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A rational connection of inflammation with peripheral arterial disease
Medical Hypotheses (2007) 69, 1190–1195
http://intl.elsevierhealth.com/journals/mehy
A rational connection of inflammation with peripheral arterial disease Jie Li a, Jian-Jun Li
a,*
, Qian Li b, Zhen Li a, Hai-Yan Qian
a
a
Department of Cardiology, Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, People’s Republic of China b Undergraduate College of Life Science, Peking University, Beijing 100023, People’s Republic of China Received 7 February 2007; accepted 7 February 2007
Summary Peripheral arterial disease (PAD) includes a wide range of manifestations in the lower limb, from asymptomatic to symptomatic disease ranging from intermittent claudication to critical limb ischemia, with ulcers, rest pain, or gangrene. It is manifestation of generalized atherosclerosis and this is clearly shown by the high prevalence of coexistence coronary and cerebral arterial disease in these patients. The cumulative findings on molecular and cellular biology have dramatically changed our concept of atherosclerotic disease. Recently, it has become clear that inflammation is fundamental to the process of atherosclerosis. Although the relation between inflammation and PAD is not well characterized, the emerging data demonstrated that PAD is a common manifestation of atherosclerosis that is associated with a systemic inflammation. The most important risk factors for PAD are similar to those of atherosclerotic disease elsewhere: age, male sex, diabetes mellitus, smoking, hypertension, hyperlipidemia, and hereditary factors. Serum levels of inflammatory markers, especially after exercise, have been found to be higher in patients with PAD than in controls, and associated with prognosis as well as restenosis in patients with PAD after revascularization. In the general United States adult population, inflammation is independently associated with PAD in a cross-sectional, nationally large representative sample. All of those evidences indicate that PAD is one aspect of atherosclerosis, a disease rationally connects with inflammation, which may further change our preventive and therapeutic strategies. c 2007 Elsevier Ltd. All rights reserved.
Introduction The prevalence of symptomatic peripheral arterial disease (PAD) in Western civilizations is high, particularly in the elderly population with 3–6% of men affected [1]. During recent years, percutane* Corresponding author. Tel.: +86 10 88386077; fax: +86 10 68331730. E-mail address: [email protected] (J.-J. Li).
ous transluminal angioplasty was established as a minimal invasive treatment option for patients with PAD. However, despite a primary success rate of above 90%, the long-term benefit is limited by the development of recurrent lumen narrowing (restenosis) in about 30–50% within 6 months [2]. The attention is being paid to, therefore, on the pathophysiological mechanism of PAD, which may hold the promise to modify our long-term preventive and therapeutic strategies.
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.02.043
Inflammation and PAD In fact, the process of PAD is very similar to coronary atherosclerotic disease not only in disease-attributed risk factors, overall therapeutic approaches, but also in the potential pathogenesis [3,4]. It is manifestation of generalized atherosclerosis and this is clearly shown by the high prevalence of coexistence coronary and cerebral arterial disease in patients with PAD. Atherosclerosis consists of cholesterol deposition in the intima of large and medium size arteries, accompanied by a chronic inflammatory process. This is clearly characterized by foci of macrophages and T-lymphocytes, proliferation and migration of smooth muscle cells, matrix formation and neovascularization [5]. Accordingly, atherosclerosis has world-widely considered as an inflammatory disease [5–7]. There is pivotal evidence that inflammation is also involved in the vascular response following peripheral vascular injury, suggesting PAD may be also an inflammation-associated disease. In this content, a rational connection between inflammation and PAD was discussed for purpose of attracting the attention of clinical research and therapeutic considerations.
Clinical aspects of PAD The definition of PAD covers all arteries except the ones in the heart and brain. In this article, we focus on the chronic arterial occlusive disease in the arteries of the leg. PAD consists of a wide range of atherosclerotic manifestations in the lower limb, from asymptomatic atherosclerosis to symptomatic disease ranging from intermittent claudication (IC) to critical limb ischemia (CLI), with ulcers, rest pain, or gangrene. The symptoms of PAD include pain on walking-IC, which is the earliest and most frequent presenting symptom. As the disease progression, the patients might suffer from rest pain and/or ischemic ulceration and gangrene due to hypoperfusion-CLI. IC has a prevalence of 3–6% in men at the age of 60–70 years according to large population studies [1]. Among these patients, 50–75% remain stable without progression of symptoms, with a 5-year risk of amputation of only 2%. If the disease progression to CLI, however, major amputation is required in more than one third of the patients [8]. Pharmacological arteriogenesis-stimulating therapy may be a way to reduce the risk for disease progression from claudication to CLI. Although the progression of PAD is fairly benign, it is a strong marker for future cardiovascular events [9]. For instance, for patients with CLI, the 1-year mortality is 20% [10]. In addition, the
1191 most important risk factors for PAD are similar to those of atherosclerotic disease elsewhere: age, male sex, diabetes mellitus, smoking, hypertension, hyperlipidemia, and hereditary factors [3,11], suggesting that control of those risk factors may attenuate the disease progression. PAD is a clinical diagnosis with typical history of lower extremity pain on walking, signs of ischemia in the foot, lack of palpable pulse, and a decreased ankle-brachial index (ABI) as an objective measure of severity of disease. In healthy subjects, the ABI is greater than 1.0. In claudication, the index is decreased to 0.5–0.9 and in patients with CLI to less than 0.5 [12]. Further diagnoses, such as ultrasound and contrast angiography, are usually reserved for patients likely to undergo invasive treatment. The management of patients with PAD consists of lifestyle modifications and pharmacotherapy addressing the risk factors to minimize the risk for disease progression and mortality in myocardial infarction and stroke. For most patients with claudication, invasive treatment is not offered, and exercise is tried to increase the walking distance. Symptomatic invasive treatment consists of surgical or endovascular revascularization. Unfortunately, about 20–30% of patients with CLI cannot be treated by any of these methods and the only option for them is often amputation. However, for this group of patients, there is a great need for alternative treatment strategies, for example, pharmacological arteriogenesis-stimulating therapy [4].
