Peripheral Arterial Disease Subjects Research Articles

Fetuin-A Levels Are Increased in Patients With Type 2 Diabetes and Peripheral Arterial Disease

OBJECTIVELow 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 METHODSWe 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.RESULTSType 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.CONCLUSIONSIn 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.

Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3months of exercise training

Plasma nitrite is a major oxidation product of nitric oxide. It has also recently been suggested to perform an endocrine-like function as a nitric oxide donor in hypoxic tissues, allowing vasodilation. Exercise performance is limited in peripheral arterial disease because of an inadequate blood supply to working tissues. We hypothesized that exercise training in peripheral arterial disease subjects will improve "plasma nitrite flux" and endothelial function, to accompany increased exercise performance. Peripheral arterial disease subjects were tested at baseline and after 3 months supervised or home exercise training. Venous blood (arm) was drawn at rest and 10 min after a maximal graded treadmill test. Samples were added to heparin and centrifuged and plasma was snap-frozen for analysis by reductive chemiluminescence. Brachial artery endothelial function was measured in response to a hyperemic stimulus (flow-mediated dilation). At 3 months the peripheral arterial disease-supervised exercise group showed increases in claudication onset pain time (+138 s, p< or =0.05), peak walking time (+260 s, p< or =0.01), VO(2peak) (1.3 ml/kg/min, p< or =0.05), brachial artery flow-mediated dilation (+2%, p< or =0.05), and plasma nitrite flux (+33% p< or =0.05). There were no changes in the peripheral arterial disease-home exercise group. The change in plasma nitrite flux predicted the change in claudication onset pain (r(2)=0.59, p< or =0.01). These findings suggest that changes in plasma nitrite are related to endothelial function and predict exercise performance in peripheral arterial disease.

Abstract 5089: Impaired Calf Skeletal Muscle Glucose Uptake in Subjects With Peripheral Artery Disease and Intermittent Claudication

Objectives : Severity of claudication symptoms does not correlate well with ankle brachial index (ABI) in patients with peripheral artery disease (PAD), suggesting that non-hemodynamic mechanisms may play an important role. Given the association of PAD with insulin resistance, we hypothesized that local calf muscle glucose uptake is impaired in PAD, and therefore that local insulin resistance may contribute to the pathophysiology of claudication. Methods: We studied 37 subjects with PAD (ABI ≤ 0.9) and stable claudication and 11 healthy controls who underwent dynamic positron emission tomography (PET) imaging of the legs with 18-FDG during a hyperinsulinemic-euglycemic clamp (insulin @ 2 mU/kg/min). Using fused PET/CT images, regions of interest were drawn in the primary muscle groups of the lower leg. Average glucose uptake was quantified using the graphical Patlak analysis. Whole body insulin sensitivity was assessed as the glucose disposal rate (M) from the insulin clamp. Data are presented as median [interquartile range, IQR] or mean± standard error (SE). Results: Compared to healthy, age-matched controls, PAD subjects were insulin resistant (M = 3.4 mg/kg/min [IQR 2.7– 4.8] vs. 5.0 [3.7– 6.6], p=0.019) even after excluding those with diabetes (24% of PAD subjects), p=0.04. Average calf muscle glucose uptake was significantly lower in PAD subjects (48.6±2.6 mmol/kg/min) compared with healthy controls (62.9±6.5 mmol/kg/min), p=0.009. Similar impairments were observed in the subgroup of PAD subjects without diabetes (49.5±3.1, p=0.04 vs. healthy controls). Whole body insulin sensitivity explained 10% of the variability in local calf muscle glucose uptake (r 2 =0.10, p=0.04). Conclusions: We demonstrate that subjects with claudication are insulin resistant and have reduced calf muscle glucose uptake, independent of coexistent diabetes. The poor correlation between whole body insulin sensitivity and lower extremity glucose uptake suggests unique determinants of leg glucose uptake in PAD. These findings support our underlying hypothesis that impaired calf muscle substrate utilization due to local insulin resistance may be a novel mechanism underlying the pathophysiology of intermittent claudication.

