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Published online before print March 20, 2003, 10.1148/radiol.2272020137
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(Radiology 2003;227:419-425.)
© RSNA, 2003

Vascular and Interventional Radiology

Endovascular Revascularization Below the Knee: 6-month Results and Predictive Value of C-reactive Protein Level1

Martin Schillinger, MD, Markus Exner, MD, Wolfgang Mlekusch, MD, Markus Haumer, MD, Helmut Rumpold, MD, Ramazanali Ahmadi, MD, Schila Sabeti, MD, Oswald Wagner, MD and Erich Minar, MD

1 From the Departments of Angiology (M.S., R.A., S.S., E.M.) and Laboratory Medicine (M.E., W.M., M.H., H.R., O.W.), University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Received February 21, 2002; revision requested April 22; final revision received August 29; accepted September 23. Address correspondence to M.S. (e-mail: martin.schillinger@akh-wien.ac.at).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine the association between pre- and postintervention serum C-reactive protein (CRP) levels and 6-month restenosis after endovascular treatment of atherosclerotic lesions in arteries below the knee.

MATERIALS AND METHODS: Eighty-nine patients with peripheral arterial disease underwent primary successful percutaneous transluminal angioplasty (PTA) of the distal popliteal, anterior tibial, posterior tibial, and fibular arteries. Six-month patency was evaluated with the ankle brachial index (ABI) and color-coded duplex ultrasonography (US). The association between restenosis and preintervention and 48-hour postintervention CRP levels was assessed with multiple logistic regression analysis.

RESULTS: ABI improved from a preintervention median of 0.54 to a postintervention median of 0.75 (P < .001). The primary technical success rate was 94% (100 of 106). In 50 patients, a suboptimal technical result was achieved with 30%–40% residual stenosis at the dilated segment. The median ABI at 6 months was 0.65, and it was inversely correlated with preintervention (r = -0.27, P = .009) and 48-hour postintervention (r = -0.40, P < .001) CRP levels. With duplex US at 6 months, restenosis (>=50%) occurred in 36 patients. Patients with a preintervention CRP level of 0.23–0.92 mg/dL (2.3–9.2 mg/L) had a 3.7-fold increased adjusted risk for restenosis (P = .05); patients with a preintervention CRP level greater than 0.92 mg/dL (9.2 mg/L) had a 4.7-fold increased adjusted risk (P = .03). Postintervention CRP values greater than 2.42 mg/dL (24.2 mg/L) were associated with a 10.7-fold adjusted risk for restenosis (P = .002). Suboptimal PTA result was the only other parameter associated with an increased risk for restenosis (odds ratio, 3.7; P = .03).

CONCLUSION: Pre- and postintervention CRP levels were associated with restenosis after PTA of the distal popliteal and tibioperoneal arteries, which indicates that inflammation plays a crucial role in the pathophysiology of this process.

© RSNA, 2003

Index terms: Arteries, restenosis, 92.454, 92.458, 92.721 • Arteries, transluminal angioplasty, 92.1282, 92.454, 92.721 • Arteritis, 92.29, 92.454, 92.458


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Endovascular treatment of atherosclerotic obstructions below the knee in patients with peripheral arterial disease (PAD) is technically feasible (1–7), and a considerable improvement in the patient’s clinical outcome may be achieved compared with that achieved with conservative medical treatment (4–8). However, patency rates of the treated vessels after primary successful interventions are disappointing (2,9). Nevertheless, minimally invasive revascularization frequently remains the preferred therapeutic option in patients with multiple morbidities, atherosclerotic comorbidities, and cardiovascular risk factors (10), since alternative surgical reconstructions of the arteries below the knee are technically demanding and are related to a considerable perioperative morbidity and mortality (11).