Inflammation and PAD Sir William Osler was the first to talk about the involvement of inflammation and infection in the pathogenesis of atherosclerosis, almost a 100 years age [6]. Inflammation has now been shown to contribute fundamentally to atherogenesis. The cumulative findings on molecular and cellular biology have dramatically changed our concept of atherosclerotic disease. Inflammation has already been considered as an integral part of atherosclerosis and it has received much attention as an important pathogenetic component in its development. Data suggest different pathways for its initiation and progression, which in turn are different from those triggering acute cardiovascular disease [5]. Even though atherosclerosis is a multifocal disease, the risk factors contributing to its development in different organs and different segments are not identical [13]. Additionally, conflicting results have opened debate on the role of inflammation on small-vessel disease physiopathology in different arterial territories [14]. However, emerging data
1192 have already shown that inflammation is an important trigger for the initiation and development of PAD.
Evidence of inflammation in PAD Since the acute-phase response may be induced by damage to the vascular endothelium caused by atherosclerotic process, plasma levels of inflammatory mediators may simply represent the extent of atherosclerotic disease [6]. Alternatively, increased local or systemic inflammation due to chronic infection, chronic inflammatory disease, smoking, obesity, or impaired glucose tolerance may precede (the progression of) atherosclerosis. Increased plasma levels of inflammatory markers have been identified in patients at risk for future manifestations of atherosclerosis in many epidemiological studies. Thus, C-reactive protein (CRP) has been shown to be elevated in patients with an increased risk of developing symptoms of atherosclerotic disease [15]. Recently, serum levels of inflammatory markers, such as CRP, have been found to be higher in patients with PAD than in controls. Signorelli et al. [16] assessed whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group was affected by PAD with claudication, while the other group consisted of healthy controls. Concentrations of interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin, L-selectin, and P-selectin concentrations and plasma concentrations of vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were also determined. All determinants were performed in patients at rest and after the treadmill exercise. The data showed that resting value of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were significantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001). These results confirmed that white blood cell activation was characteristic of systemic atherosclerosis and that these inflammation markers increased in conditions of hemodynamic stress in patients with PAD. In fact, it is well-demonstrated that increased in CRP have been associated with markers of disease activity, including atherosclerotic plaque macrophage content and frequency of thin fibrous caps.
Li et al. Data has also shown that increase in biochemical markers of systemic inflammation were associated with an increasing cardiovascular risk similar to that seen with lower extremity atherosclerotic activity. In asymptomatic populations, increases in the inflammatory marker CRP have been associated with higher risk of acute coronary syndromes and symptomatic PAD. Beckman et al. [17] tested the hypothesis that a combination of measurements of different aspects of atherosclerosis, including burden of atherosclerosis and levels of inflammation, would contain more predictive information than either alone in an outpatient population. They enrolled 110 patients who were referred to the non-invasive vascular laboratory for sequential Doppler pressure measurements of the lower extremities. They measured ABI and serum markers of inflammation and followed subjects for a mean of 2.25 years. Fifty subjects did not have PAD (ABI P 0.9), whereas 60 did (ABI < 0.9). Markers of inflammation, including CRP were higher in subjects who had PAD (3.83 ± 0.9 versus 2.11 ± 1.1, p = 0.019). During follow-up, 42% developed an event (myocardial infarction, stroke, unplanned coronary or lower extremity revascularization, or death). Decreasing ABI (v2 7.3, p = 0.026) and increasing CRP (v2 22.1, p < 0.001) increased the risk an event. Risk increased six-fold between the lowest and highest groups for all events and four-fold for hard events (myocardial infarction, stroke, and death) using both CRP and ABI. They concluded that patients who have PAD and increased inflammation are at highest risk for adverse cardiovascular outcomes, suggesting that characterizing atherosclerosis on the basis of these parameters provides important prognostic information in patients with PAD. In addition, the role of inflammation and Chlamydia pneumoniae in the development of coronary artery and PAD has also been thoroughly studied. In a cross-section study, Kaperonis et al. [18] demonstrated that inflammation (expressed as CRP levels) and chronic C. pneumoniae infection (IgA seropositivitiy), have an important role in lower limb atherosclerosis and correlated with the activity of the disease. More interesting, a recent study, examined this relation and its consistency across important subgroups in a cross-sectional, nationally representative sample of the adult United States population [19]. CRP, fibrinogen, leukocyte count, and PAD were assessed in a sample of 4787 participants aged P40 years in the National Health and Nutrition Examination Survey 1999–2002. PAD was defined as an ankle-brachial blood pressure index <0.9. Graded relations were present between
