Management of anticoagulant therapy using a portable point-of-care international normalized ratio device and social networking service in a patient with a left ventricular assist device.

Device infection and stroke are still frequently reported as complications of left ventricular assist devices, and strict management of anticoagulation therapy is sometimes difficult at the time of infection status. We report the case of a 55-year-old man with a HeartMate II (Abbott, Inc., Abbott Park, IL, USA) as a bridge to cardiac transplantation. The patient measured his prothrombin time-international normalized ratio (PT-INR) by himself using a point-of-care device at home and reported the result promptly on a social networking service (SNS). Physicians instructed the patient on how to adjust his dose of warfarin based on the result and suggested the next time of measurement on the SNS. Until cardiac transplantation, we adjusted the dose of warfarin 106 times using the SNS because of unexpected PT-INR fluctuations caused by antibiotics. The time in the therapeutic range was maintained at 83.2% without complications, including major bleeding, stroke, or pump replacement; however, there was transient intra-pump thrombosis triggered by severe dehydration due to hyperthyroidism. .

Leukocyte integrin signaling regulates FOXP1 gene expression via FOXP1-IT1 long non-coding RNA-mediated IRAK1 pathway.

Leukocyte integrin-dependent downregulation of the transcription factor FOXP1 is required for monocyte differentiation and macrophage functions, but the precise gene regulatory mechanism is unknown. Here, we identify multi-promoter structure (P1, P2, and P3) of the human FOXP1 gene. Clustering of the ß2-leukocyte integrin Mac-1 downregulated transcription from these promoters. We extend our prior observation that IL-1 receptor-associated kinase 1 (IRAK1) is physically associated with Mac-1 and provide evidence that IRAK1 is a potent suppressor of human FOXP1 promoter. IRAK1 reduced phosphorylation of histone deacetylase 4 (HDAC4) via inhibiting phosphorylation of calcium/calmodulin dependent protein kinase II delta (CaMKIIδ), thereby promoting recruitment of HDAC4 to P1 chromatin. A novel human FOXP1 intronic transcript 1 (FOXP1-IT1) long non-coding RNA (lncRNA), whose gene is embedded within that of FOXP1, has been cloned and found to bind directly to HDAC4 and regulate FOXP1 in cis manner. Overexpression of FOXP1-IT1 counteracted Mac-1 clustering-dependent downregulation of FOXP1, reduced IRAK1 downregulation of HDAC4 phosphorylation, and attenuated differentiation of THP-1 monocytic cells. In contrast, Mac-1 clustering inhibited FOXP1-IT1 expression with reduced binding to HDAC4 as well as phosphorylation of CaMKIIδ to activate the IRAK1 signaling pathway. Importantly, both IRAK1 and HDAC4 inhibitors significantly reduced integrin clustering-triggered downregulation of FOXP1 expression in purified human blood monocytes. Identification of this Mac-1/IRAK-1/FOXP1-IT1/HDAC4 signaling network featuring crosstalk between lncRNA and epigenetic factor for the regulation of FOXP1 expression provides new targets for anti-inflammatory therapeutics.

Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis.

Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14⁻/⁻ mice. We observed that MRP-14 and MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14⁻/⁻ mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14⁻/⁻ mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.

Prolylcarboxypeptidase promotes angiogenesis and vascular repair.

