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Vascular and Interventional Radiology |
1 From the Departments of Angiology (M.S., R.A., S.S., M.H., E.M.) and Laboratory Medicine (M.E., W.M., H.R., O.W.), University of Vienna Medical School, Vienna General Hospital, Währinger Gürtel 18-20/6J, A-1090 Vienna, Austria. Received November 9, 2001; revision requested December 17; revision received February 8, 2002; accepted April 2. Address correspondence to M.S. (e-mail: martin.schillinger@akh-wien.ac.at).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: In a prospective cohort study, 172 consecutive patients with peripheral artery disease of Fontaine stage IIa, IIb, or III who underwent successful PTA of the superficial femoral and popliteal arteries were included. Patency at 6 months was evaluated by using oscillography, ankle-brachial index, and color-coded duplex ultrasonography. The association of restenosis and CRP, SAA, and fibrinogen levels at baseline, 24 hours, and 48 hours after intervention was assessed by means of multivariate analysis with adjustment for known risk factors for restenosis.
RESULTS: Restenosis was found in 56 patients (33%) within 6 months. CRP values at baseline (adjusted odds ratio, 2.2; 95% CI: 1.1, 4.2) and 48 hours after intervention (adjusted odds ratio, 2.3; 95% CI: 1.6, 3.1) 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.
CONCLUSION: The extent of vascular inflammation as measured by means of acute-phase reactants before and after PTA of the femoropopliteal artery is associated with 6-month restenosis. Baseline and 48-hour CRP levels were independent predictors of postangioplasty outcome.
© RSNA, 2002
Index terms: Arteries, femoral, 922.1282, 922.454, 922.721 • Arteries, popliteal, 924.1282, 924.454, 924.721 • Arteries, restenosis, 928.454, 928.458, 928.721 • Arteries, transluminal angioplasty, 928.1282, 928.454, 928.721 • Arteritis, 928.29, 928.454
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Balloon angioplasty induces a vascular inflammatory response at the dilated vessel segment and a postinterventional increase of serum CRP, SAA, and fibrinogen levels (19). The vascular inflammatory process is suggested to stimulate vascular smooth-muscle cell proliferation and late neointimal growth (8,9). Vascular smooth-muscle cell proliferation and hypertrophic neointimal formation at the treated segment frequently lead to restenosis. The extent of the vascular inflammatory response after intimal and medial injury may thus be related to intermediate-term outcome after percutaneous transluminal angioplasty (PTA).
The aim of the present study was to determine the association of pre- and postprocedural serum levels of CRP, SAA, and fibrinogen at 6-month evaluation of restenosis after PTA of the femoropopliteal artery.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Peripheral PTA of the femoropopliteal arteries was scheduled for 308 patients. Fifty-four patients (18%) had Fontaine stage IV PAD with ischemic macroscopic tissue damage, and 68 patients (22%) underwent femoropopliteal artery stent implantation. These patients were not eligible for the study. One hundred eighty-six patients with Fontaine stage IIa, IIb, or III PAD who underwent PTA of the femoropopliteal artery were eligible for the study. Nine patients had primary PTA failure, two had early reocclusions and underwent local thrombolysis, and three were lost to follow-up, leaving 172 patients for the final analysis (92% of eligible patients). The median age of the 172 patients was 72 years (interquartile range [IQR], 63–78 years), and 90 patients (52%) were male.
Definitions
The diagnosis of PAD was assigned by means of clinical evaluation, oscillography, ankle-brachial index (ABI), and duplex ultrasonography (US), and was confirmed by means of lower-limb angiography. For categorization of PAD, the Fontaine classification was used (20). Diabetes mellitus was defined as having fasting blood glucose levels above 6.1 mmol/L, as measured three times, and as having pathologic oral glucose tolerance test results or hemoglobin 1Ac levels greater than 6.5%. Hyperlipidemia was defined as having fasting total serum cholesterol levels greater than 5.16 mmol/L, low-density lipoprotein cholesterol levels greater than 3.4 mmol/L, or serum triglycerides levels greater than 2.05 mmol/L. Arterial hypertension was diagnosed according to the World Health Organization criteria. Patients who smoked more than three cigarettes per day were regarded as current smokers. Coronary arterial disease was classified according to the Canadian Cardiovascular Society classification, and routine evaluation included dobutamine echocardiography, myocardium scintigraphy, and coronary angiography in selected cases. Duplex US was used to assess the grade of atherosclerotic lesions in the carotid arteries.