Inflammation and PAD inflammatory markers and PAD. The multivariate adjusted odds ratios of PAD associated with the highest versus the lowest quartile of CRP, fibrinogen, and leukocyte count were 2.14 (95% confidence interval [CI] 1.41–3.25), 2.49 (95% CI 1.27–4.85), and 1.67 (95% CI 0.84–3.31), respectively (each p trend <0.05 across quartiles). Associations between inflammation and PAD were similar across gender, obesity, and diabetic subgroups. However, the odds ratios of PAD for the highest CRP quartile versus the three lowest quartiles were 3.10 (95% CI 1.76–5.45) for non-Hispanic blacks versus 1.50 (95% CI 0.98–2.28) for non-Hispanic whites and 1.11 (95% CI 0.57–2.17) for Mexican American (p interaction = 0.049) and 5.59 (95% CI 1.82–17.17) for patients aged 40–54 years versus 2.01 (95% CI 1.13–3.58) for patient aged 55–69 years and 0.98 (95% CI 0.65–1.48) for patients aged P70 years (p interaction = 0.018). Odds ratios of PAD for the highest fibrinogen quartile versus the lowest three quartiles were 3.26 (95% CI 1.69– 6.28) for current smokers versus 0.83 (95% CI 0.51 to 1.35) for never smokers (p interaction = 0.006). They concluded that in the general United States adult population, inflammation is independently associated with PAD. Basically, atherosclerosis consists of cholesterol deposition in the intima of large and medium size arteries, accompanied by a chronic inflammatory process. This is characterized by foci of macrophages and T-lymphocytes, proliferation and migration of smooth muscle cells, matrix formation and neovascularization. Therefore, attention is being paid to systemic markers/mediators in which reflect the inflammatory activity in the plaque. Fiotti N and coworkers [20] evaluated the pattern of the main pro-inflammatory cytokines TNF-a, IL-1b, and IL-6, their soluble receptor/antagonist, and a variety of inflammatory markers, in patients with PAD. Eight patients with PAD suffering from IC, eight with CLI and eight controls were studied. Blood samples were collected at baseline in all groups and, for control and CI, immediately after and 4 h after a 30-min treadmill test. In the baseline, no differences in cytokine plasma levels were detected among the three groups. In contrast, soluble receptors of TNF (types I and II) and of IL-6, and IL-1b receptor antagonist (IL-1ra) were increased in IC and CLI patients, as compared to control. Of note, IL-1ra correlated with the occurrence and stage of the disease in a highly significant proportion of the patients, reaching a predicative value for the disease of p < 0.0001. The opposite trend was observed for the soluble receptor of IL1b. Notably, in the patients no alterations could be found in white blood cell counts, expression of
1193 CD11c adherence molecule by circulating monocytes or, in vitro, O2 release from zymosan-activated neutrophils. Moreover, plasma levels of platelet activating factor (PAF), of neutrophil elastase and of the acute phase reactants CRP and a1acid glycoprotein were not found to be significantly altered. In contrast, the acute-phase protein a1antitrypsin (a1AT) and haptoglobin (HG) were found to be increased. After the treadmill test, IL-1b and TNF-a remained at baseline levels following exercise, and IL-6 dropped to undetectable levels. Among cytokine antagonist, again the most relevant changes concerned the IL-1ra, which was significantly increased immediately after the treadmill test, both in IC and control, and returned to baseline levels after 4 h. In contrast, soluble TNF-a, IL1b and IL-6 receptors, PAF, and the other markers of leukocyte activation were found to be unchanged. Soluble TNF-a and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase protein a1AT and HG have been reported to exert antiinflammatory functions. The increase plasma levels of these agents, together with low levels of inflammatory cytokines and other pro-inflammatory mediators such as PAF and a1-acid glycoprotein, appear to draw an undescribed picture, so far, of upregulation of a composite systemic anti-inflammatory mechanism in atherosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for developing new insights into the pathogenesis of the atherosclerotic disease.
Inflammation and prognosis of PAD Studies in patients with PAD have reported an association between inflammatory markers and severity of disease or worsening of symptoms. However, few have studied the prognostic significance of inflammatory markers in asymptomatic subjects, measured many years before the onset of symptomatic PAD requiring treatment. Engstrom et al. [21] investigate 5619 healthy men without walkinginduced calf pain to assess the relationship between inflammation-sensitive plasma proteins (ISPs) including fibrinogen, a1-antitrypsin, haptoglobin, ceruloplasmin, and orosomucord and future revascularization. Result showed that 70 patients (1.2%) underwent revascularization because of severe PAD at a mean of 16.5 years after the baseline. They found that ISPs, measured 16 years earlier in apparently healthy men without walking-induced calf pain, were associated with increased risk for development of PAD revascularization.
1194 In addition, many recent studies have focused on the diversity of mechanisms by which inflammation can promote blood clotting. Recently, Unlu et al. [22] investigated the relationship between plasma concentrations of inflammatory and hemostatic markers and the severity of atherosclerosis. In this prospective cohort study, 45 consecutive patients with PAD of ABI < 0.90, and 44 patients without PAD of ABI 0.90–1.50 were included. D-dimer, fibrinogen, CRP, serum amyloid A, and prothrombin time were measured at the recruitment. They found that median values of serum amyloid A, Ddimer, and CRP were significant higher in the PAD group than in those without PAD group (p < 0.001). The patients with PAD had moderately higher fibrinogen levels than without PAD (p < 0.01). In multivariable regression analysis adjusting for all blood factors as well as potential confounds, patients with PAD, levels of serum amyloid A, and CRP showed a highly significant, inverse association with the ABI. Elevated D-dimer and fibrinogen levels were also found to be related to lower ABI, where no association was observed between prothrombin time levels. They concluded that higher CRP, serum amyloid A, and D-dimer levels are showing positive association with the presence of PAD. CRP and serum amyloid A levels are direct relations between the ABI and the extent of vascular inflammation.
