Inflammation in Peripheral Artery Disease

HomeCirculationVol. 122, No. 18Inflammation in Peripheral Artery Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBInflammation in Peripheral Artery Disease Gregorio Brevetti, MD, Giuseppe Giugliano, MD, Linda Brevetti, MD and William R. Hiatt, MD Gregorio BrevettiGregorio Brevetti From the Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples “Federico II,” Naples, Italy (G.B., G.G., L.B.), and Department of Medicine/Cardiology, University of Colorado School of Medicine and CPC Clinical Research, Denver (W.R.H.). , Giuseppe GiuglianoGiuseppe Giugliano From the Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples “Federico II,” Naples, Italy (G.B., G.G., L.B.), and Department of Medicine/Cardiology, University of Colorado School of Medicine and CPC Clinical Research, Denver (W.R.H.). , Linda BrevettiLinda Brevetti From the Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples “Federico II,” Naples, Italy (G.B., G.G., L.B.), and Department of Medicine/Cardiology, University of Colorado School of Medicine and CPC Clinical Research, Denver (W.R.H.). and William R. HiattWilliam R. Hiatt From the Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples “Federico II,” Naples, Italy (G.B., G.G., L.B.), and Department of Medicine/Cardiology, University of Colorado School of Medicine and CPC Clinical Research, Denver (W.R.H.). Originally published2 Nov 2010https://doi.org/10.1161/CIRCULATIONAHA.109.918417Circulation. 2010;122:1862–1875Peripheral 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.7–11It 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 various arterial beds. As early as 1815, the year that cholesterol was discovered although not yet correlated to atherosclerosis, the London surgeon Joseph Hodgson published a monograph on vascular disease in which he cited inflammation as the underlying cause of atherosclerosis.12,13 In 1858, the German pathologist Rudolf Virchow14 found inflammatory cells in vascular plaques, but it was Sir William Osler15 who, in 1908, implicated inflammation and infection in the pathogenesis of atherosclerosis. However, the inflammation hypothesis was ignored for nearly a century, during which time atherosclerosis was firmly believed to be a cholesterol disease. The causative role of inflammation in the atherogenic process was established only at the end of the last millennium when many lines of evidence suggested alternative mechanisms to the cholesterol theory, and Russell Ross16 branded atherosclerosis an inflammatory disease. In actual fact, atherosclerosis is not simply a disorder of pathological lipid deposition but is regarded as a dynamic and progressive pathophysiological process arising from a combination of endothelial dysfunction and inflammation interacting with the standard risk factors that contribute to the initiation, clinical manifestations, and cardiovascular risk of all atherosclerotic diseases.17,18Endothelial dysfunction in PAD has been discussed previously.18 The present review is devoted to the role played by inflammation in PAD, summarizing the data showing that increased levels of inflammatory markers are associated with the development of PAD, its cardiovascular comorbidity, and risk of developing cardiac and cerebrovascular ischemic events. The final part of the review describes the inflammatory mechanisms presumed to contribute to claudication and its severity.Inflammation and Risk of Developing PADInflammation is important for the initiation and progression of PAD, and the inflammatory mediators involved in this process are similar to those contributing to the development of coronary artery disease (CAD).19–27 There are several candidate inflammatory triggers, including traditional risk factors that exert a proatherogenic role, at least in part, through an inflammatory mechanism. Cigarette smoking and diabetes mellitus, the strongest predictors of developing PAD, promote oxidative stress, which directly and indirectly enhances inflammatory pathways.28–33 Inflammation may also be a factor in hypertension, which affects about 80% of PAD patients.34 Indeed, angiotensin II elicits the production of reactive oxygen species and the expression of vascular cell adhesion molecule-1 from endothelial cells.35,36 Angiotensin II increases the expression of proinflammatory cytokines such as interleukin-6 and monocyte chemoattractant protein-1 by arterial smooth muscle cells.36–38 In addition, dyslipidemia may activate inflammatory functions by modifying the oxidation of low-density lipoproteins and of very low-density lipoproteins.39,40 However, unlike in