Balloon angioplasty induces an inflammatory response and a postintervention increase in serum C-reactive protein (CRP) level (12). CRP is an acute-phase reactant which is produced in the liver in response to systemic inflammatory stimuli, mainly through the interleukin pathway. It sensitively reflects the extent of vascular inflammation (13,14) and indirectly displays the cytokine-dependent inflammatory process in the arterial wall (13,15), namely, macrophage activation and proliferation of endothelial cells and vascular smooth muscle cells (16–18). Inflammation is involved in the development of restenosis after balloon angioplasty (16,17,19,20). In particular, vascular smooth muscle cell proliferation and hypertrophic neointima formation lead to lumen narrowing at the treated segment. Elevated levels of acute-phase reactants such as CRP were shown to be associated with an increased risk for restenosis after coronary (21,22) and femoral (23–25) angioplasty. This association might also be found after angioplasty of the distal popliteal artery, as well as of the anterior tibial, posterior tibial, and fibular arteries. Therefore, the aim of the present study was to determine the association between pre- and postintervention serum levels of CRP and 6-month restenosis after endovascular treatment of atherosclerotic lesions in the arteries below the knee.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Study Design and Inclusion and Exclusion Criteria
The study was designed as a prospective cohort study. During a 14-month study period, 106 consecutive inpatients with PAD underwent balloon angioplasty of atherosclerotic obstructions of arteries below the knee at the angiology department of a tertiary care university hospital. Of these, two patients with stent implantation due to immediate subtotal or total reocclusion were not eligible for the study. We further excluded six patients with primary percutaneous transluminal angioplasty (PTA) failure (primary technical success rate, 94% [100 of 106]) to maintain a homogeneous study end point, since the causes for technical failure and the pathophysiologic mechanism of restenosis were probably different. Seven patients were lost to follow-up, and two patients with a history of chronic inflammatory disease (one patient with systemic lupus erythematosus and one patient with primary chronic polyarthritis) were excluded from the study because of chronically increased CRP levels. We included 89 (84%) of 106 patients with primary technical success and complete follow-up in the final analysis. The median age of these patients was 76 years (interquartile range [IQR], 70–80 years). Forty (45%) patients were men (median age, 73 years; IQR, 62–78 years), and 45 (55%) were women (median age, 77 years; IQR, 72–81 years).

The study complied with the Declaration of Helsinki and was approved by the local ethics committee. Inclusion and exclusion criteria, the study protocol, and all categorizations were determined prior to the initiation of the study. All patients provided their written informed consent. Assessment of patient data was in accordance with the TransAtlantic Inter-Society Concensus for the treatment of PAD (26).

Definitions
The diagnosis and Fontaine classification (26) of PAD were assessed with clinical evaluation, pulse-wave oscillography, ankle brachial index (ABI) measurements, and duplex ultrasonography (US), and findings were confirmed with angiography of the lower limb. Diabetes mellitus was diagnosed in patients who had a fasting blood glucose level greater than 110 mg/dL (6.1 mmol/L) measured on three occasions, in patients with oral glucose tolerance test results suggestive of disease, or in patients with a glycosylated hemoglobin A1c level greater than 0.06 (>6.5%). Hyperlipidemia was diagnosed in patients who had a fasting total serum cholesterol level greater than 200 mg/dL (5.17 mmol/L), a low-density lipoprotein value greater than 130 mg/dL (3.36 mmol/L), or a serum triglyceride level greater than 180 mg/dL (2.03 mmol/L), and it was considered to be present in all patients receiving lipid-lowering medication.

The grade of stenosis on the angiograms was categorized in 10% increments to facilitate comparison with findings at duplex US. Primary technical success was classified in interventions with a remaining stenosis of 40% or less at the dilated segment on the final angiogram; technical failure was classified in interventions with a remaining stenosis greater than 40% at the dilated segment. Patients with primary technical success but a remaining diameter reduction of greater than 30% to 40% or less at the dilated segment after PTA on the final angiogram were classified as those with "primary technical success with suboptimal result." Runoff was classified according to the number and morphology of the tibioperoneal arteries: Patients with two or three tibioperoneal vessels patent to the foot without significant stenosis (>=50%) were classified as having good runoff; otherwise, patients were classified as having poor runoff. Restenosis was classified as 50% or greater diameter reduction at the dilated vessel segment within the first 6 months after PTA. We used ABI and color-coded duplex US with a 5-MHz linear-array color probe (XP 10; Acuson, Mountain View, Calif) for categorization of restenosis according to the protocol described later (24,27,28). The maximum peak systolic velocity in the dilated region was determined and compared with the peak systolic velocity in the preceding normal segment. A focal increase in the peak systolic velocity of at least 140% (corresponding to a peak velocity ratio of >=2.4) was considered indicative of a stenosis of greater than 50% at that site (29).