Primary technical success was defined as a remaining stenosis of up to 30% at the dilated segment after the angioplasty procedure. Residual stenosis after successful PTA, indicating a suboptimal PTA result, was defined as a remaining diameter reduction of 10%–30% at the dilated segment according to the final angiogram. Inflow was categorized according to the presence or absence of atherosclerotic lesions proximal to the dilated segment. Poor run-off was defined as either occlusion or marked stenosis (
50%) of the femoropopliteal artery distal to the treated segment and/or occlusion or marked stenosis of at least two crural arteries. Restenosis was defined as a 50% or greater reduction in diameter at the dilated vessel segment within the first 6 months after PTA. ABI and color-coded duplex US (5-MHz, linear-array color probe [model XP 10; Acuson, Mountain View, Calif]) were used for categorization of restenosis according to the protocol described below (17,21,22). 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 peak systolic velocity of at least 140% (corresponding to a peak velocity ratio of 2.4) was considered indicative of stenosis of greater than 50% at that site (23).
Patient Data
At admission, patient medical history and data from physical examination were recorded by means of a standardized questionnaire. Routine laboratory test and urinalysis results and chest radiography were used to exclude coexistent inflammatory diseases. Clinical history and physical examination were evaluated with special attention to cardiovascular risk factors and comorbidities, such as age, sex, smoking habits, hyperlipidemia, arterial hypertension, diabetes mellitus, coronary arterial disease, history of cerebrovascular events, and current medication. Findings of mandatory preinterventional color-coded duplex US, ABI, oscillography, and angiography were documented.
Laboratory Parameters
A complete series of routine laboratory investigations, including complete blood count, hemoglobin 1Ac, low- and high-density lipoprotein cholesterol, and serum creatinine tests, were performed at baseline before PTA. Antecubital venous blood samples for determination of CRP, SAA, and fibrinogen levels were obtained at baseline before intervention and at 8, 24, and 48 hours after intervention. For measurement of serum CRP values, a high-sensitivity assay (N Latex CRP Mono; DADE Behring, Deerfield, Ill) was used. SAA values were measured with N Latex SAA (DADE Behring). For measurement of fibrinogen values, Fibrinogen Clauss (Stago/Roche, Basel, Switzerland) was used. The detection levels of high-sensitivity CRP, SAA, and fibrinogen were 0.03 mg/dL, 3.8 mg/L, and 20 mg/dL, respectively; the coefficients of variation were 4.6%, 6.4%, and 5.2%, respectively. Complete baseline, 8-hour, and 24-hour laboratory data (CRP, SAA, and fibrinogen values) were obtained in all patients. Forty-eight-hour laboratory data were obtained in 168 patients (98%).
Interventions
A standardized protocol was used for peripheral angiography and PTA. All interventions were performed by two experienced interventionalists (R.A., E.M.). Angioplasty was performed with the balloon diameter corresponding to the proximal nondiseased vessel diameter. Duration of fluoroscopy and dose of contrast agent were recorded. The nonionic low-osmolality contrast agent Optiray 320 (Mallinckrodt, Hazelwood, Mo) was used for all interventions. Patients received 5,000 IU of heparin intraarterially. Location, grade, extent, and morphology of stenosis or occlusion were documented, as well as the results of PTA in terms of initial technical success, postprocedural residual stenosis, and number of crural run-off vessels. Color-coded duplex US, ABI, and oscillography were performed 24 hours after PTA to document initial technical success and residual stenosis at the dilated segment and to exclude early thrombotic reocclusion. Peri- and postinterventional complications at the site of arterial puncture and at the dilated vessel segment were documented up to 48 hours after intervention. Hematoma and peripheral emboli were classified as minor complications. All pseudoaneurysms at the site of puncture could be managed conservatively by means of prolonged manual or US-guided compression, without the use of thrombin injection or surgical revision. Major bleeding (hemoglobin level decrease > 2 mg/dL) and all complications necessitating emergency surgery or local thrombolysis within 48 hours were classified as major complications. All patients received antithrombotic medication of 100 mg of acetylsalicylic acid (Thrombo-Ass; Lannacher, Lannach, Austria) daily.