Inflammation and restenosis of PAD During recent years, percutaneous transluminal angioplasty was established as a minimal invasive treatment option for patients with PAD. However, despite a primary success rate of above 90%, the long-term benefit is limited by the development of restenosis in about 30–50% within 6 months. There is pivotal evidence that inflammation is involved in the vascular response following balloon injury. Perivascular inflammation plays a key role in the development of restenosis after percutaneous transluminal angioplasty. The adherence of leukocytes to the activated endothelium, an essential feature in the restenosis process, is mediated by the cellular adhesion molecule E-selectin. Selectins facilitate the adhesion of inflammatory cellular components to the activated vascular endothelium, and thus promote localized vascular inflammation. E-selectin, in particular, is considered most important for the pathophysiology of restenosis. Recently, Mlekusch et al. [23] investigated 175 consecutive patients with PAD and IC or CLI who underwent primary successful femoropoliteal balloon angioplasty, and demonstrated that patients with an E-selectin plasma level above
Li et al. 44.9 mg/dL (third tertile) had a 1.9-fold increased adjusted risk for restenosis (95% CI 1.09–3.30). This data indicated that E-selectin plasma levels are modulated by the E-selectin Ser 128Arg genotype, and predict the risk for restenosis after femoropopliteal angioplasty in patients with PAD. However, a direct association of the Ser128Arg polymorphism with late postangioplasty failure could not be demonstrated. Moreover, data from Schillinger et al. [24] also showed that vascular inflammation is associated with restenosis after percutaneous transluminal angioplasty of the femoropopliteal artery. In their prospective cohort study, 172 consecutive patients with PAD of Fantain stage IIa, IIb, or III who underwent successful angioplasty of the superficial femoral and popliteal arteries were included. Patency at 6 months was evaluated by using oscillography, ABI, and color-coded duplex ultrasonography. The association of restenosis and CRP, serum amyloid A (SAA), and fibrinigen levels at baseline, 24 h, and 48 h after intervention was assessed by means of multivariate analysis with adjustment of known risk factors for restenosis. The results showed that restenosis was found in 56 patients (33%) within 6 months. CRP values at baseline and 48 h after intervention were independently associated with 6-month restenosis. SAA and fibrinogen values at any time interval were not significantly associated with patency in the multivariate models, suggesting that extent of vascular inflammation as measured by means of acute-phase reactant before and after angioplasty of the femoropopliteal artery is associated with 6-month restenosis, and baseline and 48 h CRP levels were independent predictors of postangioplasty outcome. In brief, PAD is one aspect of atherosclerosis, a disease associated with inflammation. Inflammation is an integral part of atherosclerosis and it has received much attention as an important pathogenetic component in its development.
Clinical implications Lower extremity PAD most frequently presents with lower limb pain on walking-IC. As the disease progression the patients might suffer from rest pain and/or ischemic ulceration-CLI. Mechanisms of functional impairment and decline in patients with lower extremity PAD are not fully understood. However, recent studies suggested that inflammation might initiate and exacerbate PAD through a complex constellation of vascular effects. These include the adherence of
Inflammation and PAD
1195
leukocytes to the vessel wall; increased membrane permeability; and the production of cytokines, leading to the recruitment of macrophages and the proliferation of macrophages and smooth muscle cells within the vessel wall. Finally, perivascular inflammation plays also a key role in the development of restenosis after percutaneous transluminal angioplasty of PAD. The management of patients with PAD consists of life-style modifications and pharmacotherapy addressing the risk factors to minimize the risk for disease progression and mortality in myocardial infarction and stroke. Symptomatic invasive treatment consists of surgical or endovascular revascularization. In addition, the pharmacological arteriogenesis-stimulating therapy is an alternative for the treatment of PAD. More importantly, because measurements of serum acute-phase parameters allow a sensitive quantification of the vascular inflammatory process, the attention is being paid to, therefore, on the pathophysiological mechanism of PAD, which holds the promise to change our therapeutic strategies.
Acknowledgements This article is partly supported by a Fu Wai Hospital Grant (2004190), National Natural Scientific Foundation (30670861), and Specialized Research Fund for the Doctoral Program of Higher Education (20060023044) of China awarded by Dr. Jian-Jun Li, MD, PhD.
References [1] TransAtlantic Inter-Society Consensus (TASC). Management of peripheral arterial disease (PAD). Eur J Vasc Endovasc Surg 2000;19:S1–S250. [2] Tsakiris DA, Tschopl M, Jaeger K, et al. Circulating cell adhesion molecules and endothelial markers before and after transluminal angioplasty in peripheral arterial occlusive disease. Atherosclerosis 1999;142:193–200. [3] Kannel WB, McGee DL. Update on som epidemiologic features of intermittent claudication. J Am Geriatr Soc 1985;33:13–8. [4] Palmer-kazen U, Wahlberg E. Arteriogenesis in peripheral arterial disease. Endothelium 2003;10:225–32. [5] Li J-J. Inflammation: an important mechanism for different clinical entities of coronary artery disease. Chin Med J 2005;118:1817–26. [6] Hanson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95.