Patient Data
At admission, the patient’s medical history and data from physical examination were recorded by means of a standard questionnaire by two of the authors (M.S., W.M.) in consensus. We used results of routine laboratory tests, urinalysis, and chest radiography to exclude any coexistent acute or chronic inflammatory disease, such as infection, collagen disease, or arthritis. Findings of mandatory preinterventional color-coded duplex US, oscillography, and angiography and the ABI were recorded. We evaluated adequacy of inflow to the target segment by using duplex US. All noninvasive measurements were performed with supervision of one of three authors (M.S, M.H., E.M.).

Laboratory Investigations
Routine laboratory investigations, including hemoglobin A1c, low- and high-density lipoprotein cholesterol, and serum creatinine levels and a complete blood cell count, were performed before PTA. Antecubital venous blood samples for determination of CRP were collected at preintervention before PTA and at 8, 24, and 48 hours after intervention. We used a high-sensitivity assay (N Latex CRP Mono; Dade Behring, Vienna, Austria), with a sensitivity of 0.03 mg/dL (0.3 mg/L), a coefficient of variation of 4.6%, and a normal range of less than 0.5 mg/dL (5.0 mg/L) for measurement of serum CRP values. Laboratory analyses were performed with supervision of one of two authors (M.E., H.R.).

Interventions
PTA of the arteries below the knee was performed with an ipsilateral downstream approach according to a standard protocol by two experienced interventionists (R.A., E.M.). We used the nonionic, low-osmolality contrast agent ioversol (Optiray 320; Mallinckrodt, St Louis, Mo) in a dilution of 1:1 for all interventions. Before angioplasty, patients received 5,000 IU of heparin intraarterially. Artery location (ie, distal popliteal, proximal anterior tibial, posterior tibial, or fibular arteries) and length and grade of the target lesions were derived from the initial angiogram by the interventionist. Angioplasty was then performed, with the balloon diameter corresponding to the diameter of the proximal nondiseased vessel. Hand inflation with a pressure of 10–14 atm for 30 seconds to 2 minutes was used for dilation of the target lesion. Duration of fluoroscopy and dose of contrast agent, as well as the results of PTA in terms of initial technical success, postprocedural residual stenosis, and runoff, were recorded.

Color-coded duplex US, ABI measurement, and oscillography were performed 24 hours after PTA to exclude early restenosis. Periintervention and postintervention complications at the site of arterial puncture and at the dilated vessel segment were documented up to 48 hours after the intervention by two independent observers (M.S., W.M.) other than the interventionists. All patients received antithrombotic medication with 100 mg of acetylsalicylic acid daily during the whole study period, starting at least 2–4 days prior to the intervention. No other antiinflammatory medication except acetylsalicylic acid was administered during the first 48 hours after the intervention. Concomitant interventions performed in the ipsilateral superficial femoral artery were also recorded.

Follow-up
Patients were routinely followed up for 6 months in the outpatient clinic to analyze the occurrence of restenosis: ABI measurement, oscillography, evaluation of patient complaints, and physical reexamination were performed at 6 months in all patients, with supervision of one of three authors (M.S., M.H., E.M.). Patients with a new onset of claudication or an increase in complaints, as well as patients with a substantial reduction of ABI measurement (ie, deterioration by at least 0.15 from the maximum postprocedural level), were further examined with color-coded duplex US (24,27,28). In cases with unclear duplex US findings caused by suboptimal visibility or for confirmation of restenosis, conventional fluoroscopic angiography was performed. In diabetic patients with incompressible arteries because of mediasclerosis (ie, calcified arteries), which precludes accurate pressure measurements, pulse waveform analysis and measurement of toe blood pressure by using digit plethysmography were used to judge deterioration (30). Overall, 81 (91%) of 89 patients underwent duplex US at the time of follow-up, and 68 (76%) patients underwent follow-up angiography.

