Balloon Angioplasty and Stent Implantation Induce a Vascular Inflammatory Reaction

Transcription

1 J ENDOVASC THER 59 CLINICAL INVESTIGATION Balloon and Stent Implantation Induce a Vascular Inflammatory Reaction Martin Schillinger, MD; Markus Exner, MD*; Wolfgang Mlekusch, MD; Markus Haumer, MD; Ramazanali Ahmadi, MD; Helmut Rumpold, MD*; Oswald Wagner, MD*; and Erich Minar, MD Departments of Angiology and *Laboratory Medicine, University of Vienna Medical School, Vienna, Austria Purpose: To investigate whether peripheral balloon angioplasty with and without stent implantation independently causes an inflammatory vascular response measured by serum acute-phase reactants. Methods: This was a prospective cohort study enrolled 388 consecutive patients (28 men; median age 70 years, interquartile range 59 76) with peripheral artery disease undergoing balloon angioplasty (n 87), stent implantation (n 40), and diagnostic angiography (control group, n 6). C-reactive protein (CRP) measured by standard and high-sensitivity assays, serum amyloid A (SAA), fibrinogen, and white blood cell (WBC) count were obtained at baseline and at 8, 24, and 48 hours postintervention. Polynomial logistic regression analysis was used to assess the independent association of acute-phase reactants and the interventional group. Results: CRP levels measured by both standard and the high-sensitivity assays significantly increased after balloon angioplasty (standard CRP, p 0.02; high-sensitivity CRP, p 0.02) and stent implantation (standard CRP, p 0.004; high-sensitivity CRP, p 0.008) compared to the control group adjusting for age, sex, duration of fluoroscopy, volume of contrast, and periprocedural complications. SAA values differed only between the stent group and controls (p 0.05). Fibrinogen and WBCs were not different among the 3 interventional groups. Conclusions: Balloon injury and stent implantation induce a vascular inflammatory response at the dilated vessel segment measurable by serum acute-phase parameters. The standard CRP assay is adequate to quantify acute-phase response in these patients. J Endovasc Ther Key words: lower limb arteries, acute-phase reaction, C-reactive protein, serum amyloid A, fibrinogen There is increasing evidence that inflammatory processes are involved in the pathogenesis of atherosclerosis, as well as restenosis after balloon angioplasty. Acute-phase reactants are related to atherosclerosis in the peripheral, coronary, and extracranial cerebral arteries. Elevated baseline values of these inflammatory parameters were shown to be associated with an increased risk for restenosis after peripheral and coronary angioplasty. 2 5 Circulating markers of inflammation reflect the activity of the disease, with accumulation of macrophages and proliferation of endothelial cells and vascular smooth muscle cells. 6 The plasma proteinsc-reactive protein (CRP), serum amyloid A (SAA), and fibrino- Address for correspondence and reprints: Martin Schillinger, MD, Department of Internal Medicine II, Vienna General Hospital Medical School, Währinger Gürtel 8 20/6J, 090 Vienna, Austria. Fax: , martin.schillinger@akh-wien.ac.at 2002 by the INTERNATIONAL SOCIETY OF ENDOVASCULAR SPECIALISTS Available at