Heparin Cofactor II is an Independent Protective Factor against Peripheral Arterial Disease in Elderly Subjects with Cardiovascular Risk Factors

Heparin cofactor II (HCII) specifically inactivates thrombin action at the injured vascular wall. We have reported that HCII is a protective factor against coronary in-stent restenosis and carotid atherosclerosis; however, it is unclear whether there is any correlation between plasma HCII levels and the development of peripheral arterial disease (PAD). Plasma HCII activity and the ankle brachial pressure index (ABI) were determined in 494 elderly subjects with cardiovascular risk factors. PAD was diagnosed by ABI below 0.9, and 62 subjects were diagnosed with PAD. The relationship between factors that affect cardiovascular events and the prevalence of PAD was statistically evaluated. Mean HCII activity in PAD subjects was significantly lower than in non-PAD subjects (87.5+/-19.7% v.s. 94.6+/-17.8%, p=0.009). Multivariate logistic regression analysis showed that age (odds ratio [OR]: 1.062, p=0.0016), current smoking (OR 3.028, p=0.002) and diabetes mellitus (OR 2.656, p=0.008) were independent and progressive determinants of PAD. In contrast, HCII was an independent inhibitory factor of PAD (OR: 0.982, p=0.048). Plasma HCII activity is inversely related to the prevalence of PAD. HCII may function as the sole protective factor against PAD in elderly people with cardiovascular risk factors.

Prevalência e fatores de risco associados à doença arterial periférica no projeto corações do Brasil

Peripheral arterial disease (PAD) is associated with increased cardiovascular risk. In Brazil, data on PAD prevalence and risk factors are scarce. To assess prevalence and risk factors related to PAD in Brazilian urban centers with more than 100,000 inhabitants. National, multicenter, cross-sectional study of 1,170 individuals (>18 years), from 72 major Brazilian urban centers participating in the "Hearts of Brazil Project". PAD diagnosis was based on ankle-brachial index (ABI) <or=0.90. The statistical analysis used the corrected Chi-square (Pearson) test for complex samples and confidence intervals. P< 0.05 was considered statitically significant. PAD prevalence was 10.5%. Intermittent claudication (IC) was present in only 9% of PAD patients. A significant association was found between PAD and the following factors: diabetes, total and abdominal obesity, stroke and ischemic heart disease (IHD). There was a trend of higher PAD prevalence among individuals with hypertension, heart failure, chronic renal failure on dialysis, as well as those who had smoked over 20 pack-years. For females, presence of IHD was associated with a 4.9-fold greater risk of PAD. Among males, a 6.6-fold increased risk of PAD was found for diabetic in comparison to non-diabetic individuals. PAD prevalence was markedly high, considering the low mean age of the studied population (44+/-14.7 yrs). IC was detected in a minority of PAD subjects, indicating a considerable number of asymptomatic individuals. Diabetes, obesity, stroke and IHD were the stronger predictors of PAD. The authors concluded that ABI measurement should be considered in the evaluation of moderate to high cardiovascular risk patients.

Plasma Levels of Soluble Tie2 and Vascular Endothelial Growth Factor Distinguish Critical Limb Ischemia From Intermittent Claudication in Patients With Peripheral Arterial Disease