CAD, dyslipidemia has relatively less importance in predicting the risk of lower-extremity occlusive disease.41 Other conditions that imply a systemic inflammatory response and may predispose the arterial vessels of the lower limbs to atherosclerosis are single-nucleotide polymorphisms in genes encoding inflammatory molecules, infections, and nonvascular systemic diseases such as rheumatoid arthritis and systemic lupus erythematosus.Whatever the inflammatory trigger, a large number of cross-sectional and longitudinal studies demonstrate a close link between inflammation and PAD.19–27 Noteworthy, each of the inflammatory molecules investigated in those studies is not simply a marker of inflammation but plays an active role in peripheral atherogenesis.42–48In 1998, Ridker et al, 19 in a prospective, nested case-control study carried out in apparently healthy men enrolled in the Physician's Health Study, found that the relative risk of developing PAD increased significantly with each increasing quartile of baseline C-reactive protein (CRP) concentration, such that men in the highest quartile (>2.1 mg/L) had a 2-fold increased risk compared with men in the lowest quartile (<0.55 mg/L). Notably, this result was independent of body mass index, hypercholesterolemia, diabetes mellitus, and a family history of premature atherosclerosis. The relationship between CRP and PAD risk has also been demonstrated in young healthy women.20 The Physician's Health Study also showed that elevated levels of soluble intercellular adhesion molecule-1, but not of soluble vascular cell adhesion molecule-1, are independently associated with the development of PAD.21 In analyses adjusted for age and smoking (2 major risk factors for PAD), the odds ratio in the highest compared with the lowest quartile of soluble intercellular adhesion molecule-1 was 3.9 (95% confidence interval [CI], 1.7 to 8.6). Importantly, elevated soluble intercellular adhesion molecule-1 remained significantly associated with the development of PAD after additional adjustment for lipid and nonlipid factors, including CRP. This finding, in association with the fact that combination of elevated levels of both biomarkers appeared to identify individuals at the greatest risk, suggests that CRP and intercellular adhesion molecule-1 play independent roles in the development of peripheral atherosclerosis.The Edinburgh Artery Study produced results similar to those of the Physician's Health Study.19,27 During a follow-up of 17 years, 209 of 1519 subjects (14%) developed PAD. Of these, most (ie, 169) were diagnosed as having intermittent claudication. After correction for age and sex, a number of inflammatory molecules, among which were CRP, interleukin-6, soluble intercellular adhesion molecule-1, and lipoprotein(a), were found to be associated with increased PAD risk. However, at variance with the Physician's Health Study, the hazard ratio for PAD of soluble intercellular adhesion molecule-1 was attenuated after adjustment for classic risk factors. This between-study discrepancy is probably due to differences in experimental design and statistical methods. Thus, there is a strong signal that systemic inflammation plays a role in peripheral atherosclerosis over and above the traditional risk factors.Genetics, Inflammation, and PADSome family studies have assessed the heritability of PAD.49–51 In the National Heart, Lung, and Blood Institute Twin Study in which 8.2% of the population had PAD, concordance rates for twin-pair similarity for low ankle-brachial index (ABI) were 33% for monozygotic pairs and 31% for dizygotic pairs.49 These findings indicate that the twin of a participant with PAD was 4 times more likely to have PAD than a randomly selected individual. Results suggested that genetic factors determined ≈48% of the variability in ABI after adjustment for cardiovascular disease risk factors. A subsequent study assessed the heritability of low ABI among participants in the Framingham Offspring Study.50 Overall, genetic determinants contributed to 21% of the variability in the ABI, a modest heritable effect, and cardiovascular disease risk factors contributed to 14% of the variability. Results also indicated that the majority of the interindividual variability in the ABI could not be explained by genetic or environmental determinants. In the Genetic Epidemiology Network of Arteriopathy study, after adjustment for cardiovascular disease risk factors, heritability for the ABI was 19.5% for blacks and 21.2% for non-Hispanic whites.51 Together, these studies suggest a moderate, significant heritability for PAD. Unfortunately, to