Statistical Analysis
Data are presented as the median and the IQR (range, 25th to 75th percentile). Percentages were determined for dichotomous variables. The {chi}2 test, or the {chi}2 test for trend if appropriate, was used to compare proportions. For univariate comparison of unpaired continuous data, the Mann-Whitney U test was used; paired continuous data were compared by means of the Wilcoxon paired test. The Spearman rank correlation coefficient was calculated for correlation of continuous variables. Multiple logistic regression models were applied to assess the effect of CRP on 6-month patency and to adjust for known risk factors of restenosis. Baseline variables that showed a trend (P < .2) between patients with and patients without restenosis were entered to control for confounding effects. The CRP value was classified into tertiles and was entered into the model as a categorical variable.

Separate models were calculated for the CRP level at baseline and at 48 hours after intervention. We did not intend to adjust for multiple testing, because of a close correlation between CRP levels at these time intervals, which almost may be used interchangeably as risk predictors. Results of the logistic regression model were presented as the odds ratio (OR) and the 95% CI. Stratified analysis was performed to account for differences between the distal popliteal and proximal tibioperoneal arteries. Interaction was assessed by using additive and multiplicative interaction terms, the linearity of the logit assumption was checked for continuous predictor variables, and an analysis of residuals was performed. Regression diagnostics and overall model fit were performed according to standard procedures (31). A difference with a P value less than .05 was considered statistically significant. All calculations were performed with statistical software (Microsoft Excel for Windows 2000, Microsoft, Redmond, Wash; SPSS, version 10.0 for Microsoft Windows, SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PTA Below the Knee
The indication for endovascular treatment of the arteries below the knee in 89 patients was PAD, with Fontaine stage IIb in 49 (55%) patients, Fontaine stage III in 11 (12%) patients, and Fontaine stage IV in 29 (33%) patients. Maximum walking distance was a median of 50 m (IQR, 20–70 m) in the group of 49 patients with claudication. The median grade of stenosis of the target lesion was 90% (IQR, 80%–100%) at preintervention duplex US, and the median grade of stenosis was 90% (IQR, 80%–100%) at initial angiography, which showed a correlation of r = 0.94 (P < .001). Sixty-nine (78%) of 89 patients underwent PTA of the distal popliteal artery, whereas 20 (22%) patients underwent PTA of the proximal anterior tibial artery (n = 9), the proximal posterior tibial artery (n = 6), and the proximal fibular artery (n = 5); 11 (12%) patients underwent dilation of two tibioperoneal arteries during the same session. Thirty-eight (43%) of 89 patients underwent concomitant PTA of the ipsilateral superficial femoral artery. ABI improved from a preintervention median of 0.54 (IQR, 0.33–0.67) to a 24-hour postintervention median of 0.75 (IQR, 0.59–0.93) (P < .001).

Complications
Postintervention complications occurred in 22 (25%) of 89 patients, and these complications included arterial dissection (n = 9, 10%), distal embolization (n = 3, 3%), and pseudoaneurysm at the site of arterial puncture (n = 10, 11%). All complications resolved with conservative medical treatment. Patients with distal embolization received intravenously administered heparin with the dose adjusted to the activated partial thromboplastin time (ie, two to three times greater than normal) for 48 hours. A pseudoaneurysm was treated with prolonged manual or US-guided compression. No significant difference in the rate of complications was observed in patients with isolated crural PTA compared with patients with concomitant PTA in the superficial femoral artery (10 [20%] of 51 vs 12 [32%] of 38; P = .2).

Follow-up
The median ABI at 6 months was 0.65 (IQR, 0.44–0.82). The 6-month ABI was inversely correlated with preintervention CRP levels (r = -0.27, P = .009) and with postintervention CRP levels at 8 hours (r = -0.34, P = .002), 24 hours (r = -0.31, P = .004), and 48 hours (r = -0.40, P < .001). In 36 (40%) of 89 patients, 6-month restenosis at the dilated vessel segment was found by using duplex US and was confirmed by using angiography. During the 6-month follow-up, five patients with restenosis underwent reintervention at the dilated segment, two patients underwent bypass surgery, two patients underwent minor amputation, and one patient underwent major amputation. Clinical characteristics of patients with and patients without restenosis at 6 months after PTA are presented in Table 1: Restenosis was found more frequently in patients with a suboptimal PTA result, in patients with poor runoff observed on the final angiogram, and in patients with a lower body mass index.