Our purpose was to determine whether factors that regulate angiogenesis are altered in peripheral arterial disease (PAD) and whether these factors are associated with the severity of PAD. Alterations in angiogenic growth factors occur in cardiovascular disease (CVD), but whether these factors are altered in PAD or correlate with disease severity is unknown. Plasma was collected from patients with PAD (n = 46) and healthy control subjects (n = 23). Peripheral arterial disease patients included those with intermittent claudication (IC) (n = 23) and critical limb ischemia (CLI) (n = 23). Plasma angiopoietin-2 (Ang2), soluble Tie2 (sTie2), vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR-1), and placenta growth factor (PlGF) were measured by enzyme-linked immunoadsorbent assay. In vitro, endothelial cells (ECs) were treated with recombinant VEGF to investigate effects on sTie2 production. Plasma concentrations of sTie2 (p < 0.01), Ang2 (p < 0.001), and VEGF (p < 0.01), but not PlGF or sVEGFR-1, were significantly greater in PAD patients compared with control subjects. Plasma Ang2 was significantly increased in both IC and CLI compared with control subjects (p < 0.0001), but there was no difference between IC and CLI. Plasma VEGF and sTie2 were similar in control subjects and IC but were significantly increased in CLI (p < 0.001 vs. control or IC). Increased sTie2 and VEGF were independent of CVD risk factors or the ankle-brachial index, and VEGF treatment of ECs in vitro significantly increased sTie2 shedding. Levels of VEGF and sTie2 are significantly increased in CLI, and sTie2 production is induced by VEGF. These proteins may provide novel biomarkers for CLI, and sTie2 may be both a marker and a cause of CLI.

O80. Changes in plasma nitrite response and arterial endothelial function in peripheral arterial disease subjects following 3 months of exercise training

O80. Changes in plasma nitrite response and arterial endothelial function in peripheral arterial disease subjects following 3 months of exercise training

Does Lower-Extremity Arterial Disease Predict Future Falling Among Older Men and Women?

The purpose of this study was to determine whether lower-extremity peripheral arterial disease (PAD) is an independent risk factor for falls among older persons. Men and women 55 years old and older participated. Subjects with PAD (n = 86) were identified from a noninvasive vascular laboratory and a general medicine practice. Randomly selected controls without PAD (n = 82) were identified from the same medicine practice. Subjects were categorized into PAD (ankle brachial index, <0.90) or controls (ankle brachial index, 0.90 to 1.50). Subjects underwent a comprehensive baseline evaluation for fall risk. Prospective fall data were obtained using monthly mail-in postcards and structured telephone interviews over a mean follow-up of 9.6 +/- 2.9 months. Two independent investigators blinded to PAD status reviewed each fall incident for its eligibility. A total of 37 subjects (22%) had at least 1 eligible fall. In an unadjusted Cox regression model, the relative risk of falling was lower among PAD subjects than among controls (relative risk, 0.54; 95% confidence interval, 0.28 to 1.06). After adjustment for age, gender, history of frequent falls in the last year, number of comorbidities, and balance and gait abnormalities, PAD was significantly associated with a lower risk of falling (relative risk, 0.43; 95% confidence interval, 0.21 to 0.87) as compared with controls. PAD is associated with a lower risk of falling as compared with persons without PAD among older men and women. Future study is needed to determine whether reduced levels of physical activity among patients with PAD account for the lower rate of falling observed here.

β2-Microglobulin as a Biomarker in Peripheral Arterial Disease

Peripheral arterial disease (PAD) is common but commonly unrecognized. Improved recognition of PAD is needed. We used high-throughput proteomic profiling to find PAD-associated biomarkers. Plasma was collected from PAD patients (ankle brachial index of <0.90; n=45) and subjects with risk factors but without PAD (n=43). Plasma was analyzed with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to quantify 1619 protein peaks. The peak intensity of a 12-kDa protein was higher in PAD patients. Western blot analyses and immunoaffinity studies confirmed that this protein was beta2-microglobulin (B2M). In a validation study, B2M was measured by ELISA in plasma in age- and gender-matched PAD (n=20) and non-PAD (n=20) subjects. Finally, we studied a larger cohort of subjects (n=237) referred for coronary angiography but without known PAD. Plasma B2M levels were higher in PAD patients than in non-PAD patients with coronary artery disease. Plasma B2M correlated with ankle brachial index and functional capacity. Independent predictors of PAD were diabetes mellitus, age, and the combination of B2M and C-reactive protein level. In PAD patients, circulating B2M is elevated and correlates with the severity of disease independent of other risk factors. These findings might provide a needed biomarker for PAD and new insight into its pathophysiology. Further studies in other populations are needed to confirm the utility of measuring B2M in cardiovascular disease risk assessment.