Follow-up
Patients were routinely followed up for 6 months in the outpatient clinic to analyze the occurrence, frequency, and severity of restenosis: ABI, oscillography, evaluation of patient symptoms, and physical reexamination were performed at 6 months in all patients. Patients with new onset of claudication or increase of complaints, as well as patients with marked reduction of ABI values (deterioration by at least 0.15 from the maximum postprocedural level) were further evaluated with mandatory color-coded duplex US (17,21,22). Noninvasive baseline and follow-up investigations (duplex US, oscillography, and ABI determination) were performed under the supervision of one of the authors (M.S., W.M., M.H., E.M.). Overall, 153 patients (89%) were reevaluated at 6 months by means of color-coded duplex US, and 98 patients (57%) underwent follow-up angiography because of questionable restenosis.
Statistical Analysis
Continuous data are presented as the median and IQR (range from the 25th to the 75th percentile). Percentages were determined for dichotomous variables. The 
2 test or the 2 test for trend, if appropriate, was used to compare proportions. For univariate comparison of continuous data, the Mann-Whitney U test was used. The Spearman rank correlation coefficient was calculated for correlation of continuous variables. A multivariate logistic regression model was applied to assess the independent effect of acute-phase reactants on 6-month patency. Baseline variables, which showed a trend (P < .2) between patients with and patients without restenosis, were entered as predictor variables to control for confounding effects. Results of the logistic regression model were presented as the odds ratio (OR) and 95% CI. The goodness-of-fit for the model was assessed by using the Hosmer-Lemeshow test (24). A P value of less than .05 was considered to indicate a statistically significant difference. All calculations were performed with Excel for Windows 2000 (Microsoft, Redmond, Wash) and SPSS Version 10.0 for Windows (SPSS, Chicago, Ill).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In 56 patients (33%), restenosis at the dilated vessel segment was found at duplex US. Clinical characteristics of patients with and patients without restenosis at 6 months are presented in Table 1: Restenosis was found more frequently in female patients, in patients with diabetes mellitus, and in patients with a higher Fontaine stage of PAD at initial presentation. Furthermore, residual stenosis after PTA, signs of dissection on the final angiogram, poor run-off, and length of the lesion were associated with 6-month restenosis.
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CRP0to48hours, as well as for 48-hour SAA and SAA0to48hours. The models were adjusted for sex, diabetes mellitus, PAD Fontaine stage, residual stenosis greater than 30% at the dilated segment after angioplasty, length of lesion (per 10-mm increments), poor run-off, signs of dissection on the final angiogram, and procedural complications. Baseline CRP, 48-hour CRP, and CRP0to48hours were independently associated with 6-month postangioplasty outcome (Table 3). SAA level at 48 hours (per mg/L) did not show an independent association with outcome (OR, 1.1; 95% CI: 1.0, 1.1; P = .08), but higher SAA level increase from baseline to 48 hours (in 100% increments) was related to a slightly increased risk for restenosis (OR, 1.1; 95% CI: 1.1, 1.2; P = .004).
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CRP0to48hours, and SAA0to48hours remained significantly associated with restenosis (data not shown). |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The frequency of restenosis in this patient series compared well with former published findings (22,25–28), and risk factors for restenosis, as indicated by means of univariate analysis in the present study, correspond to the current knowledge of factors predicting unfavorable outcome after PTA of the femoropopliteal artery (20,28–30).