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  		TABLE 1. Comparison of Demographic, Clinical, and Angiographic Characteristics in Patients with and Patients without Restenosis 6 Months after PTA

 
CRP Level and Restenosis
Preintervention and 8-, 24-, and 48-hour postintervention CRP levels were significantly associated with the occurrence of restenosis at 6 months, and patients with 6-month restenosis had significantly higher pre- and postintervention serum CRP levels compared with those in patients without restenosis (Figure). According to the normal cutoff (0.5 mg/dL [5.0 mg/L]) of CRP levels in the healthy background population as determined with the local laboratory standards, patients with restenosis (24 [67%] of 36) more frequently had increased preintervention CRP levels compared with patients with normal preintervention CRP levels (24 [45%] of 53) (P = .05). Preintervention CRP values were significantly correlated with 48-hour postintervention CRP levels (r = 0.62, P < .001), which indicated that patients with higher preintervention CRP levels also had higher postintervention CRP levels and vice versa. No significant differences between preintervention and 48-hour postintervention CRP values were observed in patients with and patients without suboptimal PTA results (baseline CRP level, P = .3; 48-hour postintervention CRP level, P = .6). Furthermore, no significant correlation between pre- and postintervention CRP values and number of dilated vessels, length and grade of lesions, cardiovascular risk factors (ie, presence of diabetes mellitus, hypertension, and hyperlipidemia and a history of smoking), and comorbidities (ie, coronary arterial disease, carotid arterial stenosis) was observed.



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  		Graph shows increased pre- and postintervention CRP serum levels in patients with restenosis compared with patients without restenosis after PTA below the knee. Box plots indicate median and IQR (range, 25th to 75th percentile) and whiskers indicate total range.

 
Multiple logistic regression analysis was performed to assess the association between CRP level and 6-month restenosis and to adjust for confounding effects of other risk factors. Separate models were applied for preintervention and 48-hour postintervention CRP levels. The models were adjusted for the following: age (classified according to tertiles), sex (male vs female), body mass index (classified according to tertiles), presence of diabetes mellitus, PAD stage (Fontaine IIa, IIb, III, or IV), whether a suboptimal PTA result was present, and whether poor runoff was present. Preintervention and 48-hour postintervention CRP levels were significantly associated with 6-month postangioplasty outcome (Table 2). Patients with a preintervention CRP level greater than 0.23 mg/dL (2.3 mg/L) had a 3.7-fold increased adjusted risk for restenosis; patients with a preintervention CRP level greater than 0.92 mg/dL (9.2 mg/L) had a 4.7-fold increased adjusted risk. Patients with a 48-hour postintervention CRP level greater than 2.42 mg/dL (24.2 mg/L) had a 10.7-fold increased OR for poor postangioplasty outcome (Table 2). Within 48 hours after PTA, the CRP level increased in all patients, as seen in the Figure, but only those with levels greater than 2.42 mg/dL (24.2 mg/L) had an increased risk for restenosis.


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  		TABLE 2. Multiple Logistic Regression Models for Prediction of 6-month Patency after PTA Below the Knee

 
A suboptimal PTA result was the only other factor significantly associated with restenosis (OR, 3.7; 95% CI: 1.1, 12.7; P = .03) in the multiple regression model. Poor runoff and presence of diabetes mellitus showed a weak association with restenosis that did not, however, show a significant difference at the 5% level in the multiple regression model (Table 2).