Amino acids stimulate leg muscle protein synthesis in peripheral arterial disease

Older patients with peripheral arterial disease (PAD) and intermittent claudication have impaired walking ability resulting from reduced lower extremity blood flow. Evidence suggests that leg muscle abnormalities may also contribute to walking intolerance in claudicants. In healthy elderly people, leg muscle protein synthesis can be augmented by nutritional supplementation with amino acids; preliminary data suggest that this increases muscle mass, walking ability, and functional status. In this study, we investigated whether amino acid supplementation would improve leg muscle protein synthesis in elderly PAD subjects, given that reduced leg blood flow might restrict the availability of amino acids to muscle. Two groups participated in the study: a group of 11 claudicants (mean age, 62 years; mean ankle-brachial index, 0.62; 46% male) and a group of 9 age- and sex-matched healthy controls (mean ankle-brachial index, 1.1). Both groups underwent measurement of leg blood flow by using strain gauge plethysmography, as well as measurement of baseline and amino acid-stimulated protein synthesis in leg muscle. Protein synthesis was quantified from calf muscle biopsy samples by measurement of the fractional synthetic rate (FSR) of protein, by using the incorporation of the stable isotope l-[ring-(2)H(5)]-phenylalanine into muscle protein. Total protein was extracted from muscle samples, and gas chromatography/mass spectroscopy methodology was used to measure incorporation rates. After measurement of basal FSR, all subjects were given an oral drink of 15 g of essential amino acids, and the measurements of FSR were repeated. Data are expressed as mean +/- SD; statistical analysis of differences between the two groups (with and without amino acid supplementation) was performed by using analysis of variance with repeated measures. Calf blood flow was reduced in the PAD subjects compared with controls (1.44 +/- 0.53 mL/min per 100 mg of tissue vs 2.40 +/- 0.57 mL/min per 100 mg of tissue; P = .005; t test). FSR in the basal state was equivalent between the two groups (healthy, 0.060% +/- 0.025% per hour; PAD, 0.061% +/- 0.029% per hour; P = .97). Equivalent increases (P < .05) occurred in both groups in response to oral amino acid supplementation (healthy, 0.087% +/- 0.012% per hour; PAD, 0.104% +/- 0.041% per hour; P > .05; analysis of variance). Despite reduced leg blood flow, elderly PAD patients synthesize calf muscle protein in the basal state in a fashion similar to that in healthy elderly people. More importantly, administration of exogenous amino acids produces a significant increase in protein synthesis in these patients that is also equivalent to that in healthy elderly people. Our goal is to use these results as the basis for an intervention study to determine whether long-term oral amino acids, by augmenting calf muscle protein synthesis, increase calf muscle mass, walking ability, and functional status in elderly claudicants.

Skeletal muscle StO2 kinetics are slowed during low work rate calf exercise in peripheral arterial disease

The time course of muscle oxygen desaturation (StO2 kinetics) following exercise onset reflects the dynamic interaction between muscle blood flow and muscle oxygen consumption. In patients with peripheral arterial disease (PAD), muscle StO2 kinetics are slowed during walking exercise; potentially reflecting altered muscle oxygen consumption relative to blood flow. This study evaluated whether StO2 kinetics measured using near infrared spectroscopy (NIRS) would be slowed in PAD during low work rate calf exercise compared with healthy subjects under conditions in which blood flow did not differ. Eight subjects with PAD and eight controls performed 3 min of calf exercise at 5, 10, 30, and 50% of maximal voluntary contraction (MVC). Calf blood flow responses were measured by plethysmography. Power outputs were similar between groups for all work rates. In PAD, the time constants of StO2 kinetics were significantly slower than controls during 5% MVC (13.5 +/- 1.7 vs. 6.9 +/- 1.2 s, P < 0.05) and 10% MVC work rates (14.5 +/- 2.7 vs. 6.8 +/- 1.1 s, P < 0.05). Blood flow assessed when exercise was interrupted after 30 s did not differ between PAD and control subjects at these work rates. In contrast, the StO2 time constants were not different between groups during 30 and 50% MVC work rates, where blood flow responses in PAD subjects were lower as compared with controls. Thus in PAD, the slowed StO2 kinetic responses under conditions of unimpaired calf blood flow reflect slowed muscle oxygen consumption in PAD skeletal muscle during low work rate plantar flexion exercise as compared with healthy skeletal muscle.