[7] Li J-J, Hu S-S. Early, intensive and long-term statin therapy in acute coronary syndrome: focus on an anti-inflammatory mechanism. Vasc Dis Prevent 2005;2(3):181–6. [8] Luther M, Lepantalo M, Alback A, Matzke S. Amputation rates as a measure of vascular surgical results. Brit J Surg 1996;83:241–4. [9] Newman AB, Sutton-Tyrell K, Vogt MT, Kuller LH. Morbidity and mortality in hypertensive adults with low ankle-arm blood pressure index. JAMA 1993;270:487–9. [10] Gruppo di Studio dell Ischemia Cronica degli Arteri Inferior. Long-term mortality and its predicator in patients with critical leg ischemia. Eur J Vasc Endovasc Surg 1997;14:91–5. [11] Aboyans V, Criqui MH, Denenberg JO, et al. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation 2006;113:2623–9. [12] Quriel K, Zarins CK. Doppler ankle pressure: an evaluation of three methods of expression. Arch Surg 1982;117: 1297–300. [13] Criqui MH, Browner D, Fronek A, et al. Peripheral arterial disease in large vessels is epidemiologically distinct from small vessel disease. Am J Epidemiol 1989;129:1110–9. [14] Li J-J, Li Y-S, Zhang Y, et al. Inflammation: a possible pathogenic link to cardiac syndrome X. Med Hypotheses 2006;66:87–91. [15] Li J-J, Fang C-H. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular disease. Med Hypotheses 2004;62:499–506. [16] Signorelli SS, Mazzarino MC, Pino LD, et al. High circulating levels of cytokines (IL-6 and TNFa), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test. Vasc Med 2003;8:15–9. [17] Beckman JA, Preis O, Ridker PM, et al. Comparison of usefulness of inflammatory markers in patients with versus without peripheral arterial disease in predicting adverse cardiovascular outcomes (myocardial infarction, stroke, and death). Am J Cardiol 2005;96:1374–8. [18] kaperonis EA, Liapis CD, kakisis JD, et al. Inflammation and Chlamydia pneumoniae infection correlate with severity of peripheral arterial disease. Eur J Vasc Endovasc Surg 2006;31:509–15. [19] Wildman RP, Muntner P, Chen J, et al. Relation of inflammation to peripheral arterial disease in the National Health and Nutrition Examination Survey, 1999–2002. Am J Cardiol 2005;96:1579–83. [20] Fiotti N, Giansante C, Ponte E, et al. Atherosclerosis and inflammation. Pattern of cytokine regulation in patients with peripheral arterial disease. Atherosclerosis 1999;145: 51–60. [21] Engstrom G, Site-Flondell D, Lindblad B, et al. Risk of treatment of peripheral disease is related to inflammationsensitive plasma proteins: a prospective cohort study. J Vasc Surg 2004;40:1101–5. [22] Unlu Y, Karapolat S, Karaca Y, Kiziltunc A. Comparison of levels of inflammatory markers and hemostatic factors in the patients with and without PAD. Thromb Res 2006;117:357–64. [23] Mlekusch W, Exner M, Schillinger M, et al. E-selectin and restenosis after femoropopliteal angioplasty: prognostic impact of the Ser 128Arg genotype and plasma levels. Thromb Haemost 2004;91:171–9. [24] Schillinger M, Exner M, Mlekusch W, et al. Vascular inflammation and percutaneous transluminal angioplasty: association with restenosis. Radiology 2002;225:21–6.
Available online at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/mehy
A rational connection of inflammation with peripheral arterial disease Jie Li a, Jian-Jun Li
a,*
, Qian Li b, Zhen Li a, Hai-Yan Qian
a
a
Department of Cardiology, Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, People’s Republic of China b Undergraduate College of Life Science, Peking University, Beijing 100023, People’s Republic of China Received 7 February 2007; accepted 7 February 2007
Summary Peripheral arterial disease (PAD) includes a wide range of manifestations in the lower limb, from asymptomatic to symptomatic disease ranging from intermittent claudication to critical limb ischemia, with ulcers, rest pain, or gangrene. It is manifestation of generalized atherosclerosis and this is clearly shown by the high prevalence of coexistence coronary and cerebral arterial disease in these patients. The cumulative findings on molecular and cellular biology have dramatically changed our concept of atherosclerotic disease. Recently, it has become clear that inflammation is fundamental to the process of atherosclerosis. Although the relation between inflammation and PAD is not well characterized, the emerging data demonstrated that PAD is a common manifestation of atherosclerosis that is associated with a systemic inflammation. The most important risk factors for PAD are similar to those of atherosclerotic disease elsewhere: age, male sex, diabetes mellitus, smoking, hypertension, hyperlipidemia, and hereditary factors. Serum levels of inflammatory markers, especially after exercise, have been found to be higher in patients with PAD than in controls, and associated with prognosis as well as restenosis in patients with PAD after revascularization. In the general United States adult population, inflammation is independently associated with PAD in a cross-sectional, nationally large representative sample. All of those evidences indicate that PAD is one aspect of atherosclerosis, a disease rationally connects with inflammation, which may further change our preventive and therapeutic strategies. c 2007 Elsevier Ltd. All rights reserved.
Introduction The prevalence of symptomatic peripheral arterial disease (PAD) in Western civilizations is high, particularly in the elderly population with 3–6% of men affected [1]. During recent years, percutane* Corresponding author. Tel.: +86 10 88386077; fax: +86 10 68331730. E-mail address: [email protected] (J.-J. Li).
ous transluminal angioplasty was established as a minimal invasive treatment option for patients with PAD. However, despite a primary success rate of above 90%, the long-term benefit is limited by the development of recurrent lumen narrowing (restenosis) in about 30–50% within 6 months [2]. The attention is being paid to, therefore, on the pathophysiological mechanism of PAD, which may hold the promise to modify our long-term preventive and therapeutic strategies.
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.02.043
Inflammation and PAD In fact, the process of PAD is very similar to coronary atherosclerotic disease not only in disease-attributed risk factors, overall therapeutic approaches, but also in the potential pathogenesis [3,4]. It is manifestation of generalized atherosclerosis and this is clearly shown by the high prevalence of coexistence coronary and cerebral arterial disease in patients with PAD. Atherosclerosis consists of cholesterol deposition in the intima of large and medium size arteries, accompanied by a chronic inflammatory process. This is clearly characterized by foci of macrophages and T-lymphocytes, proliferation and migration of smooth muscle cells, matrix formation and neovascularization [5]. Accordingly, atherosclerosis has world-widely considered as an inflammatory disease [5–7]. There is pivotal evidence that inflammation is also involved in the vascular response following peripheral vascular injury, suggesting PAD may be also an inflammation-associated disease. In this content, a rational connection between inflammation and PAD was discussed for purpose of attracting the attention of clinical research and therapeutic considerations.