Prolylcarboxypeptidase (PRCP) is associated with leanness, hypertension, and thrombosis. PRCP-depleted mice have injured vessels with reduced Kruppel-like factor (KLF)2, KLF4, endothelial nitric oxide synthase (eNOS), and thrombomodulin. Does PRCP influence vessel growth, angiogenesis, and injury repair? PRCP depletion reduced endothelial cell growth, whereas transfection of hPRCP cDNA enhanced cell proliferation. Transfection of hPRCP cDNA, or an active site mutant (hPRCPmut) rescued reduced cell growth after PRCP siRNA knockdown. PRCP-depleted cells migrated less on scratch assay and murine PRCP(gt/gt) aortic segments had reduced sprouting. Matrigel plugs in PRCP(gt/gt) mice had reduced hemoglobin content and angiogenic capillaries by platelet endothelial cell adhesion molecule (PECAM) and NG2 immunohistochemistry. Skin wounds on PRCP(gt/gt) mice had delayed closure and reepithelialization with reduced PECAM staining, but increased macrophage infiltration. After limb ischemia, PRCP(gt/gt) mice also had reduced reperfusion of the femoral artery and angiogenesis. On femoral artery wire injury, PRCP(gt/gt) mice had increased neointimal formation, CD45 staining, and Ki-67 expression. Alternatively, combined PRCP(gt/gt) and MRP-14(-/-) mice were protected from wire injury with less neointimal thickening, leukocyte infiltration, and cellular proliferation. PRCP regulates cell growth, angiogenesis, and the response to vascular injury. Combined with its known roles in blood pressure and thrombosis control, PRCP is positioned as a key regulator of vascular homeostasis.

Intravascular optical coherence tomography detection of atherosclerosis and inflammation in murine aorta.

OBJECTIVE: The goal of this study was to evaluate the feasibility of imaging the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice for the detection of atherosclerosis and macrophages using optical coherence tomography (OCT) compared with histology. METHODS AND RESULTS: Atherosclerosis was induced by high-fat diet in 7-week-old ApoE(-/-) mice for 10 (n=7) and 22 (n=7) weeks. Nine-week-old ApoE(-/-) mice (n=7) fed a standard chow diet were used as controls. OCT images of a 10-mm descending aorta in situ were performed in 4 mice for each, and plaque and macrophages were determined at 0.5-mm intervals. Automated detection and quantification of macrophages were performed independently using a customized algorithm. Coregistered histological cross-sections were stained with hematoxylin-eosin, Mac-3, and von Kossa. Three mice in each group had en face OCT imaging to detect macrophages, which were compared with lipid-positive area with Sudan IV. OCT images were successfully acquired in all mice. OCT and histology were able to discriminate macrophages and plaque among the 3 groups and showed excellent correlation for (1) visual detection of plaque (r=0.98) and macrophages (r=0.93), (2) automated detection and quantification of macrophages by OCT versus Mac-3-positive area (r=0.92), and (3) en face OCT detection of macrophages versus Sudan IV-positive area (r=0.92). CONCLUSIONS: Murine intra-aortic OCT is feasible and shows excellent correlation with histology for detection of atherosclerotic plaque and macrophages.

Vascular inflammation and repair: implications for re-endothelialization, restenosis, and stent thrombosis.

The cellular and molecular processes that control vascular injury responses after percutaneous coronary intervention involve a complex interplay among vascular cells and progenitor cells that control arterial remodeling, neointimal proliferation, and re-endothelialization. Drug-eluting stents (DES) improve the efficacy of percutaneous coronary intervention by modulating vascular inflammation and preventing neointimal proliferation and restenosis. Although positive effects of DES reduce inflammation and restenosis, negative effects delay re-endothelialization and impair endothelial function. Delayed re-endothelialization and impaired endothelial function are linked to stent thrombosis and adverse clinical outcomes after DES use. Compared with bare-metal stents, DES also differentially modulate mobilization, homing, and differentiation of vascular progenitor cells involved in re-endothelialization and neointimal proliferation. The effects of DES on vascular inflammation and repair directly impact clinical outcomes with these devices and dictate requirements for extended-duration dual antiplatelet therapy.

Critical role for Syk in responses to vascular injury.

Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet-dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.

Kruppel-like factor 15 regulates smooth muscle response to vascular injury--brief report.