Effect of acute exercise on endothelial progenitor cells in patients with peripheral arterial disease

To determine whether exercise increases endothelial progenitor cells (EPCs) in patients with peripheral vascular disease, we developed a multi-parameter flow cytometry assay to rigorously assess EPCs and mature endothelial cells (ECs) in control subjects and patients with peripheral artery disease (PAD) subjected to graded exercise. Blood was collected from young healthy subjects (n = 9, mean age 33 years), older healthy subjects (n = 13, mean age 66 years), and older subjects with PAD (n = 15, mean age 69 years) before and 10 minutes after exercise. White blood cells were isolated and stained with a five-color antibody panel: FITC-anti-CD31, PE-anti-CD146, PE-anti-CD133, PerCP-Cy5.5-anti-CD3,-CD19,-CD33, PE-Cy7-anti-CD34, and APC-anti-VEGF-R2. Viability was assessed by propidium iodide exclusion. Viable, low, side scatter singlets that were CD3-, 19-, and 33-negative were counted. While baseline levels of EPCs and ECs were similar among all subjects, young healthy subjects demonstrated significantly greater (p < 0.05) levels of progenitor cells (PCs) than older healthy and PAD subjects. Levels of EPCs and ECs tended to increase in all subjects after exercise; however, increases in PCs were only observed in young healthy and PAD subjects. Further, trends in the magnitude of change of subsets with exercise were most similar between young and PAD subjects. Our findings suggest that aging may reduce baseline circulating levels of PCs, but not EPCs or ECs, and that exercise-induced mobilization of subsets may differ depending on age and presence of PAD.

Multi-country study on the prevalence and clinical features of peripheral arterial disease in asian type 2 diabetes patients at high risk of atherosclerosis

Objective PAD-SEARCH was the first international study to investigate the prevalence of peripheral arterial disease (PAD) in Asian type 2 diabetic patients and to demonstrate the relationships between putative risk factors and PAD. Subjects and methods In total 6625 type 2 diabetic patients aged 50 and older were enrolled and determined ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) in Korea, China, Taiwan, Hong Kong, Indonesia, Thailand and the Philippines. Results Mean patient age was 63.7 ± 8.2 years and mean duration of diabetes was 10.3 ± 8.0 years. One thousand one hundred and seventy-two (17.7%) subjects were diagnosed as PAD by ABI (≤0.9). PAD subjects had a significantly longer duration of diabetes, hypertension, higher HbA1c, and a significantly lower mean BMI than non-PAD subjects. In terms of lipid profiles, triglyceride was the only significant variable. Notably, mean ABI and baPWV in females were significantly poorer than age matched males in subjects with a normal ABI. However, mean ABI and baPWV in males were significantly poorer than in age matched females in subjects with PAD. Conclusions These findings suggest that PAD is a common complication in Asian type 2 diabetic patients. Therefore, PAD screening and treatment should be emphasized for Asian diabetic patients with high risk factors.

