The late-phase inflammatory response after drug-eluting stent implantation

Recent advances in drug-eluting stent (DES) technology have succeeded in preventing restenosis. In addition to inhibiting smooth muscle cell proliferation, DES greatly inhibits the local inflammatory response in the acute phase after implantation, leading to prevention of restenosis. However, a unique issue in DES implantation is an impairment of reendothelialization, which may result in abnormal wound healing. Consequently, a late-phase inflammatory relapse could appear in the long term after DES implantation. In this study, we measured serum levels of inflammatory markers, including interleukin (IL)-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metalloproteinase-9, and myeloperoxidase, as well as high-sensitivity C-reactive protein at follow-up coronary angiography (mean 9 months) in 54 patients who received DES stenting who did not experience restenosis, and compared them with 51 patients receiving bare-metal stents (BMS) without restenosis. The level of IL-6 was over the measurement threshold (≥2.22 pg/ml) in 12 patients (21 %) in the DES group, but in only 2 patients (4 %) in the BMS group (P = 0.003). IL-8 was significantly higher in the DES group than in the BMS group (4.51 ± 2.40 vs 3.84 ± 1.34 pg/ml, P = 0.015). The levels of other biomarkers were similar between the two groups. DES showed an increase in inflammatory cytokines in the late phase after implantation in comparison with patients who received BMS, suggesting late-stage inflammation. Therefore, the wound-healing response after DES implantation might be different from that after BMS.     

The inflammatory response to stent grafting of the thoracic aorta.

AIM: The aim of this study was to evaluate the inflammatory reactions in patients with thoracic aortic aneurysms before, during and after stent graft treatment and to relate markers of leukocyte activation to the use of radiographic contrast media. METHODS: Blood samples were drawn from 7 patients undergoing elective stent graft treatment for thoracic aneurysms. The samples were analyzed for leukocyte and platelet counts and the concentrations of iohexol (radiographic contrast medium), myeloperoxidase, lactoferrin, neutrophil activating peptide-2 (NAP-2), soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1 (sVCAM-1), the complement activation products C3bc and the terminal complement complex (TCC). The preoperative results were compared with 10 healthy blood donors of similar age. RESULTS: Preoperatively, the aneurysm patients had significantly elevated concentrations of myeloperoxidase, neopterin and complement activation products compared to controls. Myeloperoxidase and lactoferrin increased after the first contrast dose and peaked at 8 h postoperatively. Platelet counts decreased, while NAP-2, sVCAM-1 and TCC increased from 8 h postoperatively. CONCLUSION: We conclude that patients with thoracic aneurysms have a low-grade inflammation prior to intervention. Stent graft treatment induces further activation, and markers of endothelial, platelet, and complement activation were increased for several days after the procedure. Radiographic contrast media could be an important contributor to the activation of neutrophil leukocytes.     

Carbon coating of stents has no effect on inflammatory response to primary stent deployment

The aim of this study was to investigate the effects of stent carbon coating on inflammatory response. The authors serially measured plasma concentrations of C-reactive protein (CRP), fibrinogen, and several cytokines (tumor necrosis factor, interleukin [IL]-1-beta, IL-6, and IL-8) in patients with single-vessel coronary stenosis who underwent primary stent implantation. None of the subjects had inflammatory or infectious disease at the time of the procedure. Forty-six patients (38 males; mean age 55 +/-9 years) were studied. Blood samples were collected before and at 2, 4, 6, 24, and 48 hours after stent implantation. Patients were randomly assigned 1 of 2 different stent types, an uncoated MAC (AMG Raesfeld-Erle, Germany) (UC-MAC) or a carbon-coated MAC (CC-MAC) stent. Implantations were performed without predilatation, and stents were deployed at a maximum pressure of 6 atmospheres for 90 seconds. Of the 46 patients, 14 had stable, 27 had unstable, and 5 had atypical angina. According to ACC/AHA classification, 35 lesions (76.1%) were type A, 10 (21.7%) were type B, and 1 (2.2%) was type C. Single stenosis of 28 left anterior descending, 12 circumflex, and 6 right coronary arteries were treated. Serum IL-6 increased in both the UC-MAC and CC-MAC groups, with concentrations significantly elevated above baseline at 6 hours, and then decreasing after 24 hours (baseline, 6-hour, and 24-hour values = 3.1 +/-2.3, 5.7 +/-3.8, and 6.3 +/-4.6 pg/mL, respectively, in UC-MAC; 3.7 +/-2.6, 6.2 +/-6.0, and 4.6 +/-3.7 pg/mL, respectively, in CC-MAC [p=0.002]). Plasma fibrinogen, CRP, and leukocyte concentrations also increased in both groups over the 24 hours (p < 0.05). The elevations of IL-6, CRP, and fibrinogen were similar in the 2 groups. The percent increases in IL-6, fibrinogen, and CRP were not associated with stent length, size, or clinical presentation (all p > 0.05). The results showed that stent implantation increases plasma IL-6, fibrinogen, and CRP concentrations, but carbon coating of the stent does not seem to affect this inflammatory response.     