Stratification between distal popliteal and proximal tibioperoneal arteries showed consistent results for both vessel areas in univariate logistic regression analyses: In the strata of 69 patients in whom PTA was performed in the distal popliteal artery, preintervention CRP values greater than 0.93 mg/dL (9.3 mg/L) (third tertile) (OR, 3.7; 95% CI: 1.1, 12.8; P = .04) and 48-hour postintervention CRP levels greater than 2.51 mg/dL (25.1 mg/L) (third tertile) (OR, 7.5; 95% CI: 1.9, 30.0; P = .004) were associated with a significantly increased risk for restenosis. In the strata of 20 patients in whom PTA was performed in the tibioperoneal artery, preintervention CRP values greater than 0.59 mg/dL (5.9 mg/L) (upper half) (OR, 6.0; 95% CI: 1.0, 44.4; P = .05) and 48-hour postintervention CRP levels greater than 1.14 mg/dL (11.4 mg/L) (upper half) (OR, 11.7; 95% CI: 1.0, 147.6; P = .05) were associated with poor postangioplasty outcome. Similarly, in the strata of patients in whom concomitant angioplasty of the superficial femoral artery was and was not performed, the CRP level was significantly associated with restenosis.

A follow-up angiogram was obtained in 68 (76%) of 89 patients. In 36 patients who were suspected of having restenosis after duplex US, angiography was performed to confirm recurrent lumen narrowing. Findings at angiography confirmed a restenosis of 50% or greater in all 36 patients. Thirty-two patients who were not suspected of having restenosis in the dilated segment after duplex US underwent angiography of the initially treated lower limb during endovascular treatment of de novo lesions in the ipsilateral or contralateral superficial femoral artery. None of these patients had an angiographically observed restenosis of 50% or greater at the dilated segment. To account for the fact that in only 68 (76%) of 89 patients was a follow-up angiogram obtained, the association between preintervention and 48-hour postintervention CRP levels and angiographically excluded or proven restenosis was evaluated by univariate logistic regression analysis: Patients with a preintervention CRP level greater than 0.91 mg/dL (9.1 mg/L) (third tertile) had a 4.4-fold increased risk for restenosis (95% CI: 1.3, 15.4; P = .02), and patients with a 48-hour postintervention CRP level greater than 2.61 mg/dL (26.1 mg/L) (third tertile) had a 12.0-fold increased risk for restenosis (95% CI: 2.7, 53.3; P = .001).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Endovascular treatment of the arteries below the knee can be performed with an excellent technical success rate and a low incidence of major adverse events. However, disappointing short-term patency rates prevent general applicability to unselected patients. Preintervention CRP levels greater than 0.23 mg/dL (2.3 mg/L) and 48-hour postintervention CRP levels greater than 2.42 mg/dL (24.2 mg/L) indicate an increased risk for restenosis within 6 months and suggest that inflammation plays a key role in the processes leading to intermediate-term recurrences after PTA in this vessel area.

Particularly in patients with crural artery obstructions and critical limb ischemia, PTA is an accepted therapeutic alternative to open surgery. Clinical outcome in these patients in terms of improved limb salvage rates after the procedure seemed to justify the minimally invasive approach (4–8,32,33). However, frequently recurring stenosis in up to 70% of patients within 24 months at the treated segment is the major drawback of the method (9). Hence, the identification of risk factors for restenosis may help in the selection of patients who are likely to benefit from below-knee PTA. This may apply to patients with critical limb ischemia, as well as to patients with severe lifestyle-limiting claudication, as included in this study. Primary technical success rate and patency in the present series of patients compare well with data in previously published articles (2,32,34,35). However, suboptimal PTA results were observed in a high proportion of cases, and complications occurred frequently. Severely calcified lesions, multisegmental vessel disease, and a high proportion of patients with diabetes mellitus probably contributed to this effect. However, our findings were similar to observations in other articles in that severe complications that required surgical revision seemed to be rare (4,34). In this study, clinical variables indicative of imminent adverse outcome correspond to the current knowledge of risk factors for restenosis. Diabetes mellitus was described earlier as a predictor of restenosis after crural PTA (1), and poor runoff in terms of single-vessel runoff was also shown to be associated with reduced patency rates (35,36). Nevertheless, endovascular procedures performed below the knee still may be considered for patients with diabetes mellitus or for patients with single-vessel runoff disease in cases of critical limb ischemia and in cases in which surgical reconstruction is contraindicated.

Vascular wall injury during balloon dilation of the coronary and peripheral arteries induces a perivascular inflammatory response (12,20,37). The inflammatory process is a trigger for vascular smooth muscle cell proliferation and constrictive neointima formation and thus is involved in the pathogenesis of postangioplasty restenosis. Measurement of serum CRP levels sensitively quantifies the extent of vascular inflammation (12). The preprocedure CRP level has been reported to be a risk factor for restenosis after coronary angioplasty (21,22) and after PTA of the superficial femoral artery (23–25).

