Development Of Peripheral Arterial Disease Research Articles

Hemodynamic Analysis of a Compliant Femoral Artery Bifurcation Model using a Fluid Structure Interaction Framework

The influence of wall motion on the hemodynamic characteristics of the human femoral bifurcation and its effects on the development of peripheral artery disease has not been previously investigated. This study aimed in investigating the hemodynamics of a compliant patient-specific femoral artery bifurcation model by a fluid structure interaction (FSI) scheme. The complex physiological geometry of the femoral artery bifurcation was reproduced from sequentially obtained transverse CT scan images. Velocity waveforms derived from phase contrast MR images were extracted and mapped to define boundary conditions. Equations governing blood flow and wall motion were solved using an FSI framework that utilizes commercial codes: FLUENT for computational fluid dynamics and ANSYS for computational structural dynamics. The results showed that wall compliance decreased flow velocities at the relatively high curvature geometries including common and superficial femoral artery (SFA), and it created strong recirculation in the profunda femoris artery close to the bifurcation. In the SFA region near the apex, time averaged wall shear stress (TAWSS) differences up to 25% between compliant and rigid models were observed. The compliant model also exhibited lower TAWSS and oscillatory shear at the superior section of the common femoral artery close to the bifurcation. The presence of wall motion, however, created minor differences in the general flow-field characteristics. We conclude that wall motion does not have significant influence on the global fluid dynamic characteristics of the femoral artery bifurcation. Longer arterial segments need to be simulated to see the effect of wall motion on tortuousity which was previously cited as an important factor in the development of atherosclerosis at the femoral artery.

Successful management of critical limb ischemia with intravenous sodium thiosulfate in a chronic hemodialysis patient

Vascular calcification is common among hemodialysis (HD) patients and contributes to the development of peripheral arterial disease. A 57-year-old Japanese man who had been on HD for 30 years was referred to us for severe pain with multiple ulcers on his toes and fingers. He was an ex-smoker and had no diabetes mellitus. On admission, he had ulcers on his big toes bilaterally and right 2nd - 4th fingers. Peripheral pulses were strong and his ankle-brachial pressure index was above 1.3. Laboratory data were as follows: calcium 9.9 mg/dl, albumin 3.3 g/dl, phosphate 3.0 mg/dl, Ca x P product 30, and parathyroid hormone 98 pg/ml. He had a parathyroidectomy in 1998 and 1999. X-rays of his hands and legs showed diffuse subcutaneous arteriolar calcification. Angiography revealed no local stenotic lesions. Despite intensive therapies including hyperbaric oxygen therapy, painful gangrene developed on his right big toe and the pain was so intense that he could not go to sleep in a supine position. We infused intravenous sodium thiosulfate (20 g) 3 times weekly, based on previous reports. Within 4 - 5 days, he experienced rapid and dramatic symptom relief. The score of the visual analogue pain scale improved from 10/10 - 2/10. The signs of ischemia, measured by transcutaneous partial oxygen pressure and thermography, improved significantly. During the infusion of sodium thiosulfate, the patient complained of nausea, vomiting and hyperosmia. These adverse symptoms were resolved after discontinuation of the infusion. Pain relief was sustained and he could walk after 2 weeks of infusion. Our case supports the use of sodium thiosulfate as a novel therapeutic choice for critical limb ischemia with severe vascular calcification in chronic HD patients.

Analysis of G(-174)C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease

Aims: To determine whether the G(−174)C interleukin 6 (IL-6) polymorphism influences the development of peripheral arterial disease (PAD) in individuals with type 2 diabetes. This was investigated by comparing the...

Raised serum thyrotrophin in women with peripheral arterial disease.