Coronary stent implantation may seal the inflammatory response in patients with acute coronary syndromes

The change in CD40L levels before and 24 h coronary stenting was compared in patients presenting with acute coronary syndromes and for elective angioplasty. Baseline CD40L levels were lower in stable subjects, whereas unstable patients had a significant decrease of CD40L after stenting. This might suggest that coronary stenting, despite of being a local therapy, can help to seal a systemic inflammatory response in acute coronary syndromes.     

Persistent systemic inflammatory response after stent insertion in patients with malignant bile duct obstruction

Background—Surgery in patients with malignantbile duct obstruction is associated with high postoperative morbidityand mortality. Tumour necrosis factor α (TNF-α) plays a key role inthe pathogenesis of these complications.
Aims—To determine the effect of biliary drainageon plasma concentrations of TNF-α, its soluble circulating receptors(sTNFr), and other proinflammatory cytokines.
Methods—Plasma concentrations of TNF-α,sTNFr-P75, interleukin 6 (IL-6), and IL-1α were measured in 25 patients with malignant bile duct obstruction before and afterendoscopic stent insertion.
Results—Mean serum bilirubin was 157 µmol/lbefore stent insertion and 35.2 µmol/l one week post stent insertion.There was complete relief of jaundice in 77% of patients by fourweeks. Plasma concentrations of TNF-α and IL-1α were below thedetection limit of the assays in all samples. Median plasma sTNFr-P75in the cancer patients was 960 ng/l (range 400-6600) before stent insertion and remained unchanged at one and four weeks after stenting. Plasma sTNFr-P75 in cancer patients was significantly higher(p<0.01) than in healthy controls (250 (200-650) ng/l).Before stent insertion, plasma IL-6 concentrations were detectable(above 5 ng/l) in 17(68%) patients. After relief of biliaryobstruction IL-6 levels fell from a prestent median of 13.2 to lessthan 5 ng/l at one week after stent insertion. Plasma concentrations ofIL-6 were undetectable in 76% of patients at this time.
Conclusion—Activation of the TNF/sTNFr complex isunchanged after biliary drainage in patients with malignant bile ductobstruction. This may explain why preoperative drainage does notinfluence the high morbidity and mortality associated with surgery inthese patients.

Keywords:jaundice; tumour necrosis factor α; biliarydrainage; pancreatic cancer

     

Effectiveness of statin-eluting stent on early inflammatory response and neointimal thickness in a porcine coronary model.