date, no definitive genetic markers have been identified for PAD. Genetic determinants of PAD may reveal proteins implicated in the pathophysiology of lower-extremity atherosclerosis, thereby identifying mechanisms for the development and progression of lower-extremity atherosclerosis. In this context, the finding that a polymorphism of the EE genotype of intercellular adhesion molecule-1 significantly increases the risk of PAD reinforces the concept that inflammation plays a relevant role in PAD development.52 Furthermore, Flex et al53 studied 157 PAD patients and 206 control subjects and found that gene polymorphisms not only of intercellular adhesion molecule-1 but also of interleukin-6, E-selectin, monocyte chemoattractant protein-1, and matrix metalloproteinases 1 and 3 were independently associated with PAD. Conversely, distribution of CRP genotypes did not differ significantly between patients and control subjects. Although that study had several limitations (It is a relatively small case-control study and thus recruitment bias may not be excluded, and the study population was relatively small and is not representative of all PAD patient groups), it provides a rationale for the association between many inflammatory molecules and PAD risk. Indeed, plasma levels and/or functional activity of these inflammation determinants may be influenced by functional single-nucleotide polymorphisms of the corresponding genes. However, these are small studies of single candidate genes that are probably underpowered to detect independent relationships between any particular gene polymorphism and PAD.Infection and PAD RiskThe importance of inflammation in atherogenesis prompted the idea that an infectious agent could be the link between chronic inflammation and PAD. The most compelling evidence comes from seroepidemiological studies of 3 pathogens: Chlamydia pneumoniae, Helicobacter pylori, and Cytomegalovirus. To examine the relations between infection, inflammation, and occurrence of PAD, Bloemenkamp et al,54 in a multicenter, population-based, case-control study, measured IgG antibody titers and CRP levels in 228 young women affected by PAD and 643 control women. After adjustment for potential confounders, the odds ratios for PAD women with serological evidence of infection with C pneumoniae, H pylori, and Cytomegalovirus were 2.0 (95% CI, 1.3 to 3.1), 1.6 (95% CI, 1.1 to 2.2), and 1.6 (95% CI, 1.1 to 2.3), respectively. In addition, the cumulative number of infections was positively related to the risk of PAD, and this relationship was stronger in women with a high CRP level than in those with a low CRP level. This suggests that an inflammatory response might indeed be involved in the process that relates infection with PAD. In a small study, anti–C pneumoniae IgA titers and CRP levels were higher in PAD patients than in control subjects.55 On multivariate analysis, only smoking, CRP, and anti–C pneumoniae IgA remained independently associated with the disease. More intriguing are the results of the Bruneck study, a population-based study of the epidemiology and pathogenesis of atherosclerosis and arterial disease.56 In a large random population of 1000 subjects, antibodies to C pneumoniae, but not H pylori and Cytomegalovirus, were weakly but significantly associated with PAD (odds ratio 1.09; 95% CI, 1.00 to 1.18). The association was attenuated (odds ratio 1.07; 95% CI, 0.98 to 1.18) when some potential confounders were included in the multivariate model. However, when femoral intima-media thickness was used as an outcome variable instead of femoral atherosclerosis, C pneumoniae remained a significant risk factor for PAD in multivariate analysis.Some caveats have a bearing on the results of these seroepidemiological studies. First, several factors can confound the results.57 For example, smokers may have a higher incidence of C pneumoniae–induced bronchitis. Therefore, evidence of infection with C pneumoniae may merely be a marker of tobacco use, which is one of the main risk factors for PAD development.28 Second, there is a publication bias against studies with negative findings. Finally, atherosclerosis is very common in developed countries, and many adults have serological evidence of prior infections with Cytomegalovirus and C pneumoniae. It is difficult to distinguish coincidence from causality when the majority of the population studied has evidence of both infection and atherosclerosis.Nonetheless, support for the infection theory comes from studies showing an association between poor oral health and PAD. The Veterans Affairs Dental Longitudinal Study