, Wang P. A Prediction Model for the Peripheral
Arterial Disease Using NHANES Data. Medicine (Baltimore) 2016; (16):
e3454. doi: 10.1097/MD 0000000000003454.
Cathepsin-D, adiponectin, TNF-alpha, IL-6 and hsCRP plasma levels in subjects with diabetic foot and possible correlation with clinical variables: A multicenter study
- J Ahmad
- M Zubair
- A Malik
- M Siddiqui
- S K Wngnoo
Ahmad J, Zubair M, Malik A, Siddiqui M, Wngnoo SK. Cathepsin-D, adiponectin, TNF-alpha, IL-6 and hsCRP plasma levels in subjects with
diabetic foot and possible correlation with clinical variables: A multicenter
study. Foot 2012; 22: 194-199.
Association between ankle-brachial index and risk factor profi le in patients with newly diagnosed with intermittent claudication
- Z Ye
- Z Ali
- G G Klee
- T H Mosley
- I J Kullo
- S S Daskalopoulou
- M Pathmarajah
- S K Kakkos
Ye Z, Ali Z, Klee GG, Mosley TH Jr, Kullo IJ. Associations of candidate biomarkers of vascular disease with the ankle-brachial index and
peripheral arterial disease. Am J Hypertens 2013; 26 (4): 495-502.
25. Daskalopoulou SS, Pathmarajah M, Kakkos SK et al. Association between ankle-brachial index and risk factor profi le in patients with
newly diagnosed with intermittent claudication. Circ J 2008; 72: 441-448.