In the present study, serum CRP levels at baseline and during the initial days after angioplasty were associated with 6-month restenosis after PTA performed in the distal popliteal and tibioperoneal arteries. Preintervention inflammatory activity and the extent of the vascular inflammatory response during the days after balloon angioplasty seem to be involved in the process of restenosis. Increased CRP levels are a marker of an increased cardiovascular risk in healthy individuals and in patients with atherosclerosis (13,14,18,38–40). Low-level chronic inflammatory activity in the vascular tissue is suggested to cause an increase in the CRP level in patients with atherosclerosis (39,40), which reflects the activity of the disease. Higher preintervention CRP values may indicate a higher activity of the disease and thus an increased susceptibility for hypertrophic vascular remodeling and excessive neointima formation after balloon angioplasty.

The association between postintervention CRP level and restenosis supports the hypothesis that the extent of inflammatory reaction after PTA plays a pivotal role in the pathologic mechanism of restenosis. Patients with more extensive vascular inflammation after balloon dilation might be more vulnerable to recurrent lumen narrowing. Furthermore, preintervention CRP levels correlated with 48-hour postintervention CRP levels, which suggests that the extent of postintervention inflammation is influenced by the baseline inflammatory activity. However, it remains indeterminate whether the CRP level is only an indicator of an increased risk of restenosis or causally contributes to its occurrence. One mechanism of a causal role could be activation of the complement system, local vascular inflammatory reaction, or subsequent tissue damage (41).

For clinical applicability of these findings in patients with PAD, only the preintervention CRP level would be of any importance as a clinical risk predictor. The association between postintervention CRP level and restenosis suggests that a therapeutic approach with antiinflammatory therapy may be worth examining experimentally. Nevertheless, patients with critical limb ischemia will need revascularization for limb salvage irrespective of increased CRP levels. Patients with increased preintervention CRP levels, however, may be regarded as being at high risk for restenosis and may benefit from close follow-up or, if available, from adjunctive measures to prevent restenosis. Such measures include intraluminal brachytherapy (27,42) or implantation of the upcoming drug-eluting stents (43,44).

In the present study, follow-up evaluation was dependent on the ABI measurement in conjunction with the patient’s symptoms, and duplex US was used as the standard technique to confirm restenosis. Duplex US has its limitations for evaluation of crural arteries; however, the sensitivity for detecting a hemodynamically relevant arterial lesion was demonstrated to be accurate even in the tibioperoneal segment (45,46). Since follow-up angiograms were not obtained routinely, these promising data have to be reassessed in a further study with angiographic follow-up documentation, although the proportion of follow-up angiograms was relatively high (76%), and consistent findings were observed when only patients who had undergone follow-up angiography were included.

In conclusion, endovascular treatment of atherosclerotic obstructions below the knee is technically feasible, but the rate of complications is high. Restenosis frequently occurs within 6 months after primary successful interventions in approximately 40% of patients. Preintervention and postintervention CRP levels were significantly associated with restenosis after PTA below the knee, which indicates that inflammation plays a crucial role in the pathophysiology of this process.


   FOOTNOTES
 
See also the article by Schillinger et al (pp 516–521 ) and the editorial by McCowan (p 314–315 ) in this issue.

Abbreviations: ABI = ankle brachial index, CRP = C-reactive protein, IQR = interquartile range, OR = odds ratio, PAD = peripheral arterial disease, PTA = percutaneous transluminal angioplasty

Author contributions: Guarantors of integrity of entire study, E.M., M.S.; study concepts, M.S., M.E., H.R., O.W., E.M.; study design, M.S., W.M., M.H., R.A., S.S.; literature research, M.S.; clinical studies, E.M., R.A., M.H.; data acquisition, M.S., W.M., M.E.; data analysis/interpretation, all authors; statistical analysis, M.S.; manuscript preparation, M.S.; manuscript definition of intellectual content, all authors; manuscript editing, M.S.; manuscript revision/review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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