To determine the role of Kruppel-like factor (KLF) 15, a zinc finger transcriptional factor that is expressed in vascular smooth muscle cells (VSMCs) in vascular biology. VSMCs respond to mechanical injury via a tightly orchestrated series of gene regulatory events. KLF15 is broadly expressed in both arterial and venous vascular beds in a VSMC restricted fashion. KLF15 expression is markedly reduced by both pharmacological and mechanical stimuli. To examine the specific role of KLF15 in the vascular response to injury, we performed femoral artery wire injury in KLF15(-/-) and wild-type mice. KLF15(-/-) mice develop exaggerated neointimal growth, with evidence of increased SMC proliferation and migration within the neointima. In concordance, gain and loss of function studies in isolated VSMCs demonstrate that KLF15 can directly inhibit SMC proliferation and migration. To our knowledge, these data are the first to identify KLF15 as a novel inhibitor of VSMC proliferation and migration and to implicate this factor as a critical regulator of the vascular response to injury.

The intrinsic complement regulator decay-accelerating factor modulates the biological response to vascular injury.

OBJECTIVE: To investigate whether the presence of decay-accelerating factor (or CD55), an intrinsic complement regulator, protects against the development of vascular disease, given that complement activation can affect leukocytes and platelets. METHODS AND RESULTS: Leukocyte-platelet complexes are critical for the initiation and progression of atherosclerosis and restenosis; however, the mechanism by which these processes promote vascular injury is incompletely defined. We performed femoral artery wire injury in Daf1(-/-) mice and their wild-type controls. Leukocyte accumulation, cellular proliferation, and neointimal thickening were enhanced in Daf1(-/-) mice versus wild-type mice. Deficiency of either the C3a or the C5a receptor, respectively, reversed the increased vascular inflammation, cellular proliferation, and neointimal formation in Daf1(-/-) mice. CONCLUSIONS: Decay-accelerating factor control of C3a and C5a generation and prevention of the binding of these activation fragments to the C3a and C5a receptors are critical for the biological response to vascular injury. Targeting the C3a and C5a receptors may be useful for the prevention of neointimal hyperplasia.

Increased interleukin-13 levels in patients with chronic heart failure.

A great number of basic and clinical studies have demonstrated that inflammatory cytokines play an important role in development and progress of heart failure. However, there is limited information about allergic cytokine interleukin-13 (IL-13). The inflammatory responses mediated by allergic cytokines can cause significant morbidity and mortality when they become chronic. Therefore, we elucidated the role of IL-13 in the pathophysiology of chronic heart failure. We measured plasma IL-13 levels by enzyme-linked immunosorbent assay in 110 patients with chronic heart failure and 20 control subjects. Plasma IL-13 levels were increased in heart failure patients, compared with the controls, in association with NYHA functional class. In addition, IL-13 levels were correlated positively with plasma levels of brain natriuretic peptide and C-reactive protein, and negatively with left ventricular ejection fraction. Plasma IL-13 levels may be useful for evaluating disease severity in chronic heart failure.

Mechanical stretch and angiotensin II increase interleukin-13 production and interleukin-13 receptor alpha2 expression in rat neonatal cardiomyocytes.

BACKGROUND: The high affinity receptor for interleukin (IL)-13, IL-13 receptor alpha2 (IL-13Ralpha2), acts as a decoy receptor for IL-13, modulates fibrosis and has an anti-tumor effect. Recently, IL-13Ralpha2 has been considered as a therapeutic target for fibrosis and tumor growth. However, the mechanism of IL-13Ralpha2 expression in cardiomyocytes is unclear. METHODS AND RESULTS: The mechanism of IL-13Ralpha2 expression was examined using cultured rat neonatal cardiomyocytes. Cyclical mechanical stretch induced IL-13Ralpha2 mRNA expression in rat cardiomyocytes. Treatment with angiotensin II, which plays a pivotal role in mechanical stretch-induced cardiomyocyte hypertrophy, upregulated IL-13Ralpha2 mRNA expression in rat cardiomyocytes. IL-13Ralpha2 mRNA expression was also upregulated through IL-13 treatment. Furthermore, mechanical stretch and angiotensin II treatment caused IL-13 secretion from rat cardiomyocytes, which was suppressed by angiotensin type1 receptor (AT1R) RNA interference. Upregulation of IL-13Ralpha2 mRNA expression through mechanical stretch, angiotensin II treatment and IL-13 treatment was inhibited by anti-IL-13Ralpha1 antibody and STAT6 depletion through RNA interference. Positive immunohistochemical staining for IL-13Ralpha2 was observed in the myocardium of endomyocardial biopsy specimens from the failing human heart, but not in autopsy specimens from control subjects. CONCLUSION: IL-13 might act in an autocrine and paracrine fashion to upregulate IL-13Ralpha2 expression in cardiomyocytes.