Statins And Biomarkers In Claudicants With Peripheral Arterial Disease: Cross-sectional Study

This exploratory substudy of The Iron (Fe) and Atherosclerosis Study (FeAST) compared baseline inflammatory markers, including cytokines, C-reactive protein (CRP), and ferritin, in subjects with peripheral arterial disease (PAD) taking statins with subjects with PAD who were not taking statins. Inflammatory markers in the serum of 47 subjects with PAD not taking statins and a healthy cohort of 21 medication-free men were compared with 53 PAD subjects taking statins at entry to the FeAST. Healthy subjects demonstrated lower levels of tumor necrosis factor (TNF)-R1, interleukin-6 (IL-6), and CRP. TNF-alpha R1 averaged 2.28 ng/mL versus 3.52 ng/mL, p = .0025; IL-6 averaged 4.24 pg/mL versus 16.61 pg/mL, p = .0008; and CRP averaged 0.58 mg/dL versus 0.92 mg/dL, p = .0192. A higher level of IL-6 was observed in PAD statin takers versus PAD subjects not taking statins: 19.47 pg/mL versus 13.24 pg/mL, p = .0455. As expected, total cholesterol and low-density lipoprotein levels were lower in the statin-treated group, p = .0006 and p = .0001, respectively. No significant differences in inflammatory cytokines were detected for varying doses of simvastatin. Additionally, no significant differences in inflammatory biomedical markers were found in subjects with PAD alone compared with those with concomitant coronary artery disease (CAD). Unexpectedly, serum inflammatory cytokine IL-6 levels were significantly higher in PAD subjects receiving statins. There was no difference in measured inflammatory markers in PAD subjects with concomitant CAD.

The effects of leg/body position on transcutaneous oxygen measurements in age-matched healthy subjects and peripheral artery disease subjects after lower extremity arterial revascularization

The effects of leg/body position on transcutaneous oxygen measurements in age-matched healthy subjects and peripheral artery disease subjects after lower extremity arterial revascularization

Impaired muscle oxygen use at onset of exercise in peripheral arterial disease

In patients with peripheral arterial disease (PAD), abnormal muscle metabolism and impaired oxygen delivery distal to the arterial occlusions may contribute to the exercise limitation observed in this population. Muscle tissue hemoglobin saturation (StO2), measured with near-infrared spectroscopy, reflects the relative contributions of oxygen delivery and oxygen use. Thus differences in the kinetics of StO2 in response to exercise may yield important insight into the potential mechanisms associated with the PAD exercise impairment. The purposes of this study were to characterize the muscle oxygenation responses in patients with PAD and in healthy control subjects at the onset of exercise, and to compare the kinetics of StO2 desaturation. We hypothesized that at the onset of exercise the kinetics of StO2 desaturation would be slowed in PAD compared with control responses. Six patients with PAD and 6 healthy control subjects from a university center were examined in a prospective cross-sectional analysis that evaluated the desaturation kinetics of StO2 at the onset of walking exercise. On separate visits subjects performed graded treadmill exercise and 3 constant work rate treadmill tests equivalent to approximately 60% (low), approximately 80% (medium), and 100% (peak) of their peak exercise work rate. Gastrocnemious muscle StO2 response profiles (InSpectra tissue spectrometer) were measured at rest and across the rest to exercise transition. Muscle StO2 responses were characterized by an exponential mathematical model. The end point value was taken as the time constant of StO2 desaturation after onset of exercise (ie, equivalent to time to reach approximately 63% of StO2 decrease). The patients with PAD and the control subjects were of similar age and activity level. The qualitative patterns of StO2 responses at onset of exercise were also similar between patients and control subjects at all work rates. However, the kinetic time constants of StO2 desaturation were prolonged in patients with PAD versus control subjects (averaged time constant across all work rates, 21.9 +/- 9.4 seconds vs 4.9 +/- 2.2 seconds; P <.01). The slowed muscle StO2 kinetics in PAD are consistent with an impairment in muscle oxygen use at the onset of walking exercise. Impaired muscle metabolism may contribute to the altered physiologic responses to exercise and to exercise impairment in patients with PAD.

Pulmonary VO2 dynamics during treadmill and arm exercise in peripheral arterial disease.

