Mayumi Inaba

Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion

AIMS Recent studies have demonstrated that erythrocytes are a potential component in atheromatous lesions and thrombus formation in patients with ST-elevation myocardial infarction (STEMI). The purpose of this study was to determine the associations of red blood cell (RBC) component of coronary thrombi with oxidative stress and myocardial reperfusion. METHODS AND RESULTS Aspirated thrombi from 178 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, RBCs, fibrin, macrophages, and neutrophils [myeloperoxidase (MPO)]. The thrombi were divided into tertiles according to the percentage of glycophorin-A-positive area: low (glycophorin-A-positive area <33%; n = 60), intermediate (<54 to 33%; n = 59), and high group (≥54%; n = 59). We also measured plasma MPO levels on admission. In the thrombi, the number of MPO-positive cells in the high-RBC group was significantly greater than that in the low-RBC group (high, 927 ± 385; intermediate, 765 ± 406; low, 279 ± 220 cells/mm(2); P< 0.0001). Plasma MPO levels were significantly higher in the high-RBC group than that in the low-RBC group [low 43.1 (25.0-71.6); intermediate 71.0 (32.9-111.2); high 74.3 (31.1-126.4)ng/mL; P< 0.005]. Distal embolization occurred more frequently in the high-RBC group (P= 0.0009). Moreover, the signs of impaired myocardial reperfusion, as indicated by incomplete ST-segment resolution (STR) and lower myocardial blush grades (MBG), and progression of left ventricular remodelling at 6 months were frequently observed in the high-RBC group (high vs. low: STR, P= 0.056; MBG, P< 0.01; remodelling, P< 0.01). CONCLUSION The present study demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in STEMI patients.

Relationship of Thrombus Characteristics to the Incidence of Angiographically Visible Distal Embolization in Patients With ST-Segment Elevation Myocardial Infarction Treated With Thrombus Aspiration

OBJECTIVES This study sought to investigate the association between pathological characteristics of aspirated intracoronary thrombi and the incidence of angiographically visible distal embolization (AVDE) during primary percutaneous coronary intervention (p-PCI) in patients with ST-segment elevation myocardial infarction (STEMI) treated with thrombus aspiration. BACKGROUND AVDE of atherosclerotic and thrombotic material has been shown to impair myocardial perfusion and contribute to poor clinical outcome in patients with STEMI. Recent studies have shown that thrombus composition and size are associated with the incidence of AVDE. METHODS Aspirated thrombi from 164 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, erythrocytes, and inflammatory cells. RESULTS The angiographic results showed that AVDE during p-PCI occurred in 22 (13.4%) patients. Pathological analysis revealed that thrombi from patients with AVDE had a greater erythrocyte-positive area (60 ± 15% vs. 43 ± 21%, p < 0.0005) and more myeloperoxidase-positive cells (943 ± 324 cells/mm(2) vs. 592 ± 419 cells/mm(2), p < 0.0005) than those from patients without AVDE. Thrombus size, quantified as the thrombus surface area, was positively correlated with the erythrocyte component (r = 0.362, p < 0.0001). Moreover, multivariate logistic analysis demonstrated that erythrocyte-positive area in the thrombi, glucose levels on admission, larger vessel diameter (≥ 3.5 mm), and pre-balloon dilation were independent predictors of the incidence of AVDE. CONCLUSIONS This study demonstrated that the erythrocyte-rich component of aspirated thrombi may be associated with the incidence of AVDE during p-PCI in patients with STEMI.

Gender-specific correlation between plasma myeloperoxidase levels and serum high-density lipoprotein-associated paraoxonase-1 levels in patients with stable and unstable coronary artery disease