showed that of 1030 subjects followed up for >25 to 30 years, those with clinically significant periodontal disease at baseline had a 2.27 (95% CI, 1.3 to 3.90) increased risk of developing PAD.58 More recently, the Health Professionals Follow-Up Study demonstrated that the risk of PAD was significantly higher in men with a history of periodontal disease or with any tooth loss occurring during follow-up than men without periodontitis or without any tooth loss. Notably, the association was present between cumulative tooth loss and PAD (relative risk, 1.39; 95% CI, 1.07 to 1.82) but not between PAD and tooth loss in the 2 years before the end of the follow-up.59 Because the most common cause of tooth loss in older adults is periodontal disease, these findings suggest that 2 years may be too short for oral infection/inflammation to have an impact on PAD. Obviously, the infection theory would gain support should antibiotic therapy be found to reduce the incidence of PAD, but results in this regard are inconclusive.60–63 However, a recent publication evaluated the effect of a potent anti-chlamydial antibiotic on treating claudication in PAD, and the trial failed to demonstrate any clinical benefit on treadmill exercise performance or cardiovascular events.64Autoimmune Disease and PAD RiskAdditional evidence that inflammation contributes to PAD risk is that many patients with rheumatoid arthritis or systemic lupus erythematosus develop atherosclerosis in the arteries of the lower limbs.65–69 Indeed, despite a clear distinction in their pathophysiology, rheumatoid arthritis and systemic lupus erythematosus share an inflammatory process that is strikingly similar to the process leading to atherosclerosis.70 Unfortunately, however, most studies investigating the association of rheumatoid arthritis and systemic lupus erythematosus with PAD are small and cross-sectional.66–69 An exception is the study by Liang et al.65 In this retrospective medical record review of 609 patients with incident rheumatoid arthritis diagnosed during 1955 to 1994, patients were followed up from 1955 to 2000 (median, 11.8 years) for incident noncardiac vascular disease. During follow-up, 68 patients (11%) developed PAD, with a 30-year cumulative incidence of 16.1%. A Cox analysis adjusted for age, sex, body mass index, smoking, and rheumatoid factor showed that rheumatoid arthritis was a significant predictor of PAD (hazard ratio, 2.29; 95% CI, 1.20 to 4.34). Interestingly, rheumatoid arthritis was not associated with the occurrence of cerebrovascular events (hazard ratio, 1.52; 95% CI, 0.72 to 3.21). In conclusion, several lines of evidence indicate that inflammation plays a pivotal role in the development of PAD.Inflammation and Cardiovascular ComorbidityBecause atherosclerosis is a systemic disease, patients with manifest atherosclerosis in 1 vascular territory may have atheromatous plaques, although asymptomatic, in other arterial territories. Therefore, it is important to understand the epidemiology and pathogenesis that predispose to the coexistence of various manifestations of the disease, as well as the implications of multiple vascular bed involvement. Intriguingly, in the Reduction of Atherothrombosis for Continued Health (REACH) registry, a concomitant affected arterial territory was present in one quarter of patients with clinically manifested CAD, one third of patients with cerebrovascular disease, and more than half of the PAD patients.71 Given the systemic nature of atherosclerosis and the fact that its various clinical manifestations share the same risk factors, one would expect a more homogeneous distribution of vascular comorbidity. Instead, as indicated above, the prevalence of comorbid conditions seems to be related to the vascular population screened. Furthermore, in the entire population of the REACH registry (n=67 888), the 1-year atherothrombotic event rates (cardiovascular death, myocardial infarction, stroke, or hospitalization for a cardiovascular event) were 15.2% for CAD, 14.5% for cerebrovascular disease, and 21.1% for PAD patients.72 These findings strongly suggest that, of the 3 major atherosclerotic manifestations, PAD has the highest proatherosclerotic risk profile. This may be due to several factors, among which is inflammation.Inflammation and Carotid Artery DiseaseSeveral clinical and histopathological studies indicate that the severity of carotid artery disease (a manifestation of peripheral atherosclerosis) is related to inflammation.73–78 The inflammatory infiltrate of carotid plaques was more pronounced in patients with than in those without cerebral