Clinical aspects of PAD The definition of PAD covers all arteries except the ones in the heart and brain. In this article, we focus on the chronic arterial occlusive disease in the arteries of the leg. PAD consists of a wide range of atherosclerotic manifestations in the lower limb, from asymptomatic atherosclerosis to symptomatic disease ranging from intermittent claudication (IC) to critical limb ischemia (CLI), with ulcers, rest pain, or gangrene. The symptoms of PAD include pain on walking-IC, which is the earliest and most frequent presenting symptom. As the disease progression, the patients might suffer from rest pain and/or ischemic ulceration and gangrene due to hypoperfusion-CLI. IC has a prevalence of 3–6% in men at the age of 60–70 years according to large population studies [1]. Among these patients, 50–75% remain stable without progression of symptoms, with a 5-year risk of amputation of only 2%. If the disease progression to CLI, however, major amputation is required in more than one third of the patients [8]. Pharmacological arteriogenesis-stimulating therapy may be a way to reduce the risk for disease progression from claudication to CLI. Although the progression of PAD is fairly benign, it is a strong marker for future cardiovascular events [9]. For instance, for patients with CLI, the 1-year mortality is 20% [10]. In addition, the
1191 most important risk factors for PAD are similar to those of atherosclerotic disease elsewhere: age, male sex, diabetes mellitus, smoking, hypertension, hyperlipidemia, and hereditary factors [3,11], suggesting that control of those risk factors may attenuate the disease progression. PAD is a clinical diagnosis with typical history of lower extremity pain on walking, signs of ischemia in the foot, lack of palpable pulse, and a decreased ankle-brachial index (ABI) as an objective measure of severity of disease. In healthy subjects, the ABI is greater than 1.0. In claudication, the index is decreased to 0.5–0.9 and in patients with CLI to less than 0.5 [12]. Further diagnoses, such as ultrasound and contrast angiography, are usually reserved for patients likely to undergo invasive treatment. The management of patients with PAD consists of lifestyle modifications and pharmacotherapy addressing the risk factors to minimize the risk for disease progression and mortality in myocardial infarction and stroke. For most patients with claudication, invasive treatment is not offered, and exercise is tried to increase the walking distance. Symptomatic invasive treatment consists of surgical or endovascular revascularization. Unfortunately, about 20–30% of patients with CLI cannot be treated by any of these methods and the only option for them is often amputation. However, for this group of patients, there is a great need for alternative treatment strategies, for example, pharmacological arteriogenesis-stimulating therapy [4].
Inflammation and PAD Sir William Osler was the first to talk about the involvement of inflammation and infection in the pathogenesis of atherosclerosis, almost a 100 years age [6]. Inflammation has now been shown to contribute fundamentally to atherogenesis. The cumulative findings on molecular and cellular biology have dramatically changed our concept of atherosclerotic disease. Inflammation has already been considered as an integral part of atherosclerosis and it has received much attention as an important pathogenetic component in its development. Data suggest different pathways for its initiation and progression, which in turn are different from those triggering acute cardiovascular disease [5]. Even though atherosclerosis is a multifocal disease, the risk factors contributing to its development in different organs and different segments are not identical [13]. Additionally, conflicting results have opened debate on the role of inflammation on small-vessel disease physiopathology in different arterial territories [14]. However, emerging data
1192 have already shown that inflammation is an important trigger for the initiation and development of PAD.
Evidence of inflammation in PAD Since the acute-phase response may be induced by damage to the vascular endothelium caused by atherosclerotic process, plasma levels of inflammatory mediators may simply represent the extent of atherosclerotic disease [6]. Alternatively, increased local or systemic inflammation due to chronic infection, chronic inflammatory disease, smoking, obesity, or impaired glucose tolerance may precede (the progression of) atherosclerosis. Increased plasma levels of inflammatory markers have been identified in patients at risk for future manifestations of atherosclerosis in many epidemiological studies. Thus, C-reactive protein (CRP) has been shown to be elevated in patients with an increased risk of developing symptoms of atherosclerotic disease [15]. Recently, serum levels of inflammatory markers, such as CRP, have been found to be higher in patients with PAD than in controls. Signorelli et al. [16] assessed whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group was affected by PAD with claudication, while the other group consisted of healthy controls. Concentrations of interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin, L-selectin, and P-selectin concentrations and plasma concentrations of vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were also determined. All determinants were performed in patients at rest and after the treadmill exercise. The data showed that resting value of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were significantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001). These results confirmed that white blood cell activation was characteristic of systemic atherosclerosis and that these inflammation markers increased in conditions of hemodynamic stress in patients with PAD. In fact, it is well-demonstrated that increased in CRP have been associated with markers of disease activity, including atherosclerotic plaque macrophage content and frequency of thin fibrous caps.