Pentraxin3 is a novel marker for stent-induced inflammation and neointimal thickening.

Inflammation in the injured vessel wall plays an essential role in the mechanism of restenosis. Pentraxin3 (PTX3) is synthesized at the inflammatory site in response to primary inflammatory stimuli. To establish the clinical significance of plasma PTX3 levels in the pathophysiology of inflammation in the injured vessels, we serially measured the levels in 20 patients undergoing elective coronary stenting. Plasma PTX3 levels increased 15 min after coronary stenting, and reached a maximum at 24h in the coronary sinus (P<0.001 versus baseline) and peripheral blood (P<0.001 versus baseline). The transcardiac gradient of PTX3 at 15 min after PCI was higher in patients with than those without restenosis (0.40+/-0.64 versus -0.19+/-0.33 ng/ml, P=0.02). Furthermore, the increase in PTX3 at 24h was positively correlated with the increase in activated Mac-1 on the surface of neutrophils at 48 h (r=0.48, p<0.05) in the coronary sinus. Stepwise multiple regression analysis demonstrated that the relative increase in PTX3 at 24h was the most powerful predictor of late lumen loss (r=0.547, P=0.007). Coronary stenting enhanced circulating PTX3 levels in association with an inflammatory response. PTX3 may be a useful marker for evaluation of inflammatory reaction and neointimal thickening after vascular injury.

Increased circulating platelet-derived microparticles are associated with stent-induced vascular inflammation.

Inflammation as well as platelet activation at the site of local vessel-wall injury plays an essential role in the mechanism of restenosis after Percutaneous coronary intervention (PCI). Platelet-derived microparticles (PDMPs) released from activated platelets are thought to play a role in the inflammatory process, possibly interacting with leukocyte integrin Mac-1. We serially measured circulating PDMPs, high-sensitive C-reactive protein (hs-CRP) and activated Mac-1 on the surface of neutrophils in 61 patients undergoing coronary stenting. PDMPs, hs-CRP and Mac-1 increased after coronary stenting in a time-dependent manner with the maximum response at 48 h in coronary sinus blood (PDMPs: 10.3+/-8.9-32.8+/-13.8 U/ml; P<0.001, hs-CRP: 0.27+/-0.23-1.46+/-0.99 mg/dl; P<0.001, activated Mac-1, 134+/-19% relative increase, P<0.001). PDMPs were correlated with hs-CRP (R=0.58, P<0.001) and the relative increase in Mac-1 (R=0.69, P<0.001) 48 h after coronary stenting. Multiple regression analysis showed that each of PDMPs (R=0.40, P<0.05), hs-CRP (R=0.33, P<0.05) and Mac-1 (R=0.48, P<0.01) was an independent predictor of the late lumen loss. Coronary stenting enhanced circulating PDMPs in association with an inflammatory response in the injured vessel wall. PDMPs may be a useful marker for evaluation of stent-induced inflammatory status and a powerful predictor of restenosis equivalent to activated Mac-1.

High molecular weight adiponectin as a predictor of long-term clinical outcome in patients with coronary artery disease.