Slowed pulmonary O(2) uptake (Vo(2)) kinetics in peripheral arterial disease (PAD) have been attributed to impaired limb blood flow and/or peripheral muscle metabolic abnormalities. Although PAD results from atherosclerotic occlusive disease in the arteries to the lower extremities, systemic abnormalities affecting whole body O(2) delivery or vascular function in PAD could also partially explain the exercise impairment. To date, the effects of these systemic abnormalities have not been evaluated. To test the hypothesis that the slowed pulmonary Vo(2) kinetics in PAD reflects local and not systemic abnormalities, Vo(2) kinetics were evaluated after the onset of constant-load exercise of the upper and lower limbs in PAD patients and healthy controls (Con). Ten PAD patients and 10 Con without significant cardiopulmonary dysfunction performed multiple transitions from rest to moderate-intensity arm ergometry and treadmill exercise to assess their Vo(2) kinetic responses. Reactive hyperemic (RH) blood flow was assessed in the arms and legs as a measure of endothelial function. Compared with Con, PAD Vo(2) kinetic phase 2 time constants were prolonged during treadmill exercise (PAD 34.3 +/- 9.2 s vs. Con 19.6 +/- 3.5 s; P < 0.01) but not arm exercise (PAD 38.5 +/- 7.5 s vs. Con 32.5 +/- 9.0 s; P > 0.05). RH blood flow was significantly reduced in the legs (PAD 20.7 +/- 8.3 vs. Con 46.1 +/- 17.1 ml.100 ml(-1).min(-1); P < 0.01) and arms of PAD subjects (PAD 34.0 +/- 8.6 vs. Con 50.8 +/- 12.2 ml.100 ml(-1).min(-1); P < 0.01) compared with Con, but RH limb flow was not correlated with arm or treadmill Vo(2) kinetic responses in either group. In summary, slowed pulmonary Vo(2) kinetics in PAD patients occur only with exercise of the lower limbs affected by the arterial occlusive disease process and are not slowed with exercise of the unaffected upper extremities compared with controls. Furthermore, the slowed pulmonary Vo(2) kinetics of the lower extremity could not be explained by any abnormalities in resting cardiac or pulmonary function and were not related to the magnitude of reduction in limb vascular reactivity.

Tissue (muscle) oxygen saturation (StO2): a new measure of symptomatic lower-extremity arterial disease.

Near-infrared spectroscopy provides a noninvasive method of measuring tissue oxygen saturation and has been used to monitor extremity compartment syndrome. Tissue O(2) saturation (StO(2)) is potentially useful in assessing patients with peripheral arterial disease (PAD). The purposes of this feasibility study are to (1) explore the diagnostic sensitivity of StO(2) in subjects with PAD and symptoms of intermittent claudication (IC) compared with normal subjects, and (2) correlate the change in StO(2) during and after exercise with the ankle brachial index (ABI) in patients with IC. Material and methods Forty-nine subjects, 35 normal and 14 PAD, from two centers were evaluated in a prospective cross-sectional analysis comparing StO(2) by using the InSpectra tissue spectrometer and ABI at rest (baseline) and after treadmill exercise. Measurements were obtained at baseline and peak exercise (normal subjects) and at baseline, initial claudication distance (ICD) and absolute claudication distance (ACD) in PAD subjects. Endpoint values were the mean of 15 data points. Times to 50% of StO(2) recovery to baseline (T(50)) and complete recovery to baseline (T(100)) were measured. Receiver-operator characteristic curves were constructed to assess the sensitivity/specificity values associated with various StO(2) cut-points. The PAD patients were older (P =.0002) and 57% were male, compared with 37% males in the normal group. The ABI was 0.68 +/- 0.14 in PAD patients versus 1.14 +/- 0.08 in normal subjects (P <.0001). The baseline StO(2) was 65% in both groups. The peak exercise StO(2) was significantly lower and the absolute change in StO(2) and the percent change in StO(2) were significantly greater in PAD patients (P < 0.45). The T(50) and T(100) were longer in the PAD patients compared to normal subjects (P =.0001 and.002, respectively). A T(50) of >70 seconds yielded a sensitivity of 89% and a specificity of 85% for PAD. StO(2) is a new and potentially useful technique to evaluate patients with PAD. Resting StO(2) was similar in PAD-IC subjects and normals. There was a significantly greater drop in StO(2) and longer recovery times in PAD-IC subjects. Interestingly, StO(2) at the ICD and ACD was similar. StO(2) offers a different and perhaps more appropriate end point for diagnosis and monitoring of the management of patients with PAD, and may offer additional insight into the pathophysiology of exercise-induced muscle ischemia and its recovery.