Preprocedural CRP has been reported to be an independent risk factor for restenosis after coronary angioplasty (14,15) and peripheral PTA (16,17). Similarly, in the present study, baseline CRP levels were related to intermediate-term outcome after PTA of the femoropopliteal artery. Previous reports (15,16,31) of a positive association of baseline SAA and fibrinogen levels with restenosis after angioplasty were based on data from small patient series. In the present analysis, these values showed no relation to restenosis.
Elevated CRP levels are an indicator of increased cardiovascular risk in healthy individuals, as well as in patients with atherosclerosis (1,4,5,10–12). Low-level chronic inflammatory activity in the vascular tissue is suggested to cause an elevated CRP level in patients with atherosclerosis (5), reflecting the activity of the disease. Higher preprocedural CRP values may indicate a higher activity of the disease and thus an increased susceptibility for hypertrophic vascular remodeling and excessive neointimal formation after intimal and medial injury.
Intimal and medial injury after balloon angioplasty of the coronary and peripheral arteries induces a perivascular inflammatory response (7,19,32). The extent of vascular inflammation can be quantified by means of the postinterventional course of acute-phase reactants; patients undergoing balloon angioplasty of the femoropopliteal artery were reported to have a significantly higher postinterventional increase of CRP and SAA values when compared with those of patients who underwent lower-limb angiography (32). A prognostic effect of postinterventional CRP level has been reported after coronary artery stent implantation; prolonged elevation of CRP level was related to in-stent restenosis (33). Our findings suggest that the extent of postangioplasty inflammation at the dilated vessel segment contributes significantly to the processes leading to restenosis after peripheral PTA. Angioplasty causes substantial injury, which is unrecognizable with angiography, to the vessel intima and media. Neointimal formation after angioplasty has been referred to as the manifestation of a general wound healing response that is expressed specifically in vascular tissue (6). The characteristic initial phase of the temporal response to injury is inflammation, followed by extracellular matrix remodeling and intimal hyperplasia within the first months after intervention. Infiltration of inflammatory cells and subsequent medial smooth-muscle cell modulation and proliferation are hallmarks in the development of restenosis. Repetitive measurement of acute-phase reactants after balloon angioplasty might display the extent of the underlying cytokine-dependent initiation of the restenotic process.
It remains indeterminate whether acute-phase reactants are only indicators of an increased risk for restenosis or whether they causally contribute to its occurrence. One mechanism of a causal role could be the activation of the complement system, local vascular inflammatory reactions, and subsequent tissue damage (34).
Restenosis after peripheral PTA remains a major clinical problem. Multiple pre- and periprocedural risk factors have been established so far, and a multifactorial pathogenesis seems likely. Targeted treatment of the mechanisms of restenosis is not available yet; therefore, unspecific adjunctive measures, such as stent implantation (35) or endovascular brachytherapy (21,36), have to be applied to improve patency rates. Nevertheless, modulation of factors that influence the vascular inflammatory reaction after PTA may be the key for the development of novel therapeutic approaches. Until then, patients with increased CRP values at baseline and after intervention have to be regarded as being at high risk for restenosis and may be good candidates for beneficial adjunctive measures, such as endovascular brachytherapy.
Follow-up duplex US was not performed in all patients. However, we could demonstrate consistency of our findings: First, periinterventional acute-phase parameters were significantly correlated with ABI, not just with the dichotomous variable restenosis, in all patients. Second, in the subgroup of patients with duplex US follow-up (89%), similar findings were observed in the entire study population.
In conclusion, the extent of vascular inflammation as measured by means of acute-phase reactants before and during 48 hours after PTA of the femoropopliteal artery is associated with the occurrence of 6-month restenosis. Baseline and 48-hour CRP levels were independent predictors for postangioplasty outcome.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, E.M.; study concepts, M.S., M.E., W.M., H.R., R.A., E.M.; study design, M.S., S.S., M.H., O.W., E.M.; literature research, S.S., E.M.; clinical studies, R.A., E.M.; data acquisition, M.S., W.M.; data analysis/interpretation, all authors; statistical analysis, M.S.; manuscript preparation, M.S.; manuscript definition of intellectual content, editing, revision/review, and final version approval, all authors.
See also the editorial by Smith in this issue.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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