Li et al. Data has also shown that increase in biochemical markers of systemic inflammation were associated with an increasing cardiovascular risk similar to that seen with lower extremity atherosclerotic activity. In asymptomatic populations, increases in the inflammatory marker CRP have been associated with higher risk of acute coronary syndromes and symptomatic PAD. Beckman et al. [17] tested the hypothesis that a combination of measurements of different aspects of atherosclerosis, including burden of atherosclerosis and levels of inflammation, would contain more predictive information than either alone in an outpatient population. They enrolled 110 patients who were referred to the non-invasive vascular laboratory for sequential Doppler pressure measurements of the lower extremities. They measured ABI and serum markers of inflammation and followed subjects for a mean of 2.25 years. Fifty subjects did not have PAD (ABI P 0.9), whereas 60 did (ABI < 0.9). Markers of inflammation, including CRP were higher in subjects who had PAD (3.83 ± 0.9 versus 2.11 ± 1.1, p = 0.019). During follow-up, 42% developed an event (myocardial infarction, stroke, unplanned coronary or lower extremity revascularization, or death). Decreasing ABI (v2 7.3, p = 0.026) and increasing CRP (v2 22.1, p < 0.001) increased the risk an event. Risk increased six-fold between the lowest and highest groups for all events and four-fold for hard events (myocardial infarction, stroke, and death) using both CRP and ABI. They concluded that patients who have PAD and increased inflammation are at highest risk for adverse cardiovascular outcomes, suggesting that characterizing atherosclerosis on the basis of these parameters provides important prognostic information in patients with PAD. In addition, the role of inflammation and Chlamydia pneumoniae in the development of coronary artery and PAD has also been thoroughly studied. In a cross-section study, Kaperonis et al. [18] demonstrated that inflammation (expressed as CRP levels) and chronic C. pneumoniae infection (IgA seropositivitiy), have an important role in lower limb atherosclerosis and correlated with the activity of the disease. More interesting, a recent study, examined this relation and its consistency across important subgroups in a cross-sectional, nationally representative sample of the adult United States population [19]. CRP, fibrinogen, leukocyte count, and PAD were assessed in a sample of 4787 participants aged P40 years in the National Health and Nutrition Examination Survey 1999–2002. PAD was defined as an ankle-brachial blood pressure index <0.9. Graded relations were present between
Inflammation and PAD inflammatory markers and PAD. The multivariate adjusted odds ratios of PAD associated with the highest versus the lowest quartile of CRP, fibrinogen, and leukocyte count were 2.14 (95% confidence interval [CI] 1.41–3.25), 2.49 (95% CI 1.27–4.85), and 1.67 (95% CI 0.84–3.31), respectively (each p trend <0.05 across quartiles). Associations between inflammation and PAD were similar across gender, obesity, and diabetic subgroups. However, the odds ratios of PAD for the highest CRP quartile versus the three lowest quartiles were 3.10 (95% CI 1.76–5.45) for non-Hispanic blacks versus 1.50 (95% CI 0.98–2.28) for non-Hispanic whites and 1.11 (95% CI 0.57–2.17) for Mexican American (p interaction = 0.049) and 5.59 (95% CI 1.82–17.17) for patients aged 40–54 years versus 2.01 (95% CI 1.13–3.58) for patient aged 55–69 years and 0.98 (95% CI 0.65–1.48) for patients aged P70 years (p interaction = 0.018). Odds ratios of PAD for the highest fibrinogen quartile versus the lowest three quartiles were 3.26 (95% CI 1.69– 6.28) for current smokers versus 0.83 (95% CI 0.51 to 1.35) for never smokers (p interaction = 0.006). They concluded that in the general United States adult population, inflammation is independently associated with PAD. Basically, atherosclerosis consists of cholesterol deposition in the intima of large and medium size arteries, accompanied by a chronic inflammatory process. This is characterized by foci of macrophages and T-lymphocytes, proliferation and migration of smooth muscle cells, matrix formation and neovascularization. Therefore, attention is being paid to systemic markers/mediators in which reflect the inflammatory activity in the plaque. Fiotti N and coworkers [20] evaluated the pattern of the main pro-inflammatory cytokines TNF-a, IL-1b, and IL-6, their soluble receptor/antagonist, and a variety of inflammatory markers, in patients with PAD. Eight patients with PAD suffering from IC, eight with CLI and eight controls were studied. Blood samples were collected at baseline in all groups and, for control and CI, immediately after and 4 h after a 30-min treadmill test. In the baseline, no differences in cytokine plasma levels were detected among the three groups. In contrast, soluble receptors of TNF (types I and II) and of IL-6, and IL-1b receptor antagonist (IL-1ra) were increased in IC and CLI patients, as compared to control. Of note, IL-1ra correlated with the occurrence and stage of the disease in a highly significant proportion of the patients, reaching a predicative value for the disease of p < 0.0001. The opposite trend was observed for the soluble receptor of IL1b. Notably, in the patients no alterations could be found in white blood cell counts, expression of
1193 CD11c adherence molecule by circulating monocytes or, in vitro, O2 release from zymosan-activated neutrophils. Moreover, plasma levels of platelet activating factor (PAF), of neutrophil elastase and of the acute phase reactants CRP and a1acid glycoprotein were not found to be significantly altered. In contrast, the acute-phase protein a1antitrypsin (a1AT) and haptoglobin (HG) were found to be increased. After the treadmill test, IL-1b and TNF-a remained at baseline levels following exercise, and IL-6 dropped to undetectable levels. Among cytokine antagonist, again the most relevant changes concerned the IL-1ra, which was significantly increased immediately after the treadmill test, both in IC and control, and returned to baseline levels after 4 h. In contrast, soluble TNF-a, IL1b and IL-6 receptors, PAF, and the other markers of leukocyte activation were found to be unchanged. Soluble TNF-a and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase protein a1AT and HG have been reported to exert antiinflammatory functions. The increase plasma levels of these agents, together with low levels of inflammatory cytokines and other pro-inflammatory mediators such as PAF and a1-acid glycoprotein, appear to draw an undescribed picture, so far, of upregulation of a composite systemic anti-inflammatory mechanism in atherosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for developing new insights into the pathogenesis of the atherosclerotic disease.
Inflammation and prognosis of PAD Studies in patients with PAD have reported an association between inflammatory markers and severity of disease or worsening of symptoms. However, few have studied the prognostic significance of inflammatory markers in asymptomatic subjects, measured many years before the onset of symptomatic PAD requiring treatment. Engstrom et al. [21] investigate 5619 healthy men without walkinginduced calf pain to assess the relationship between inflammation-sensitive plasma proteins (ISPs) including fibrinogen, a1-antitrypsin, haptoglobin, ceruloplasmin, and orosomucord and future revascularization. Result showed that 70 patients (1.2%) underwent revascularization because of severe PAD at a mean of 16.5 years after the baseline. They found that ISPs, measured 16 years earlier in apparently healthy men without walking-induced calf pain, were associated with increased risk for development of PAD revascularization.