2 60 ACUTE-PHASE REACTANTS AND BALLOON ANGIOPLASTY J ENDOVASC THER genare sensitive, specific, and fast reacting markers of acute-phase reaction 7 9 and provide an indirect measure of a cytokine-dependent inflammatory process of the arterial wall. 0, However, the acute-phase response is a nonspecific phenomenon that may be induced by almost all kinds of tissue damage, inflammation, or systemic stress. 8 The course of acute-phase reactants after peripheral percutaneous transluminal angioplasty (PTA) compared to angiography has not been investigated. Data from small series of patients undergoing coronary interventions show that in patients with unstable angina, coronary angiography and angioplasty induced an enhanced inflammatory response. 2 In contrast, patients with stable angina undergoing elective coronary angiography displayed no significant changes in the postinterventional CRP levels. 3 Recently, an inflammatory response measured by increasing serum CRP levels after coronary stent implantation was described. 4 However, concomitant stressing factors during the angiographic procedure, such as arterial puncture, administration of contrast agent, duration of fluoroscopy, and periprocedural complications, contribute to systemic inflammatory response and might thereby mask the underlying vascular inflammatory process. As yet, it cannot be derived from published data whether balloon injury or stent implantation independently cause acute-phase reaction as measured by the course of serum parameters of inflammation. Alternatively, the postinterventional elevation of acute-phase reactants may be caused by other periprocedural factors. The aim of this study was to investigate whether peripheral balloon angioplasty with and without stent implantation independently causes an inflammatory response measured by serum acute-phase reactants. Study Design METHODS This prospective cohort study, which was approved by the local ethics committee, included all consecutive patients with peripheral artery disease (PAD) who underwent PTA with and without stent implantation in the lower limb arteries between February and October, All consecutive patients who underwent diagnostic angiography of the lower limbs within the same time period served as a control group. Patients with local thrombolysis were excluded. Candidates for the study gave written informed consent. Patients were assessed and data recorded according to the TransAtlantic Inter-Society Consensus guidelines for management of peripheral arterial disease. 5 Data from each patient s medical history were retrieved with particular attention to cardiovascular risk factors and comorbidities: age, gender, smoking habits, hyperlipidemia, hypertension, and diabetes mellitus. The Fontaine classification was used to categorize the clinical stage of PAD. Patient Population In the 8 months of this study, 388 patients (28 men; median age 70 years, interquartile range [IQR] 59 76) were enrolled. Approximately half (87, 48%) the patients underwent peripheral PTA of the lower limb arteries. PTA and stent implantation were performed in 40 (36%) cases. Sixty-one (6%) patients undergoing diagnostic angiography served as the reference group. No patients were excluded from the analysis. Twenty (5%) patients were classified Fontaine IIa, but the majority (287, 74%) were Fontaine stage IIb. Only 24 (6%) patients were Fontaine III, and 57 (5%) were Fontaine IV. Most of the patients (323, 83%) had hypercholesterolemia; 285 (73%) patients had a history of arterial hypertension, 59 (4%) were diabetic, and 59 (4%) were smokers. Concomitant coronary artery disease was found in 62 (42%) patients. and cerebrovascular disease with extracranial carotid plaques or stenosis (25%) was present in 97 (5%). Median baseline body temperature was 36.4C (IQR ). Laboratory Parameters A complete series of routine laboratory investigations including HbAc, LDL and HDL cholesterol, complete blood cell counts, and

3 J ENDOVASC THER ACUTE-PHASE REACTANTS AND BALLOON ANGIOPLASTY 6 serum creatinine were performed before PTA. Venous blood samples for determination of CRP, SAA, fibrinogen, and white blood cell (WBC) count were taken before intervention and at 8, 24, and 48 hours after treatment. Serum CRP values were measured with both a standard assay (Tina-quant, Roche AG, Basel, Switzerland) and a high-sensitivity assay (N Latex CRP Mono, Dade Behring Austria GmbH, Vienna, Austria). SAA was measured using N Latex SAA (Dade Behring Austria GmbH); Fibrinogen Clauss (Stago/Roche) was used to measure fibrinogen. The detection levels (and coefficients of variation) of standard CRP, high-sensitivity CRP, SAA, and fibrinogen were 0.5 mg/dl (4.8%), 0.03 mg/ dl (4.6%), 3.8 mg/l (6.4%), and 20 mg/dl (5.2%), respectively. Interventions Peripheral angiography and PTA with or without stent implantation followed a standardized protocol. Duration of fluoroscopy and contrast dosages were recorded, as well as the amount of heparin administered. The nonionic, low-osmolality contrast agent Optiray 320 (Mallinckrodt Medical, St. Louis, MO, USA) was used for all interventions. Intra- and postprocedural complications at the site of arterial puncture and at the dilated vessel segment were documented up to 48 hours after the intervention. Hematoma or pseudoaneurysm at the puncture site, as well as any significant dissection or peripheral emboli, were classified as minor complications. Major bleeding (hemoglobin decrease 2 mg/dl) and complications necessitating emergency surgery within 48 hours were classified as major complications. Statistical Analysis Continuous data are presented as the median and the interquartile (25 th 75 th ) range. Percentages were calculated for dichotomous variables. The Kruskal-Wallis test was used for univariate comparison of continuous data. Categorical data were compared by means of the chi-square test. The course of laboratory parameters within 48 hours post-treatment was measured by the area under the curve (AUC). Values at baseline, 24 hours, and 48 hours were included for the calculation. The AUC was adjusted for the patient s baseline value and therefore represented only the perpatient change within 48 hours. A polynomial logistic regression model was applied to independently assess the association of the course of acute-phase reactants and the type of angiographic intervention and to control for age, sex, duration of fluoroscopy, contrast dosage, and periprocedural complications. A p 0.05 was considered statistically significant. All calculations were performed by SPSS (Versions 0.0) for MS Windows (SPSS, Chicago, IL, USA). RESULTS The median length of the dilated vessel segment was 4 cm (IQR 2 7) in patients with and without stent implantation, respectively. At baseline (Table ), somewhat less than half the patients (72, 44%) had an elevated CRP value as measured by the high-sensitivity assay (CRP 0.5 mg/dl). In 28 (56%) patients, elevated SAA values (6.4 mg/l) were found before the intervention. Interestingly, patients with Fontaine IV had significantly higher standard CRP levels (p 0.000), high-sensitivity CRP levels (p 0.000), SAA levels (p 0.000), fibrinogen (p 0.000), and WBCs (p 0.006) compared to patients without ulceration. During the interventions, the median dose of contrast agent was 80 ml (IQR 0 230), and median duration of fluoroscopy was 3 minutes (IQR 7 9). The median dosage of heparin was 5000 units (IQR ) administered intra-arterially during the intervention. Minor intraprocedural complications occurred in 48 (2%) patients, but only 2 (0.5%) major complications were encountered, both iliac artery perforations during PTA necessitating emergency surgery. The acute-phase reactants CRP (as measured by both the standard and high-sensitivity assays), SAA, and fibrinogen showed an increase at 24 and 48 hours after the intervention in all patients. The course of the WBC count showed a peak at 8 to 24 hours after the interventions and decreased at 48 hours. The median increases relative to baseline at