Women with symptomatic peripheral arterial disease were screened for impaired thyroid function using a sensitive immunoradiometric assay for thyrotrophin (TSH). The arterial disease in the aortotibial segment was documented by an abnormal brachial/ankle pressure index in 80 patients. An age-matched control group of elderly women (n = 30) with a normal pressure index was established. In the control group the mean serum TSH was 1.6 +/- 1.1 milliunits/l, median 1.5 milliunits/l and this established a normal range of 0.2-3.9 milliunits/l. Seven patients (8.8 per cent) were already receiving treatment for myxoedema. In the remaining patients, the overall distribution of serum TSH was skewed to higher levels; the mean was 3.7 milliunits/l, median 2.4 milliunits/l, P less than 0.001 compared with controls and 15 (19 per cent) had a serum TSH greater than 4 milliunits/l, compared with only one (3.3 per cent) of the controls. Therefore 22 patients (28 per cent) had myxoedema or a raised serum TSH. For all subjects with a normal TSH, there was a positive correlation of serum TSH with serum cholesterol, r = 0.68, P less than 0.001. For patients with a raised TSH, there was a continuing, but non-linear, increase of serum cholesterol with TSH. These results suggest that a raised serum TSH may be one of the risk factors for the development of peripheral arterial disease in women, possibly by increasing cholesterol levels.

Relationship Between HbA1c Level and Peripheral Arterial Disease

Homeostatic glucose control may play an important role in the development of peripheral arterial disease among individuals without diabetes. We sought to evaluate the association of HbA(1c) (A1C) with peripheral arterial disease in a representative sample of the U.S. population with and without diabetes. A cross-sectional study was conducted among 4,526 National Health and Nutrition Examination Survey 1999-2002 participants > or = 40 years of age. Peripheral arterial disease was defined as an ankle-brachial index <0.9 (n = 327). Among nondiabetic subjects, the age-standardized prevalence of peripheral arterial disease was 3.1, 4.8, 4.7, and 6.4% for participants with an A1C <5.3, 5.3-5.4, 5.5-5.6, and 5.7-6.0%, respectively (P trend <0.001). The prevalence of peripheral arterial disease was 7.5 and 8.8% for diabetic participants with A1C <7 and > or = 7%, respectively. After multivariable adjustment and compared with nondiabetic participants with A1C <5.3%, the odds ratio (95% CI) of peripheral arterial disease for nondiabetic participants with an A1C of 5.3-5.4, 5.5-5.6, and 5.7-6.0% was 1.41 (0.85-2.32), 1.39 (0.70-2.75), and 1.57 (1.02-2.47), respectively, and it was 2.33 (1.15-4.70) and 2.74 (1.25-6.02) for diabetic participants with A1C <7 and > or = 7%, respectively. An association exists between higher levels of A1C and peripheral arterial disease, even among patients without diabetes. Individuals with A1C levels > or = 5.3% should be targeted for aggressive risk factor reduction, which may reduce the burden of subclinical cardiovascular disease even among those without diabetes.

Vitamin D Nutrition Does Not Cause Peripheral Artery Disease

To the Editor: We wish to point out to readers who look casually through the Brief Review by Norman and Powell1 or who have access only to its abstract that the review is not relevant to vitamin D in the context of nutrition. Furthermore, the authors failed to present evidence that suggests that vitamin D may have cardiovascular benefits. The major difficulty with the Brief Review is that it fails to distinguish between what is physiological nutrition in humans, versus the administration to rats of pharmacological amounts of vitamin D, its derived hormone, calcitriol, or analogs. The vitamin D–nicotine (VDN) model of arteriosclerosis has been used for many years2 in rats using a huge bolus dose of vitamin D (40 000 IU/rat) along with nicotine. Per kg body weight, the vitamin D dose in animal models exceeds by 200-fold what humans can derive through sun exposure (250 to 625 micrograms/d, or 10 000 to 25 000 IU/d). The term “vitamin D” should not have been used in such a generic sense. For example, take the sentence, “In postmenopausal women, vitamin D supplementation (two micrograms per day) increased CD3 and CD8+ subsets of lymphocytes.”1 Despite appearances, this does not refer to either the nutrient vitamin D or to nutritional supplementation. Instead, the two micrograms relates to double the physiological replacement …

Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke.

Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke.

Two polymorphisms in the fracalkine receptor CX 3CR1 are not associated with peripheral arterial disease

Objective: CX 3CR1 is a novel chemokine receptor located on monocytes. Recently, two polymorphisms were linked to coronary artery disease (CAD), V249I and T280M. Carriers of at least one I-allele or one M-allele were found less frequently among patients with CAD compared to controls. The aim of the present study was to investigate the influence of these polymorphisms on the development of peripheral arterial disease (PAD). Methods: 522 human subjects with documented PAD and 522 age and sex matched controls were genotyped by polymerase chain reaction followed by restriction digestion. Results: Adjusted odds ratio (OR) of carriers of the I-allele for PAD was 1.34 (95% confidential interval (CI) from 0.86 to 2.09; P=0.19). The OR associated with the M-allele for PAD was 0.65 (95% CI from 0.41 to 1.04; P=0.07), when tested in the same regression analysis with the V249I genotypes. The genotypes were not linked to age at onset or severity of the disease. A subgroup of 137 CAD patients of whom 131 could be genotyped and who did not differ in baseline parameters from the remaining PAD patients, showed VV-genotype in 52.0%, VI in 42.7% and II in 5.3% CAD (OR associated with the I-allele for CAD: 1.29; 95% CI: 0.66–2.51; P=0.46). The distribution of the T280M genotypes was 67.1, 29.8, 3.1% (TT, TM, MM) also showing no association with CAD (OR=0.77; 95% CI 0.36–1.46; P=0.37). Conclusion: In this study we could not detect a difference in genotype frequencies of the V249I and T280M polymorphisms in CX 3CR1 between PAD patients and controls. CAD concomitant with PAD was also not affected by the I- or the M-allele.

Serum concentrations of vascular endothelial growth factor and monocyte-colony stimulating factor in peripheral arterial disease.

Vascular endothelial growth factor (VEGF) strongly promotes angiogenesis, and monocyte-colony stimulating factor (M-CSF) regulates the differentiation, proliferation, and survival of monocytes. Both VEGF and M-CSF are expressed in atherosclerotic lesions. The present study was performed to clarify the role of VEGF and M-CSF in the development of peripheral artery disease (PAD). The serum VEGF and M-CSF concentrations were determined in patients with arteriosclerosis obliterans (ASO) and thromboangitis obliterans (TAO). In both patient groups the serum VEGF concentrations were significantly higher than those in the control subjects. In contrast, the serum M-CSF concentrations in the ASO patients were significantly higher than those in both the TAO patients and control subjects, but there were no differences in the M-CSF concentrations between the TAO patients and control subjects. There was no correlation between the serum concentrations of VEGF and M-CSF. In conclusion, the serum VEGF concentration was increased in ASO and TAO patients, but increased concentration of M-CSF was seen only in ASO patients. These results may reflect a difference between ASO and TAO in disease pathogenesis.

Age at onset of smoking is an independent risk factor in peripheral artery disease development

The potential effects of age at onset of smoking on cardiovascular diseases have been studied little, in contrast to the well-established evidence supporting a causal role of cigarette smoking in these diseases. We sought to analyze the relationship between age at smoking onset and development of symptomatic peripheral arterial occlusive disease (PAOD). A population-based sample of 573 active or former male smokers aged 55 to 74 years were studied. Present or previous symptomatic PAOD was confirmed by noninvasive testing. Sixty-one subjects (10.6%) had symptomatic PAOD. Prevalence of disease increased with earlier starting age (15.6% if <or=16 years versus 5.4% if >16 years) of smoking. After controlling for risk factors that meet confounding factor criteria (ie, subject age and number of pack-years), men who started smoking at age 16 or earlier had a substantially higher risk for development of PAOD (odds ratio, 2.19; 95% CI, 1.15-4.15; P =.016) than men who began to smoke at a later age. A starting age for smoking of 16 years or earlier more than doubles the risk of future symptomatic PAOD regardless of the amount of exposure to cigarette smoking.

Alcohol Consumption and Coronary Heart Disease: A Causal and Protective Factor

Although heavy alcohol consumption is one of the leading causes of preventable deaths, light to moderate consumption of alcohol is associated with a reduced risk of coronary heart disease and total mortality. These benefits have been found in both men and women who consume as little as one to six alcoholic beverages per week regardless of whether the source is wine, beer, or liquor. Further, apparent benefits include a reduced risk for the development of peripheral arterial disease, ischemic stroke, sudden cardiac death, and angina. Even small amounts of alcohol have been associated with increases in blood pressure and increased risks of some cancers, especially breast. The difference between consuming light to moderate and heavy amounts of alcohol may mean the difference between preventing and causing premature death for all causes, especially coronary heart disease.

Plasma levels of cystatin-C and mannose binding protein are not associated with risk of developing systemic atherosclerosis.

Cystatin-C, a cysteine protease inhibitor, and mannose binding lectin, an innate defense protein involved in microbial clearance, have both been hypothesized to mediate atherosclerotic plaque progression. Prospective data evaluating whether levels of these proteins are associated with incident cardiovascular disease are sparse. Employing a prospective, nested, case-control study design, baseline levels of cystatin-C and mannose binding protein were evaluated among 133 apparently healthy men who subsequently developed symptomatic peripheral arterial disease (cases) and among 133 age- and smoking-matched controls who remained free of reported vascular disease during 5 years of follow-up. Overall, median baseline levels of cystatin-C were virtually identical among case and control subjects (0.83 mg/l, p = 0.84), whereas median baseline levels of mannose binding protein among cases and controls were 2.32 mg/l and 2.20 mg/l respectively (p = 0.69). No evidence of association was found between either cystatin-C or mannose binding protein and the development of peripheral arterial disease in analyses evaluating for linear trends or for threshold effects (all p-values > 0.05). In contrast with prior retrospective and cross-sectional studies, no evidence was found that baseline levels of cystatin-C or mannose binding protein are associated with an increased risk of future arterial disease.

Flow-induced constriction in arterioles of hyperhomocysteinemic rats is due to impaired nitric oxide and enhanced thromboxane A(2) mediation.

Hyperhomocysteinemia (HHcy) is thought to promote arteriosclerosis and peripheral arterial disease, in part by impairing the function of endothelium. Because flow-induced dilation is mediated by the endothelium, we hypothesized that HHcy alters this response by interfering with the synthesis/action of NO and prostaglandins. Thus, changes in the diameter of isolated, pressurized (at 80 mm Hg) gracilis skeletal muscle arterioles (diameter approximately 170 microm) from control and methionine diet-induced HHcy rats were investigated with videomicroscopy. Increases in intraluminal flow (from 0 to 25 microL/min) resulted in dilations of control arterioles (maximum, 34+/-4 microm). In contrast, increases in flow elicited constrictions of HHcy arterioles (-36+/-3 microm). In control arterioles, the NO synthase inhibitor N:(omega)-nitro-L-arginine-methyl ester significantly attenuated (approximately 50%) dilation, whereas the additional administration of indomethacin, an inhibitor of cyclooxygenase, eliminated flow-induced dilation. In the arterioles of HHcy rats, flow-induced constriction was not affected by N:(omega)-nitro-L-arginine-methyl ester, whereas it was abolished by indomethacin or the prostaglandin H(2)/thromboxane A(2) (TXA(2)) receptor antagonist SQ 29,548 or the TXA(2) synthase inhibitor CGS 13,080. Thus, in HHcy, increases in intraluminal flow elicit constrictions of skeletal muscle arterioles due to the impaired NO and enhanced TXA(2) mediation of the response, alterations that likely contribute to the development of peripheral arterial disease.