Association between physical activity and endogenous fibrinolysis in peripheral arterial disease: a cross-sectional study.

The purpose of this study was to determine whether daily physical activity was independently related to endogenous fibrinolysis in subjects with peripheral arterial disease (PAD). One hundred and six subjects with peripheral arterial disease (PAD) and intermittent claudication were characterized on the activity level of tissue plasminogen activator (tPA, the activator of fibrinolysis), the activity level of plasminogen activator inhibitor (PAI-1, the inhibitor of fibrinolysis), daily physical activity, ambulatory function, and demographic information. Subjects were separated into low (n = 36), moderate (n = 34), and high (n = 36) physical activity tertiles based on a 48-hour monitoring period with use of an accelerometer. The tPA activity of the low physical activity group (1.30 +/- 0.16 IU/mL) was 21% and 19% lower (p<0.05) than that of the moderate (1.65 +/- 0.18 IU/mL) and the high (1.61 +/- 0.15 IU/mL) physical activity groups, respectively. The PAI-1 activity of the low physical activity group (21.41 +/- 1.14 AU/mL) was 15% and 23% higher than that of the moderate (18.61 +/- 1.34 AU/mL) and the high (17.47 +/- 1.14 AU/mL) physical activity groups, respectively. Group differences in tPA activity and PAI-1 activity persisted after our controlling for group differences in measured and self-reported ambulatory measures. Daily physical activity is related to a more favorable endogenous fibrinolytic profile in PAD subjects with intermittent claudication. Subjects who expend fewer than 175 kcal/day in physical activities (approximately 35 minutes) are particularly susceptible to having a prothrombotic state. Subjects should be encouraged to participate in at least 35 minutes of physical activity each day to enhance fibrinolysis.

RELATIONSHIP BETWEEN HISTORY OF FALLING AND QUALITY OF LIFE IN SUBJECTS WITH PERIPHERAL ARTERIAL DISEASE

PURPOSE: To determine whether peripheral arterial disease (PAD) subjects with a history of falling have a lower quality of life(QOL) than their non-falling counterparts. METHODS: A total of 120 PAD subjects (26%) who had fallen over the past year and 346 PAD subjects (74%) who had not fallen were evaluated. In addition to history of falling, 8 domains of health-related QOL was assessed by the Medical Outcomes Study short form 36 item questionnaire. Scores of each domain range between 0 and 100, with a score of 0 representing the worst health possible and a score of 100 representing perfect health. RESULTS: The QOL domain related to physical functioning was lower (p < 0.05) in the fallers than in the non-fallers (44 ± 2 vs. 55 ± 1; mean ± SEM). Additionally, the fallers had lower QOL scores (p < 0.05) for role limitations due to physical health (30 ± 4 vs. 62 ± 2), role limitations due to emotional problems (33 ± 4 vs. 74 ± 2), vitality (42 ± 2 vs. 63 ± 1), mental health (66 ± 1 vs. 79 ± 1), social functioning (61 ± 2 vs. 83 ± 1), and general health (43 ± 1 vs. 61 ± 1). No difference (p > 0.05) was found for the QOL domain related to bodily pain between the fallers and non-fallers (53 ± 2 vs. 60 ± 1). CONCLUSION: Lower QOL pertaining to both physical and mental health was associated with a history of falling in PAD subjects with intermittent claudication. Consequently, a history of falling affects many facets of daily living in this population.