1194 In addition, many recent studies have focused on the diversity of mechanisms by which inflammation can promote blood clotting. Recently, Unlu et al. [22] investigated the relationship between plasma concentrations of inflammatory and hemostatic markers and the severity of atherosclerosis. In this prospective cohort study, 45 consecutive patients with PAD of ABI < 0.90, and 44 patients without PAD of ABI 0.90–1.50 were included. D-dimer, fibrinogen, CRP, serum amyloid A, and prothrombin time were measured at the recruitment. They found that median values of serum amyloid A, Ddimer, and CRP were significant higher in the PAD group than in those without PAD group (p < 0.001). The patients with PAD had moderately higher fibrinogen levels than without PAD (p < 0.01). In multivariable regression analysis adjusting for all blood factors as well as potential confounds, patients with PAD, levels of serum amyloid A, and CRP showed a highly significant, inverse association with the ABI. Elevated D-dimer and fibrinogen levels were also found to be related to lower ABI, where no association was observed between prothrombin time levels. They concluded that higher CRP, serum amyloid A, and D-dimer levels are showing positive association with the presence of PAD. CRP and serum amyloid A levels are direct relations between the ABI and the extent of vascular inflammation.
Inflammation and restenosis of PAD During recent years, percutaneous transluminal angioplasty was established as a minimal invasive treatment option for patients with PAD. However, despite a primary success rate of above 90%, the long-term benefit is limited by the development of restenosis in about 30–50% within 6 months. There is pivotal evidence that inflammation is involved in the vascular response following balloon injury. Perivascular inflammation plays a key role in the development of restenosis after percutaneous transluminal angioplasty. The adherence of leukocytes to the activated endothelium, an essential feature in the restenosis process, is mediated by the cellular adhesion molecule E-selectin. Selectins facilitate the adhesion of inflammatory cellular components to the activated vascular endothelium, and thus promote localized vascular inflammation. E-selectin, in particular, is considered most important for the pathophysiology of restenosis. Recently, Mlekusch et al. [23] investigated 175 consecutive patients with PAD and IC or CLI who underwent primary successful femoropoliteal balloon angioplasty, and demonstrated that patients with an E-selectin plasma level above
Li et al. 44.9 mg/dL (third tertile) had a 1.9-fold increased adjusted risk for restenosis (95% CI 1.09–3.30). This data indicated that E-selectin plasma levels are modulated by the E-selectin Ser 128Arg genotype, and predict the risk for restenosis after femoropopliteal angioplasty in patients with PAD. However, a direct association of the Ser128Arg polymorphism with late postangioplasty failure could not be demonstrated. Moreover, data from Schillinger et al. [24] also showed that vascular inflammation is associated with restenosis after percutaneous transluminal angioplasty of the femoropopliteal artery. In their prospective cohort study, 172 consecutive patients with PAD of Fantain stage IIa, IIb, or III who underwent successful angioplasty of the superficial femoral and popliteal arteries were included. Patency at 6 months was evaluated by using oscillography, ABI, and color-coded duplex ultrasonography. The association of restenosis and CRP, serum amyloid A (SAA), and fibrinigen levels at baseline, 24 h, and 48 h after intervention was assessed by means of multivariate analysis with adjustment of known risk factors for restenosis. The results showed that restenosis was found in 56 patients (33%) within 6 months. CRP values at baseline and 48 h after intervention were independently associated with 6-month restenosis. SAA and fibrinogen values at any time interval were not significantly associated with patency in the multivariate models, suggesting that extent of vascular inflammation as measured by means of acute-phase reactant before and after angioplasty of the femoropopliteal artery is associated with 6-month restenosis, and baseline and 48 h CRP levels were independent predictors of postangioplasty outcome. In brief, PAD is one aspect of atherosclerosis, a disease associated with inflammation. Inflammation is an integral part of atherosclerosis and it has received much attention as an important pathogenetic component in its development.
Clinical implications Lower extremity PAD most frequently presents with lower limb pain on walking-IC. As the disease progression the patients might suffer from rest pain and/or ischemic ulceration-CLI. Mechanisms of functional impairment and decline in patients with lower extremity PAD are not fully understood. However, recent studies suggested that inflammation might initiate and exacerbate PAD through a complex constellation of vascular effects. These include the adherence of
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leukocytes to the vessel wall; increased membrane permeability; and the production of cytokines, leading to the recruitment of macrophages and the proliferation of macrophages and smooth muscle cells within the vessel wall. Finally, perivascular inflammation plays also a key role in the development of restenosis after percutaneous transluminal angioplasty of PAD. The management of patients with PAD consists of life-style modifications and pharmacotherapy addressing the risk factors to minimize the risk for disease progression and mortality in myocardial infarction and stroke. Symptomatic invasive treatment consists of surgical or endovascular revascularization. In addition, the pharmacological arteriogenesis-stimulating therapy is an alternative for the treatment of PAD. More importantly, because measurements of serum acute-phase parameters allow a sensitive quantification of the vascular inflammatory process, the attention is being paid to, therefore, on the pathophysiological mechanism of PAD, which holds the promise to change our therapeutic strategies.
Acknowledgements This article is partly supported by a Fu Wai Hospital Grant (2004190), National Natural Scientific Foundation (30670861), and Specialized Research Fund for the Doctoral Program of Higher Education (20060023044) of China awarded by Dr. Jian-Jun Li, MD, PhD.
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