Biology OriginalProlonged application of clopidogrel reduces inflammation after percutaneous coronary intervention in the porcine model☆
Introduction
Pretreatment with P2Y12 receptor blockers, such as clopidogrel, has been found to reduce death and myocardial infarction after percutaneous coronary intervention (PCI). This benefit may be linked not only to the reduction of platelet reactivity but also to the blunting of procedure-related inflammatory response [1], [2], [3]. By inhibition of an adenosine diphosphate receptor, thienopyridines attenuate platelet degranulation and the expression of multiple platelet surface adhesion molecules involved in platelet interactions with inflammatory cells, such as leukocytes [4], [5]. Clopidogrel provides marked protection from ischemic events and is reported to be most efficacious in patients with high baseline C-reactive protein (CRP) levels [4].
CRP, an acute-phase protein present in circulating plasma, seems to contribute to thrombogenicity in patients with atherosclerotic disease [6]. Increased CRP levels are associated with worse clinical outcome [7]. CRP was suggested to mediate vascular and myocardial damage through enhancement of clotting by induction of the expression of tissue factor (TF), the primary initiator of blood coagulation [8], [9], and the formation of procoagulant microvesicles [10], [11]. Moreover, recent experimental work in animals suggests balloon angioplasty or stenting as being responsible for inflammatory response followed by neointimal growth [12], [13]. A few studies with a limited number of patients found CRP levels after coronary stenting to be also predictive for in-stent restenosis [14], [15].
An increase of CRP in plasma has been documented to occur after thrombogenic procedures such as brachytherapy [16]. Intracoronary brachytherapy (ICBT) using β-emitters is a well-proven therapy for the treatment of coronary in-stent restenosis [17], [18]. Moreover, ionizing radiation is associated with an increased risk of late thrombotic events, which are also a major complication after the implantation of drug-eluting stents (DES) [19], [20]. The duration of treatment with clopidogrel after thrombogenic coronary interventions, such as ICBT or DES implantation, is essential to reduce the occurrence of late thrombotic events and is an issue of controversial discussion at the moment.
The aim of our study was to determine the effect of prolonged treatment with clopidogrel on CRP concentrations and blood thrombogenicity after percutaneous transluminal coronary angioplasty (PTCA) followed by ICBT in the porcine model.
Section snippets
Study design
All studies were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication no. 85-23, revised 1996). Forty-eight domestic crossbred pigs (weight, 22–27 kg) received antiplatelet therapy, including aspirin (325 mg, daily) and clopidogrel (300 mg, loading dose; 75 mg, daily dose), starting on the day before intervention. Aspirin was continued until sacrifice in all animals. Animals were sacrificed after 24 h (n=12), 1 month (n=12), and 3 months
Prolonged clopidogrel application was associated with reduced CRP levels
Protein quantification of CRP in citrated plasma by ELISA revealed higher CRP levels immediately postintervention than preintervention (60.4±6.2 vs. 50.4±4.8 μg/ml; P=.006; Table 1). Twenty-four hours postintervention, a more-than-threefold increase in CRP concentration compared to preintervention (169.7±5.3 vs. 50.4±4.8 μg/ml; P<.0001; Table 1) and a more-than-twofold elevation immediately postintervention (169.7±5.3 vs. 60.4±6.2 μg/ml; P<.0001; Table 1) were observed. One month
Discussion
Clopidogrel treatment for 3 months compared to 1 month reduced CRP levels but did not affect plasma clotting times after PCI plus ICBT in a porcine model 3 months postintervention.
In our investigation, we demonstrated PCI plus ICBT to lead to an increase in CRP concentration in the blood immediately postintervention. Maximal CRP levels were found 1 day postintervention and decreased thereafter. Previous studies have shown that increased concentrations of CRP and inflammatory cytokines, both
References (30)
- et al.
Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein
Am J Cardiol
(2001) - et al.
Tissue factor, the blood, and the arterial wall
Trends Cardiovasc Med
(2000) - et al.
Consecutive enzyme cascades: complement activation at the cell surface triggers increased tissue factor activity
Blood
(1990) - et al.
Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex
J Biol Chem
(1990) - et al.
In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia
J Am Coll Cardiol
(1998) - et al.
Use of localised intracoronary beta radiation in treatment of in-stent restenosis: the INHIBIT randomised controlled trial
Lancet
(2002) - et al.
Immunosuppressive Therapy for the Prevention of Restenosis After Coronary Artery Stent Implantation (IMPRESS Study)
J Am Coll Cardiol
(2002) - et al.
Predictive value of C-reactive protein after successful coronary-artery stenting in patients with stable angina
Am J Cardiol
(1998) - et al.
Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction
Am J Cardiol
(2002) - et al.
Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study
Lancet
(2001)
Clopidogrel treatment before percutaneous coronary intervention reduces adverse cardiac events
J Invasive Cardiol
Antiplatelet therapy after percutaneous coronary intervention
Cerebrovasc Dis
Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial
JAMA
Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model
Clin Pharmacol Ther
C-reactive protein promotes platelet adhesion to endothelial cells: a potential pathway in atherothrombosis
Br J Haematol
Cited by (11)
Inhibition of platelet function with clopidogrel is associated with a reduction of inflammation in patients with peripheral artery disease
2016, Cardiovascular Revascularization MedicineCitation Excerpt :Here, we can also show that clopidogrel reduced significantly the level of CRP compared with the placebo group. Ayral et al. showed also that a prolonged periprocedual clopidogrel treatment reduced CRP levels and TF- expression post-PCI [22,27]. Increased TF expression is known to contribute to thrombosis [28].
The effects of antiplatelet, antithrombotic, and thrombolytic agents on inflammation and circulating inflammatory biomarkers
2016, New Therapeutic Agents in Thrombosis and Thrombolysis: Third EditionClopidogrel enhances mesenchymal stem cell proliferation following periodontitis
2015, Journal of Dental ResearchAntiplatelet drugs reduce the immunoinflammatory response in a rat model of periodontal disease
2014, Journal of Periodontal ResearchClopidogrel enhances periodontal repair in rats through decreased inflammation
2014, Journal of Clinical Periodontology
- ☆
This work was supported by grants from the German Research Foundation [Sonderforschungsbereich Transregio 19 (SFB TR 19) to U.R. and to H.P.S. and Ra 799/3-1 to U.R. and K.P.].