ischemic symptoms. Furthermore, the extent of the systemic inflammatory status has been found to parallel the degree of carotid stenosis.73,74,77However, inflammation is related not only to the degree of plaque stenosis but also to plaque morphology, which plays a distinct pathophysiological role in the development of stroke.79–81 In fact, many cerebrovascular events are associated with carotid stenoses <75%, thereby implicating other mechanisms in these events (eg, cardiac or aortic embolism) with embolism from the carotid bifurcation as the most frequent pathogenetic mechanism of cerebral ischemia.82,83 Histopathological data have led to the concept that plaques with a soft lipid-rich core, a thin cap, and inflammation in cap and shoulder are unstable and prone to rupture.84–92 This type of plaque is identifiable at B-mode ultrasound by its low echogenicity. In contrast, plaques that consist mainly of fibrin and collagen, and thus are more stable, present high echogenicity.93,94Although PAD patients have a marked inflammatory status, and despite the compelling evidence of a strict relationship between inflammation and carotid vascular disease severity, this association has been poorly investigated in PAD.95–97 We previously demonstrated that hypoechoic, presumably inflamed plaques in the femoral arterial bed were related to hypoechoic plaques in the carotid arteries.98 Specifically, hypoechoic carotid plaques were identified in 55.8% patients with hypoechoic femoral plaques and in only 32.0% with echo-rich femoral plaques (P<0.001). In a multivariate analysis adjusted for age, sex, and traditional risk factors, femoral hypoechoic plaque was the only significant predictor of the presence of hypoechoic carotid plaques (odds ratio, 3.87; 95% CI, 1.53 to 9.83). In our study and others, carotid plaque echolucency was strongly associated with neutrophil and leukocyte count.80,99 This is consistent with the finding that, in patients with acute myocardial infarction, the leukocyte number increased proportionally with the number of carotid plaques defined as unstable at B-mode ultrasound.100 Similarly, Lombardo et al101 reported that, in CAD, CRP levels were higher in patients with complex unstable carotid plaques than in patients with stable plaques. Collectively, these findings seem to confirm that “plaque instability” is a polyvascular phenomenon closely linked to inflammation.100,101Inflammation, PAD, and CADThe prevalence of CAD in PAD is very high, ranging between 43% and 90%, depending on the sensitivity of the technique used to detect CAD.29,41,102–105 In contrast, the prevalence of PAD in CAD patients is generally reported to be <25%.106–110 This suggests that PAD and CAD differ with respect to the type and/or intensity of the mechanisms favoring the propagation of atherosclerosis to other vascular territories. This could be related to the fact that PAD patients could be genetically more prone to develop atherosclerosis than patients with CAD. In this regard, it is interesting to note that when PAD and CAD coexisted in the 838 patients of the Program on Surgical Control of Hyperlipidemias (POSCH) study and in the 1712 individuals of the 2 Italian cohorts of the Seven Countries Study of Cardiovascular Disease, the disease developed earlier in the peripheral than in the coronary bed.111,112 This may be related to the fact that CAD patients are treated more aggressively to lower the risk of future cardiovascular events than PAD patients, who are largely undertreated in terms of cardiovascular risk reduction.22,34,113 Therefore the PAD population remains exposed to a very high risk of developing atherosclerosis in other vascular districts. Another hypothesis is that the large vascular bed of the lower limbs, where inflamed plaques are common, may release inflammatory mediators that contribute to the development of CAD.114,115 Indeed, we recently observed that human coronary endothelial cells, incubated with serum of venous femoral blood from the affected leg, released more monocyte chemoattractant protein-1 than when they were incubated with serum of the aorta of the same PAD patients. This difference disappeared when the cells were incubated with serum withdrawn from healthy legs of control subjects.116 These in vitro results, which indicate the presence of inflammatory triggers in the venous blood leaving the affected leg, substantiate data obtained in humans.116 In fact, in CAD plus PAD patients, a higher transfemoral gradient of neutrophil myeloperoxidase content (an index of neutrophil activation and a well-established marker of inflammation) correlated