BACKGROUND: Drug-eluting stent (DES) implantation is routine during coronary revascularization because DES significantly reduce rates of restenosis and target lesion revascularization compared with bare metal stent (BMS). However, available DES have limitations, such as late thrombosis because of delayed healing with poorer endothelialization and persistent local inflammation. Statins can inhibit cell proliferation, inflammation, and restore endothelial function. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stent-induced inflammatory responses and adverse effects on endothelial function, and to inhibit neointimal hyperplasia in a porcine coronary model. METHODS AND RESULTS: Pigs were randomized into groups in which the coronary arteries (9 pigs, 18 coronaries in each group) had either a cerivastatin-eluting stent (CES) or a BMS. All animals survived without any adverse effects. Inflammatory cell infiltration evaluated using scanning electron microscopy on day 3 after stenting was significantly decreased in the treated vessels (inflammation score: 1.15+/-0.12 vs 2.43+/-0.34, p<0.0001). At day 28, endothelial function with intracoronary infusion of bradykinin was preserved in both the CES and BMS groups. Volumetric intravascular ultrasound images revealed decreased intimal volume in the CES group (28.3+/-5.4 vs 75.9+/-4.2 mm3, p<0.0001). Histomorphometric analysis showed reduced neointimal area (1.74+/-0.45 vs 3.83+/-0.51 mm2, p<0.0001) in the CES group despite similar injury scores (1.77+/-0.30 vs 1.77+/-0.22, p=0.97). CONCLUSION: In porcine coronary arteries CES significantly decreased neointimal hyperplasia with a decreased early inflammatory response and without endothelial dysfunction.     

Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation

OBJECTIVES

We sought to investigate whether statin therapy affects the association between preprocedural C-reactive protein (CRP) levels and the risk for recurrent coronary events in patients undergoing coronary stent implantation.

BACKGROUND

Low-grade inflammation as detected by elevated CRP levels predicts the risk of recurrent coronary events. The effect of inflammation on coronary risk may be attenuated by statin therapy.

METHODS

We investigated a potential interrelation among statin therapy, serum evidence of inflammation, and the risk for recurrent coronary events in 388 consecutive patients undergoing coronary stent implantation. Patients were grouped according to the median CRP level (0.6 mg/dl) and to the presence of statin therapy.

RESULTS

A primary combined end point event occurred significantly more frequently in patients with elevated CRP levels without statin therapy (RR [relative risk] 2.37, 95% CI [confidence interval] [1.3 to 4.2]). Importantly, in the presence of statin therapy, the RR for recurrent events was significantly reduced in the patients with elevated CRP levels (RR 1.27 [0.7 to 2.1]) to about the same degree as in patients with CRP levels below 0.6 mg/dl and who did not receive statin therapy (RR 1.1 [0.8 to 1.3]).

CONCLUSIONS

Statin therapy significantly attenuates the increased risk for major adverse cardiac events in patients with elevated CRP levels undergoing coronary stent implantation, suggesting that statin therapy interferes with the detrimental effects of inflammation on accelerated atherosclerotic disease progression following coronary stenting.     

Endoscopic pancreatic duct stent placement for inflammatory pancreatic diseases

The role of endoscopic therapy in the management of pancreatic diseases is continuously evolving; at present most pathological conditions of the pancreas are successfully treated by endoscopic retrograde cholangio- pancreatography （ERCP） or endoscopic ultrasound （EUS）, or both. Endoscopic placement of stents has played and still plays a major role in the treatment of chronic pancreatitis, pseudocysts, pancreas divisum, main pancreatic duct injuries, pancreatic fistulae, complications of acute pancreatitis, recurrent idiopathic pancreatitis, and in the prevention of post-ERCP pancreatitis. These stents are currently routinely placed to reduce intraductal hypertension, bypass obstructing stones, restore lumen patency in cases with dominant, symptomatic strictures, seal main pancreatic duct disruption, drain pseudocysts or fluid collections, treat symptomatic major or minor papilla sphincter stenosis, and prevent procedure-induced acute pancreatitis. The present review aims at updating and discussing techniques, indications, and results of endoscopic pancreatic duct stent placement in acute and chronic inflammatory diseases of the pancreas.     