Adiponectin is an adipocyte-specific secretory protein that is highly and specifically expressed in adipose tissue, and low plasma levels of adiponectin are associated with coronary artery disease (CAD). It has been suggested that high molecular weight (HMW) adiponectin is more important for vascular protection than total amount of adiponectin. To establish the clinical relevance of HMW adiponectin, we measured its serum levels in 149 patients with CAD. The levels were lower in vasospastic angina pectoris (3.4 +/- 2.4 microg/ml, p <0.01), stable angina pectoris (3.3 +/- 2.6 microg/ml, p <0.001), and healed myocardial infarction (3.8 +/- 2.9 microg/ml, p <0.01) than chest pain syndrome (controls) (6.6 +/- 5.4 microg/ml). The levels were also lower in multivessel CAD (3.4 +/- 2.4 microg/dl) compared with single vessel CAD (4.2 +/- 2.7 microg/ml, p <0.05) or no organic stenosis (5.1 +/- 3.5 microg/ml, p <0.01). In univariate analysis, diabetes mellitus (p = 0.03), insulin resistance (p = 0.06), high-sensitivity C-reactive protein levels (p = 0.0012), and low HMW adiponectin levels (p = 0.0001) predicted cardiovascular events during 7 years of follow-up. However, multivariate analysis showed that only HMW adiponectin levels were an independent predictor of cardiovascular events (relative risk 2.79, 95% confidence interval 1.49 to 5.24, p = 0.0014). In conclusion, serum HMW adiponectin levels may serve as a predictor of future cardiovascular events in patients with CAD as well as a marker for severity of CAD.

Postprandial hyperglycemia is a possible contributor to paroxysmal atrial fibrillation: a case report.

Atrial fibrillation, a major risk factor for stroke, is believed to occur first as paroxysmal episodes, gradually becoming more persistent, and finally progressing to chronic atrial fibrillation. Treatment of paroxysmal atrial fibrillation is an important target to prevent chronic atrial fibrillation. We describe a very unique case with postprandial hyperglycemia and obesity associated with drug-refractory paroxysmal atrial fibrillation. A 73-year-old Japanese woman with postprandial hyperglycemia suffered from drug-refractory paroxysmal atrial fibrillation. A 1600 kcal/day diet and walking three times/day for more than 30 min eliminated paroxysmal atrial fibrillation after 6 months. Diet and exercise should be considered as the initial therapy in patients with paroxysmal atrial fibrillation who also have postprandial hyperglycemia. This case suggests that postprandial hyperglycemia and insulin resistance might be one of the possible underlying mechanisms of paroxysmal atrial fibrillation.

[Methods to evaluate the vascular endothelial function].

When the vascular endothelial function fails, arterial atherosclerosis is developed. Furthermore, if the endothelial dysfunction progresses, it is known to cause angina pectoris, myocardial infarction, cerebrovascular accident. By medical therapy and replacement therapy, correction of the life style, the endothelial dysfunction is understood that it could be improved reversibly. Therefore, it is very important to evaluate the vascular endothelial function for arteriosclerotic severity and the prediction of the cardiovascular disease onset and the effect of medical therapy. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. This technique is attractive because it is noninvasive and allows repeated measurements. However, despite its widespread use, there are technical and interpretive limitations. Therefore, for clinical application of the endothelial function test, its problems must be understood well.

Short-term passive smoking causes endothelial dysfunction via oxidative stress in nonsmokers.

Recent studies have shown that passive smoking impairs vascular endothelial function and induces oxidative stress in humans. However, in most of the previous human data regarding tobacco-induced pathophysiology, vascular endothelial dysfunction and oxidative stress have been separately assessed. This study was designed to determine the association between the acute effect of passive smoking on vascular endothelial function and in-vivo oxidative stress status. We studied 30 healthy male Japanese volunteers (32 +/- 7 years) including 15 habitual smokers and 15 nonsmokers. After baseline echocardiographic, hemodynamic recording, and blood sampling, subjects were exposed to passive smoking for 30 min. Endothelium-dependent vasodilation was measured by using % flow-mediated vasodilation (%FMD) of the brachial artery and plasma levels of 8-isoprostane was measured by enzyme immunoassay before and after the passive smoking exposure. Baseline %FMD was lower (4.3% +/- 1.2% vs. 10.9% +/- 3.1%, p < 0.001) and baseline plasma 8-isoprostane level was higher (41.5 +/- 5.8 pg/mL vs. 26.9 +/- 5.4 pg/mL, p < 0.001) in smokers than those in nonsmokers. The %FMD and 8-isoprostane level did not change after passive smoking in smokers. In nonsmokers, however, the %FMD decreased (to 5.0% +/- 1.9%, p < 0.001) and the 8-isoprostane level increased (to 37.8 +/- 9.6 pg/mL, p < 0.001) significantly after 30 min passive smoking exposure, equivalently to the levels of smokers. Sixty corrected samples before and after passive smoking exposure in all patients showed a significant negative correlation between the % FMD and the plasma 8-isoprostane levels (n = 60, r = -0.69, p < 0.001). Even 30 min of passive smoking rapidly impairs vascular endothelial function, which is associated with oxidative stress. Our data provide the pathophysiological insight for the recent epidemiological evidence about the increased risk of coronary heart disease among nonsmokers exposed to passive smoking.