4 62 ACUTE-PHASE REACTANTS AND BALLOON ANGIOPLASTY J ENDOVASC THER TABLE Baseline Data of 388 Patients with Peripheral Artery Disease n 6 n 87 Stent n 40 p Age Men Standard CRP, mg/dl High-sensitivity CRP, mg/dl 63 (56 73) 38 (66%) 0.5 (0.5.45) 0.38 (0.9.34) 7 (59 77) 89 (48%) 0.5 (0.5.05) 0.53 ( ) 69 (60 75) 9 (65%) 0.5 ( ) 0.35 ( ) 0.0* * 0.3* SAA, mg/l Fibrinogen, mg/dl WBC, 0 9 /L Contrast, ml 7.05 ( ) 406 (35 466) 7.3 ( ) 70 (00 20) 4 (3 7) 7 (%) 8.5 ( ) 47 ( ) 7.8 ( ) 60 (0 240) 3 (8 2) 28 (5%) 6.0 (3.8.5) 374 ( ) 7.5 ( ) 90 (50 220) 4 (0 20) 5 (%) 0.02* 0.000* 0.06* 0.04* Fluoroscopy time, min 0.000* Overall complications 0.5 CRP C-reactive protein, SAA serum amyloid A, WBC white blood count. Continuous data given as median (interquartile range) unless otherwise stated. * Kruskal-Wallis test. Chi-square test. 48 hours were 55% (IQR 3 to 85) for the standard CRP, 238% (IQR 5 644) for the high-sensitivity CRP, 55% (IQR 8 626) for SAA, 4% (IQR 0 25) for fibrinogen, and 0% (IQR 3 to 5) for WBCs. Patients with elevated inflammatory markers at baseline showed a significant but minor increase within 48 hours compared to patients with normal values at baseline (Table 2). Patients undergoing angioplasty with and without stent implantation had a higher elevation of CRP and SAA at 24 and 48 hours compared to the angiography group (Figs. and 2). The increase in SAA values showed a higher variability than those for CRP. Polynomial logistic regression models were applied to assess the independent association of the course of acute-phase reactants and the intervention group. CRP, as measured either by standard (Table 3) or by high-sensitivity TABLE 2 Relative Increase in Acute-phase Reactants Within 48 Hours After Intervention Versus Baseline in Patients With Normal or Elevated Baseline Values Relative Increase Within 48 Hours p Normal baseline high-sensitivity CRP* (n 26) 500% (85 to 936) Elevated baseline high-sensitivity CRP (n 72) 69% (7 to 257) Normal baseline SAA (n 70) 37% (9 to 929) Elevated baseline SAA (n 28) 93% (0 to 439) CRP C-reactive protein, SAA serum amyloid A. Continuous data given as median (interquartile range) unless otherwise stated. * Normal range 0.5 mg/dl. Normal range 6.4 mg/l.