Phagocytosis and the inflammatory response

Macrophages are a cornerstone of the innate immune system. They detect infectious organisms via a plethora of receptors, phagocytose them, and orchestrate an appropriate host response. Phagocytosis is extraordinarily complex: numerous receptors stimulate particle internalization, the cytoskeletal elements mediating internalization differ by receptor system and the nature of the pathogen being internalized, and the outcome can differ by bacterium. After generating a panel of 150 monoclonal antibodies that recognizes proteins recruited to the phagosome, analysis of novel phagocytic proteins was prioritized by focusing on those that behave differently during the internalization of virulent and avirulent bacteria. Several novel proteins that have roles in membrane extension were characterized. Although the inflammatory pathways leading to appropriate host response are reasonably well defined, it is not clear how macrophages define the threat precisely. Recent work indicates that Toll-like receptors play a key role in reading a "bar code" on invading microorganisms and in eliciting a specific immune response. The mechanisms and coupling to the phagocytic response are discussed.     

The inflammatory response in pneumonia

Summary In normal conditions, alveolar macorphage (AM) is the main cell that respond against to bacteria that reach lower airways. However, if the microbial inoculum is too high or too virulent to be stopped by AM alone, these cells recruit polymorphonuclear neutrophils (PMN) into the alveoli from the vascular compartment. Cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8), secreted by the AM are able to attract PMN enhanced for phagocytosis are ready to destroy the invading pathogens. However, excessive cytokine production has deleterious effects, with a systemic inflammatory response (sepsis) that can lead to multiorganic failure and death. Other cytokines like interleukin-10 (IL-10) balance this response attenuating several inflammatory mechanisms. The inflammatory lung response in pneumonia has been well studied in animals and more recently in humans using bronchoalveolar lavage to measure some inflammatory mediators (TNF-α, IL-1β, IL-6, IL-8). From these studies, it seems that first, the inflammatory response to pneumonia is compartmentalized for most cytokines (in contrast to ARDS), except for IL-6 which is a general marker of inflammation. On the other hand, C-Reactive-Protein is an acute-phase protein synthesized by the liver through the stimuli of IL-6 that may be also an easy to measure marker of inflammation directly related to IL-6; second, some of these cytokines may be useful as prognostic markers; third, there is no clear relationship between the local lung bacterial burden and the intensity of the inflammatory response; fourth, the administration of G-CSF is a promising therapeutic approach still under clinical investigation. In the future the therapeutic goal in severe pneumonia will probably be to find the exact point at which inflammation is beneficial but not deleterious. The measurement of the inflammatory response could serve for this purpose. Received: 20 August 1997 Accepted: 2 December 1997     

Cytokine response in inflammatory myopathies

After background information about pathologic findings, this review focuses on the cytokine response in the pathogenesis of polymyositis and dermatomyositis. Cytokines are important mediators of the immune response and play a key role in these diseases by acting on inflammatory immune cells, muscle cells, and vessel cells. Various cytokines are found in myositis samples, in particular interleukin-1 and tumor necrosis factor-α, which are associated with the migration, differentiation, and maturation of inflammatory cells. Recent advances indicate that the muscle cell itself could participate in the inflammatory process. Cytokines promote changes in muscle metabolism resulting in a self-sustaining inflammatory response. Accordingly, cytokines may represent new targets for therapies.     

Statin pharmacokinetics

Reducing high levels of plasmatic lipoids (LDL-cholesterol and triglycerides) is one of the most important steps in the prevention and treatment of cardiovascular diseases. In the majority of cases, treatment based on lifestyle changes (changes in dietary habits, more physical activity) is not sufficient and pharmacotherapy becomes necessary. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are a well tolerated first-choice drug in patients with dyslipidemia. However, great variability of statin effects has been observed in different patients on the same therapy, and the cause clearly resides in different genetic characteristics of each individual, influencing the effect of therapy. The influence of different genetic variants has been described, but the control of response to hypolipidemic therapy is most likely subject to polygenic control. The analysis of multiple gene combinations may help detect the "hyper-" and "hypo-" responders, i.e. individuals with a good response to treatment (allowing for starting with a lower dose of the drug), and those with an insufficient response to treatment (in whom statin shall not be the drug of first choice), or it may help detect the patients who are more likely to develop severe adverse events. Studies with different designs describe that for instance genes (and their variants) for cytochromes, apolipoprotein E and A1 and cholesterol 7alpha-hydroxylase may be important genetic determinants of the effect of pharmacological treatment of dyslipidemia and play a role in the individualisation of treatment.