Role of age at onset of smoking on peripheral artery disease development

Role of age at onset of smoking on peripheral artery disease development

Angina and its treatment.

Angina and its treatment.

Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease; Edinburgh Artery Study Edinburgh Artery Study

The aim was to determine whether the effect of smoking on the development of peripheral or coronary artery disease might be mediated by other cardiovascular risk factors, including dietary antioxidant vitamin intake, serum low and high density lipoproteins, blood pressure, plasma fibrinogen, blood viscosity and markers of endothelial disturbance and fibrin turnover. 1592 men and women aged 55-74 years were selected at random from 11 general practices in Edinburgh, Scotland and followed-up for 5 years. The incidences of peripheral arterial disease and coronary artery disease were 5.1% and 11.1%, respectively. Both conditions were more common in moderate and heavy smokers than in never smokers: cigarette smoking was a stronger risk factor for peripheral arterial disease than for coronary artery disease. Smoking was associated with reduced dietary antioxidant vitamin intake, serum high density lipoprotein cholesterol and diastolic blood pressure and with increased alcohol intake, serum triglycerides, blood viscosity, plasma fibrinogen, and markers of endothelial disturbance (tissue plasminogen activator and von Willebrand factor antigens). Simultaneous adjustment for these risk factors reduced the relative risk of peripheral arterial disease only slightly, from 3.94 (95% CI 2.04, 7.62) to 2.72 (95% CI 1.13, 6.53) in heavy smokers and from 1.87 (95% CI 0.91, 3.85) to 1.70 (95% CI 0.72, 3.99) in moderate smokers. Similar adjustment also had little effect on the risk of coronary artery disease associated with smoking. The combined effect of smoking on the cardiovascular risk factors studied may explain part of its influence on peripheral and coronary arterial disease, but the majority of the effect appears to be due to other mechanisms.

Does nibbling or grazing protect the peripheral arteries from atherosclerosis?

It has been suggested that frequent food intake is metabolically advantageous. We investigated whether meal frequency was associated with the development of peripheral arterial disease among smokers. Hospital-based case-control study of smokers, recruited from outpatient clinics and inpatient wards at two London teaching hospitals. Two-hundred and ninety-one smokers, newly referred with peripheral arterial disease (cases) and 828 age- and sex-matched smokers without smoking-related disorders and with negative Rose questionnaire responses for intermittent claudication (controls) were recruited. All cases and controls completed a validated questionnaire concerning dietary habits. Odds ratios for peripheral arterial disease in association with several dietary variables were calculated, after adjustment for confounding variables. After adjustment for age, sex, pack-years of smoking, diabetes, hypertension and body mass index, the odds ratio for peripheral arterial disease among those smokers eating between meals (grazing) compared with those who did not, was 0.54 (95% confidence interval 0.42-0.83; P < 0.001). Among cases and controls, grazing was also associated with significantly lower plasma cholesterol concentrations (median 5.67 mmol/l in grazers compared with 6.08 mmol/l in non-grazers; P < 0.001) in those with apparently similar overall fat intakes. Neither plasma lipoprotein (a) nor fibrinogen concentrations varied with meal frequency. In smokers, grazing was associated with a reduced risk of developing symptomatic peripheral atherosclerosis. This is the first study to demonstrate the apparent benefits of grazing on a cardiovascular end-point.

Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study

Although treatment with high dose exogenous sex hormones affects cardiovascular risk, the role of physiological levels of endogenous sex hormones in the development of atherosclerotic disease in men and women is unknown. Forty men and 43 women with peripheral arterial disease and 88 age- and sex-matched controls were selected from participants in the Edinburgh Artery Study, a random survey of 1592 men and women ages 55–74 years from the general population. Compared with sex-matched controls, male cases had higher systolic blood pressure (155.5 mmHg vs. 138.7 mmHg; p ≤ 0.01) and waist hip ratio (0.92 vs. 0.89; p ≤ 0.05) and female cases had higher lifetime smoking (√ packyears 2.14 vs. 1.03; p ≤ 0.05). Mean estrone levels were slightly higher in male cases than controls (101.9 pmol/Liter vs. 92.1 pmol/Liter; p = 0.09), but this association lost significance after multivariate adjustment for age and body mass index. Mean levels of total and free testosterone, estradiol, and sex hormone binding globulin were not significantly different in cases compared with controls in either sex ( p > 0.1). These results, in accordance with previous prospective studies on coronary artery disease, do not support a role for physiological levels of endogenous sex hormones in the development of peripheral arterial disease in men or postmenopausal women.