5 J ENDOVASC THER ACUTE-PHASE REACTANTS AND BALLOON ANGIOPLASTY 63 Figure Postinterventional course of high-sensitivity C-reactive protein according to the interventional group. Box plots indicate median values, interquartile range (25 th 75 th percentile), and absolute range of high-sensitivity CRP values. Figure 2Postinterventional course of serum amyloid A (SAA) according to the interventional group. Box plots indicate median values, interquartile range (25 th 75 th percentile), and absolute range of SAA values.

6 64 ACUTE-PHASE REACTANTS AND BALLOON ANGIOPLASTY J ENDOVASC THER TABLE 3 Association Between Treatment Group and Postinterventional Course of Standard CRP Measured Using the Area Under the Curve OR 95% CI p Univariate polynomial logistic regression model.3.5 Model controlled for age and sex.3.5. to.7. to.9. to.7.2 to Model controlled for age, sex, duration of fluoroscopy, dose of contrast agent, and complications*.4.6. to.9.2 to OR odds ratio, CI confidence interval, reference group. * Likelihood ratio test, p TABLE 4 Association Between Treatment Group and Postinterventional Course of High-Sensitivity CRP Measured Using the Area Under the Curve OR 95% CI p Univariate polynomial logistic regression model.3.4 Model controlled for age and sex to.7. to.9.0 to.7. to Model controlled for age, sex, duration of fluoroscopy, dose of contrast agent, and complications*.5.5. to 2.0. to OR odds ratio, CI confidence interval, reference group. * Likelihood ratio test, p (Table 4) assay, was independently associated with the intervention group. Patients undergoing angioplasty with and without stent implantation showed higher CRP levels compared to patients with angiography alone. When adjusting for age, sex, duration of fluoroscopy, contrast dosage, and periprocedural complications, the odds ratios did not change significantly. Elevation of serum CRP was independently associated with balloon injury and stent implantation. For SAA values, this association was shown only for patients with stent implantation (Table 5). The course of fibrinogen and WBC was not associated with the interventional group. DISCUSSION Patients undergoing PTA with and without stent implantation had significantly increased levels of acute-phase reactants post-treatment compared to diagnostic angiography. The acute-phase reaction after PTA was independently associated with balloon injury and stent implantation at the dilated vessel segment, irrespective of concomitant inflammatory stimuli during the interventional procedure. Our findings support the hypothesis that balloon angioplasty induces a marked vascular inflammatory response, adequately measurable by systemic levels of acute-phase reactants. Histological studies showed that endothelial and medial damage after balloon injury and lipid core penetration of stent TABLE 5 Association Between Treatment Group and Postinterventional SAA Course Measured Using the Area Under the Curve OR 95% CI p Univariate polynomial logistic regression model.0.0 Model controlled for age and sex to.0.0 to.0.0 to to Model controlled for age, sex, duration of fluoroscopy, dose of contrast agent, and complications* to.0.0 to OR odds ratio, CI confidence interval, reference group. * Likelihood ratio test, p