OBJECTIVE Low high-density lipoprotein (HDL) cholesterol is well-established as a negative risk factor for coronary artery disease (CAD) and its anti-oxidant property has been attributed mainly to the HDL-bound enzyme paraoxonase-1 (PON-1). Recently, myeloperoxidase (MPO), a pro-oxidant enzyme released from activated neutrophils, has been shown to alter the atheroprotective function of HDL to a dysfunctional form. This study investigated the relationship between plasma MPO and serum PON-1 levels in patients with stable (SAP) and unstable angina pectoris (UAP). METHODS Plasma MPO levels and serum PON-1 concentration/activity were measured in patients with SAP (n = 226), UAP (n = 151) and in control subjects (n = 99). RESULTS Plasma MPO levels in UAP patients were significantly higher than those in SAP patients or in control subjects (UAP, 21.6[16.7-44.6]; SAP, 19.3[15.7-29.1]; control, 15.9[14.7-18.7] ng/mL; P < 0.0001). Serum PON-1 concentrations in UAP and SAP patients were significantly lower than those in control subjects (UAP, 55.6[45.9-69.7]; SAP, 55.0[46.9-64.9]; control, 62.5[51.1-78.8] μg/mL; P = 0.0002). Plasma MPO levels showed a weak inverse correlation with serum PON-1 concentrations in all subjects (R = -0.163, P < 0.0005). Moreover, in women, plasma MPO levels showed a significant inverse correlation with serum PON-1 concentrations and PON-arylesterase activity in SAP (concentration: R = -0.537, P < 0.0001; arylesterase-activity: R = -0.469, P < 0.001) and UAP (concentration: R = -0.340, P < 0.05; arylesterase-activity: R = -0.350, P < 0.05) patients, but not in men. CONCLUSION This study demonstrates that plasma MPO levels have a significant inverse correlation with PON-1 levels, especially in women, in SAP and UAP patients, and suggests that an imbalance between pro-oxidants and anti-oxidants may contribute to the progression of coronary plaque instability.

Positive association between plasma levels of oxidized low‐density lipoprotein and myeloperoxidase after hemodialysis in patients with diabetic end‐stage renal disease

End‐stage renal disease (ESRD) patients undergoing hemodialysis (HD) have a high prevalence of cardiovascular events. Low‐density lipoprotein (LDL) in dialysis patients has been shown to be susceptible to in vitro peroxidation; therefore, oxidized‐LDL (ox‐LDL) could be generated in these patients. Moreover, myeloperoxidase (MPO) released from activated neutrophils may play a role in the induction of LDL oxidation. The purpose of this study was to investigate the relationship between plasma ox‐LDL levels, plasma MPO levels, and serum high‐sensitivity C‐reactive protein (hs‐CRP) levels during initial HD in patients with diabetic ESRD. Patients (n = 28) had serial venous blood samples drawn before and after HD at the initial, second, and third sessions. Plasma ox‐LDL levels were measured using a specific monoclonal antibody (DLH3), and plasma MPO levels were measured using an enzyme‐linked immunosorbent assay kit. Plasma ox‐LDL levels and MPO levels after a single HD session increased significantly (ox‐LDL, P < 0.005; MPO, P < 0.0001) compared with levels before that HD session. However, the increase was transient since the levels returned to pre‐HD session levels. Additionally, plasma MPO levels showed a positive correlation with plasma ox‐LDL levels during HD (R = 0.62, P = 0.0029). No significant change was observed in serum hs‐CRP levels before and after each HD session. This study demonstrates that plasma MPO levels are directly associated with plasma ox‐LDL levels in diabetic ESRD patients during initial HD. These findings suggest a pivotal role for MPO and ox‐LDL in the progression and acceleration of atherosclerosis in patients undergoing HD.

Salvage surgery after chemotherapy with S-1 plus cisplatin for α-fetoprotein-producing gastric cancer with a portal vein tumor thrombus: a case report

BackgroundPatient with α-Fetoprotein (AFP)-producing gastric cancer usually has a short survival time due to frequent hepatic and lymph node metastases. Gastric cancer with portal vein tumor thrombus (PVTT) is rare and has an extremely poor prognosis.Case presentationA 63-year-old man was found to have a huge Type 3 gastric cancer with a PVTT and a highly elevated serum AFP level. Chemotherapy with S-1 plus cisplatin was given to this patient with unresectable gastric cancer for 4 months. The serum AFP level decreased from 6,160 ng/mL to 60.7 ng/mL with chemotherapy. Since the PVTT disappeared after the chemotherapy, the patient underwent total gastrectomy. Histological findings of the primary tumor after chemotherapy showed poorly differentiated adenocarcinoma without hepatoid cells and viable tumor cells remaining in less than 1/3 of the neoplastic area of mucosa and one lymph node. The cancerous cells were immunohistochemically stained by anti-AFP antibody. The patient has survived for 48 month without recurrence.ConclusionsAFP-producing gastric cancer with a PVTT has an extremely poor prognosis, but long-term survival was achieved for this dismal condition by salvage surgery after chemotherapy.