Risk factors associated with the development of peripheral arterial disease in smokers: a case-control study

Purpose and method: A hospital based case-control study was designed to investigate what aspects of smoking and what co-factors of smoking are associated with the development of peripheral arterial disease (PAD). Cases were 291 smokers, newly referred with PAD, and controls were 828 age and sex matched smokers without PAD. Results: Reported recent tobacco usage was similar in cases and controls but total tobacco exposure was associated with the risk of PAD—adjusted odds ratios (ORs) increasing with tertile of pack-years smoked to reach 1.63 (95% CI, 1.11–2.39; P=0.011), for the highest tertile (>48 pack-years) compared with smokers in the lowest tertile (<31 pack-years). Cases reported smoking significantly lower tar and nicotine yield cigarettes than controls, but tended to inhale more deeply, and had significantly higher plasma concentrations of cotinine. ORs for PAD were significantly and independently increased by systolic blood pressure ≥160 mmHg (8.1 (5.2–13.0); P<0.0001), history of hypertension (2.4 (1.5–3.2); P=0.0003) and apolipoprotein B>0.9 g/l(3.8 (2.3–7.6); P=0.008). Conclusions: Increased total exposure to tobacco and the ability to smoke tobacco in a way which maximises nicotine yield are associated with increased risk of smokers developing PAD. There is no evidence that smoking low tar cigarettes reduces this risk, whereas both hypertension (particularly systolic) and high levels of apolipoprotein B, increase this risk.

The relationship between cigarette smoking and cardiovascular risk factors in peripheral arterial disease compared with ischaemic heart disease: The Edinburgh Artery Study

Cigarette smoking is probably the most important risk factor for the development of peripheral arterial disease, but it may be less important in the aetiology of ischaemic heart disease. The objectives of this study were to determine whether any other cardiovascular risk factors showed a significant interaction with cigarette smoking which would explain the greater association between smoking and peripheral atherosclerosis. One thousand five hundred and ninety-two subjects aged 55-74 years were selected randomly from the age-sex registers of 10 general practices in Edinburgh, Scotland. The presence of peripheral arterial disease was determined by the World Health Organisation questionnaire on intermittent claudication, the ankle brachial pressure index and a reactive hyperaemia test. Heart disease was identified by the patients' recall of a doctor diagnosis of angina or myocardial infarction. There were 131 subjects with peripheral arterial disease but no ischaemic heart disease, and 169 with heart disease without peripheral disease. Significantly more smokers occurred in the peripheral than the heart disease group (P <0.01), and in current smokers the age and sex adjusted odds ratio were highly significant for peripheral arterial disease (odds ratio 5.09, 95% confidence interval 2.97-8.72, P<0.001), but not for heart disease (odds ratio 1.72, 95% confidence interval 0.98-2.33, P>0.05). Subjects with lower limb disease also had higher systolic pressures (P<0.001), serum high density lipoprotein cholesterol (P<0.01) and plasma fibrinogen (P<0.05). On logistic regression, adjusting for a range of individual risk factors had no significant impact on the effect of smoking. Plasma fibrinogen produced the biggest reduction in odds ratio (4.23, 95% confidence interval 2.44-7.35, in current smokers with peripheral arterial disease). Therefore the stronger association between smoking and peripheral arterial disease than ischaemic heart disease does not appear to be influenced by the other risk factors examined here, and must be explained by some other mechanism.