Low-density lipoprotein subfractions and the prevalence of silent lacunar infarction in subjects with essential hypertension.

Recent lipid research has focused on low-density lipoprotein (LDL) subfractions as new markers for cardiovascular risk. However, the clinical significance of measurement of LDL subfractions in subjects with essential hypertension is yet to be established. We studied the association between the prevalence of silent lacunar infarction (SLI) and LDL subfractions in patients with essential hypertension. We performed brain MRI to detect SLI and measured LDL subfractions in 100 asymptomatic non-diabetic middle-aged subjects with essential hypertension (mean age, 62 years). We fractionated LDL into three parts, LDL-1, LDL-2, and LDL-3, with LDL-3 being the oxidized subfraction. Of the 100 study subjects, 24 (24%) had one or more SLIs, while the remaining 76 (76%) were considered as a non-SLI group. The LDL-3 levels were significantly higher in the SLI group than in the non-SLI group (8.3 +/- 4.4 mg/dl vs. 6.3 +/- 2.0 mg/dl, p = 0.006). Multiple logistic regression analysis showed that LDL-3 levels alone were an independent predictor of SLI (odds ratio [OR]: 1.380; 95% confidence interval [CI]: 1.113-1.663; p = 0.003). When subjects were divided into quartiles based on LDL-3 levels, the prevalence of SLI was significantly higher in the highest LDL-3 level group than in the lowest LDL-3 level group (p = 0.0036). The present study suggests that LDL-3 levels are associated with the prevalence of SLI in subjects with essential hypertension.

Stent-induced neutrophil activation is associated with an oxidative burst in the inflammatory process, leading to neointimal thickening.

Activation of leukocytes plays an essential role in the mechanism of restenosis. Prior research has focused on monocytes and little is known about the role of neutrophils in this process. Neutrophils are known to contribute to tissue injury through oxygen-derived free radicals that nitrate tyrosine. This study was designed to elucidate clinically the role of neutrophil-mediated oxidative burst in the regulation of the post-stent inflammatory process. In 36 patients undergoing coronary stenting, we serially measured serum levels of glycosyl-phosphatidil-inositol-anchored protein (GPI)-80,a modulator of Mac-1 on the surface of neutrophils, in samples of coronary sinus as well as peripheral blood. We also simultaneously measured the serum 3-nitrotyrosine/tyrosine ratio as an index of oxidative stress. The GPI-80 level and the 3-nitrotyrosine/tyrosine ratio increased in the coronary sinus after coronary stenting in a time-dependent manner; with the maximum increase of GPI-80 level (3.1 +/- 2.9 to 8.6 +/- 4.3 ng/ml, P < 0.01) at 48 hours, and 3-nitrotyrosine/tyrosine ratio at 24 hrs (5.2 +/- 4.8 to 28.4 +/- 13.2 x 10(-4), P < 0.01), more strikingly than in the peripheral blood. In the coronary sinus blood, the 3-nitrotyrosine/tyrosine ratio was correlated with GPI-80 levels at 24 hr (R = 0.58, P < 0.001) and at 48 hr (R = 0.41, P < 0.01). Multiple regressions analysis showed that the maximum responses of GPI-80 level and 3-nitrotyrosine/tyrosine ratio were independent predictors of angiographic late lumen loss. Our results may support a hypothesis that Mac-1-dependent activation of neutrophils causes oxidative burst in the post-stent inflammatory process, possibly leading to restenosis.