Association between hemoglobin scavenger receptor and heme oxygenase–1–related anti-inflammatory mediators in human coronary stable and unstable plaques

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that is induced by intraplaque hemorrhage and degrades free heme and releases ferrous iron, which is rapidly sequestered by ferritin. In vitro studies have shown that binding of hemoglobin to hemoglobin scavenger receptor (CD163) induces HO-1 and the anti-inflammatory mediator interleukin (IL)-10. We immunohistochemically examined the relationship between CD163 expression in macrophages and intraplaque hemorrhage, HO-1, IL-10, and ferritin using coronary atherectomy specimens from patients with stable (SAP) or unstable angina pectoris (UAP). A total of 67 patients underwent atherectomy for SAP (n = 33) or UAP (n = 34). Samples were stained with antibodies against smooth muscle cells, macrophages, glycophorin-A (a protein specific to erythrocyte membranes), CD163, HO-1, IL-10, and ferritin. To identify cell types of HO-1-positive cells, double immunostaining was also performed. Double immunostaining for HO-1 and macrophages revealed that the vast majority of HO-1-positive cells were macrophages. Morphometric analysis demonstrated that CD163-positive macrophage score and the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas were significantly higher in UAP than in SAP patients (CD163, P < .005; glycophorin-A, P < .0001; HO-1, P < .0001; IL-10, P < .005; ferritin, P = .0001). Moreover, CD163-positive macrophage score was positively associated with the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas (glycophorin-A, r = 0.60, P < .0001; HO-1, r = 0.67, P < .0001; IL-10, r = 0.45, P < .0005; ferritin, r = 0.61, P < .0001). These findings suggest that enhanced expression of HO-1 and HO-1-related atheroprotective molecules plays an important role in exerting anti-inflammatory, antioxidant, and scavenging functions, which could contribute to plaque stabilization.

Enhanced expression of hemoglobin scavenger receptor and heme oxygenase‐1 is associated with aortic valve stenosis in patients undergoing hemodialysis

A high prevalence and a rapid progression of aortic valve stenosis (AS) in patients undergoing hemodialysis (HD) has been reported. In these circumstances, intraleaflet hemorrhage of aortic valve may be related to the development of AS in HD patients. We immunohistochemically examined the relationship among intraleaflet hemorrhage, neovascularization, hemoglobin scavenger receptor (CD163), and heme oxygenase‐1 (HO‐1) using surgically resected aortic valve specimens from AS patients undergoing HD. The study population consisted of 26 HD patients and 25 non‐HD patients with severe AS who had undergone aortic valve replacement. Frozen aortic valve samples surgically obtained from AS patients were stained immunohistochemically with antibodies against smooth muscle cells, macrophages, glycophorin‐A (a protein specific to erythrocyte membranes), CD31, CD163, and HO‐1. Morphometric analysis demonstrated that the CD163‐positive macrophage score, the number of CD31‐positive microvessels, and the percentage of glycophorin‐A and HO‐1‐positive area were significantly higher in HD patients than in non‐HD patients (CD163‐positive macrophage score, P < 0.0001; CD31‐positive microvessels, P < 0.0001; glycophorin‐A, P < 0.0001; HO‐1, P < 0.0001). Double immunostaining for CD163 or HO‐1 and macrophages revealed that the majority of CD163‐ or HO‐1‐positive cells were macrophages. Furthermore, CD163‐positive macrophage score was positively correlated with glycophorin‐A, HO‐1‐positive area, and the number of CD31‐positive microvessels (glycophorin‐A, R = 0.66, P < 0.0001; HO‐1, R = 0.50, P < 0.0005; microvessels, R = 0.38, P < 0.01). These findings suggest a positive association among intraleaflet hemorrhage, neovascularization, and enhanced expression of CD163 and HO‐1 as a response to intraleaflet hemorrhage in stenotic aortic valves in AS patients undergoing HD.

PERSISTENT ELEVATED LEVELS OF MRP 8/14 AND CARDIOVALCULAR EVENTS AFTER DES IMPLANTATION IN PATIENTS WITH STABLE ANGINA PECTORIS

Background: Myeloid-related protein (MRP) 8/14, a heterodimer of S100A8 (10.8 kD) and S100A9 (13.2 kD), is expressed in activated human neutrophils and macrophages. The present study was designed to investigate the time-course of changes in serum MRP-8/14 levels in patients with stable angina pectoris (SAP) undergoing drug-eluting stent (DES) implantation. Furthermore, we investigated whether serum MRP-8/14 levels predict future cardiovascular events.

INCREASED EXPRESSION AND PLASMA LEVELS OF NEOPTERIN ARE CLOSELY RELATED TO AORTIC VALVE STENOSIS IN PATIENTS WITH HEMODIALYSIS

Aortic valve stenosis (AS) occurs with increased frequency in hemodialysis (HD) patients and could contribute to the excess cardiovascular mortality. However, little is known about differences in progression of the AS process between HD and non-HD patients. Neopterin, a by-product of the guanosine