with coronary artery endothelial function (r=0.59, P<0.05).116,117 This relationship was much greater after maximally tolerated exercise (r=0.79), which increased neutrophil activation across the affected circulation, as indicated by the increase in myeloperoxidase transfemoral concentration. Thus, patients who had the greatest inflammatory response in the claudicating limb with exercise showed the greatest coronary artery endothelial dysfunction.116 These data are in line with previous studies showing that, in PAD patients, ischemic exercise promotes neutrophil activation and is associated with increased endothelial permeability at distant sites.118–122Inflammation may also contribute to the pathophysiological and clinical implications of the presence of PAD in CAD. As reported above, the prevalence of PAD is relatively low in CAD, but its presence has an important clinical relevance because it entails more widespread and severe coronary atherosclerosis and a greater prevalence of previous myocardial infarction.106,107,109,123–125 In effect, the cardiovascular risk profile is more pronounced in CAD plus PAD patients than in CAD-alone patients.106,107,123 However, the more severe coronary atherosclerosis and worse natural history in CAD plus PAD appear to be independently associated with increased markers of inflammation such as CRP, serum amyloid A, interleukin-6, and neopterin rather than with classic risk factors.106,107,124 What remains to be determined is whether and to what extent the increased levels of inflammatory molecules in CAD plus PAD result from a primary “extravascular” activation of the acute-phase response or whether they originate from the site of the active plaques in the lower limbs; both mechanisms are possible. However, the above-reported association of a high inflammatory status of the affected leg with coronary endothelial dysfunction, which is a key factor in atherosclerosis progression, may be a link between PAD and CAD severity.116 Indeed, we previously demonstrated that the severity of coronary atherosclerosis was related to the degree of inflammatory response in the affected PAD limb.126 This suggests that it is not PAD itself but its systemic inflammatory activity that is associated with a greater number of coronary stenoses, a higher prevalence of 3-vessel CAD, and a higher rate of previous myocardial infarction.126Notably, in CAD patients, the coexistence of PAD also entails more severe carotid vascular disease.127 Compared with the CAD-alone group, the CAD plus PAD group included fewer subjects without carotid plaques (22.2% versus 10.1%; P=0.035) and had more hypoechoic carotid plaques and symptomatic plaques. Inflammatory status, measured as leukocyte number, was more pronounced in CAD plus PAD than in CAD-alone patients. With multivariate analysis, the strongest predictor of hypoechoic carotid plaques was leukocyte count (odds ratio, 6.70; 95% CI, 2.13 to 21.10; P=0.001), followed by the coexistence of PAD and CAD (odds ratio, 4.20; 95% CI, 1.45 to 12.14; P=0.008). Therefore, as previously suggested, the greater number of hypoechoic, presumably unstable, carotid plaques in CAD plus PAD patients may be related to the more severe inflammatory profile in these patients compared with CAD-alone patients.106,107,123,128In conclusion, increased inflammation may help explain why the prevalence of clinically manifested CAD in PAD is much higher than the prevalence of PAD in CAD and why the coexistence of PAD in CAD patients portends more severe coronary and carotid atherosclerosis. The intriguing hypothesis that active plaques in the lower-limb arteries could play a causative role in the development and evolution of atherosclerosis in other vascular districts needs to be verified in large prospective studies.PAD, Inflammation, and Cardiovascular RiskPAD patients are exposed to a very high cardiovascular risk, which, in some studies, was found to be even greater than in isolated CAD or cerebrovascular disease patients.71,72,129,130 In CAD patients, PAD was found to be a stronger predictor for cardiovascular death and total mortality than prior myocardial infarction.131 However, unlike CAD and cerebrovascular disease, the increased cardiovascular risk of PAD patients is poorly influenced by classic risk factors and previous cardiac or cerebral ischemic events.7,8,10,11,105 As discussed above, the major prognostic indicator is PAD severity evaluated by ABI or clinical staging, but a large body of evidence suggests that inflammation may independently affect the susceptibility of PAD patients to future cardiovascular events.7–9,132–135Inde