7 J ENDOVASC THER ACUTE-PHASE REACTANTS AND BALLOON ANGIOPLASTY 65 struts result in local inflammatory response. 6 The process of subsequent neointimal formation has been referred to as manifestation of a general wound healing response expressed specifically in vascular tissue. 7 However, this acute inflammatory process is limited to the usually short segment of the dilated vessel. Remarkably, serum acutephase reactants rise up to several fold, indicating the severity of the process. However, patients with elevated inflammatory markers at baseline showed a less pronounced increase within 48 hours after intervention. The inflammatory stimulus of balloon injury in these patients seems to be diminished by preexistent inflammation. Peripheral angiography induces a mild increase of acute-phase reactants. Several periprocedural factors, such as arterial puncture and contrast medium, trigger this inflammatory reaction, which may be further augmented by postinterventional complications. Up to now, the effect of these periprocedural inflammatory stimuli on acute-phase reactants could not be separated from the inflammation at the dilated vessel site. Plaque rupture and endothelial injury after balloon angioplasty independently mediate a vascular inflammatory response that could contribute to restenosis. 8 Similarly, an acute inflammatory process after stent implantation is a hallmark in the restenotic process. 6,9,20 The local inflammatory reaction at the site of dilatation might play an important role in constrictive neointimal formation. 2,22 So far, it is unclear whether acute-phase reactants are increased as a consequence of the disease or causally contribute to its progression. One reason for a causal role could be the activation of the complement system, local vascular inflammatory reactions, and subsequent tissue damage. 23 High-sensitivity CRP assays were recommended for cardiovascular risk prediction, in particular, in otherwise healthy populations. 24 However, in patients with peripheral artery disease and, frequently, concomitant generalized atherosclerosis, the use of a standard CRP assay appears to be sufficient. 4 Acute-phase reactants are capable of quantifying the extent of localized vascular inflammation, but the predictive value of their postprocedural course on restenosis has to be further evaluated. In conclusion, balloon injury and stent implantation induce a vascular inflammatory response at the dilated vessel segment measurable by serum acute-phase parameters. A standard CRP assay is an adequate method to quantify acute-phase response in these patients. REFERENCES. Heinrich J, Schulte H, Schönfeld R, et al. Association of variables of coagulation, fibrinolysis and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain. Thromb Haemost. 995;73: Buffon A, Liuzzo G, Biasucci LM, et al. Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty. J Am Coll Cardiol. 999;34: Tschöpl M, Tsakiris DA, Marbet GA, et al. Role of hemostatic risk factors for restenosis in peripheral arterial occlusive disease after transluminal angioplasty. Arterioscler Thromb Vasc Biol. 997;7: Schillinger M, Haumer M, Schlerka G, et al. Restenosis after percutaneous transluminal angioplasty in the femoropopliteal segment: the role of inflammation. J Endovasc Ther. 200;8: Blum A, Kaplan G, Vardinon N, et al. Serum amyloid type A may be a predictor or restenosis. Clin Cardiol. 998;2: Haverkate F, Thompson SG, Pyke SDM, et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet. 997;349: Ernst E. Fibrinogen as a cardiovascular risk factor: interrelationship with infections and inflammation. Eur Heart J. 993;4(suppl): Pepys MB, Baltz ML. Acute-phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein (Review). Adv Immunol. 983;34: Young B. Gleeson M, Cripps AW. C-reactive protein: a critical review. Pathology. 99;23: Kuller LH, Tracy RP, Shaten J, et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol. 996;44:

8 66 ACUTE-PHASE REACTANTS AND BALLOON ANGIOPLASTY J ENDOVASC THER. Pepys MB. The acute-phase response and C- reactive protein. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine. 3 rd ed. Oxford: Oxford University Press, 995: Liuzzo G, Buffon A, Biasucci LM, et al. Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina. Circulation. 998;98: Azar RR, McKay RG, Kiernan FJ, et al. Coronary angioplasty induces a systemic inflammatory response. Am J Cardiol. 997;80: Gottsauner-Wolf M, Zasmeta G, Hornykewycz S, et al. Plasma levels of C-reactive protein after coronary stent implantation. Eur Heart J. 2000;2: Dormandy JA, Rutherford B. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg. 2000;3:S S Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation. 999;99: Forrester JS, Fishbein M, Helfant R, et al. A paradigm for restenosis based on cell biological clues for the development of new preventive therapies. J Am Coll Cardiol. 99;7: Serrano CV, Ramires JA, Venturinelli M, et al. Coronary angioplasty results in leucocyte and platelet activation with adhesion molecule expression. Evidence of inflammatory responses in coronary angioplasty. J Am Coll Cardiol. 997;29: Depre C, Havaux X, Wijns W. Pathology of restenosis in saphenous bypass grafts after longterm stent implantation. Am J Clin Pathol. 998;0: Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol. 999;0: Kornowski R, Hong MK, Tio FO, et al. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol. 998;3: Yutani C, Ishibashi-Ueda H, Suzuki T, et al. Histologic evidence of foreign body granulation tissue and de novo lesions in patients with coronary stent stenosis. Cardiology. 999;92: Torzewski J, Torzewski M, Bowyer DE, et al. C- reactive protein frequently co-localizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 998;8: Roberts WL, Sedrick R, Moulton L, et al. Evaluation of four automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Clin Chem. 2000;46: