[Show abstract][Hide abstract] ABSTRACT: To evaluate the effects of eicosapentaenoic acid (EPA) on regional arterial stiffness assessed by strain rate using tissue Doppler imaging.
Nineteen eligible patients were prospectively studied (mean age 62 ± 8 years, 68% men). Subjects with large vessel complications and/or diabetes mellitus were excluded. The strain rate of the ascending aorta was measured by tissue Doppler imaging as an index of regional arterial stiffness, and brachial-ankle pulse wave velocity (baPWV) was measured as an index of degree of systemic arteriosclerosis. These indices were compared before and after administration of EPA at 1800 mg/d for one year.
The plasma concentration of EPA increased significantly after EPA administration (3.0% ± 1.1% to 8.5% ± 2.9%, P < 0.001). There were no significant changes in baPWV (1765 ± 335 cm/s to 1745 ± 374 cm/s), low-density lipoprotein cholesterol levels (114 ± 29 mg/dL to 108 ± 28 mg/dL), or systolic blood pressure (131 ± 16 mmHg to 130 ± 13 mmHg) before and after EPA administration. In contrast, the strain rate was significantly increased by administration of EPA (19.2 ± 5.6 s(-1), 23.0 ± 6.6 s(-1), P < 0.05).
One year of administration of EPA resulted in an improvement in regional arterial stiffness which was independent of blood pressure or serum cholesterol levels.
World Journal of Cardiology (WJC) 08/2012; 4(8):256-9. DOI:10.4330/wjc.v4.i8.256 · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platelet-derived microparticles (PDMP) play an important role in the pathogenesis of diabetic vasculopathy, and statins or eicosapentaenoic acid (EPA) have been shown to have a beneficial effect on atherosclerosis in hyperlipidemic patients. However, the influence of EPA and statins on PDMP and adiponectin in atherosclerosis is poorly understood. We investigated the effect of pitavastatin and EPA on circulating levels of PDMP and adiponectin in hyperlipidemic patients with type II diabetes. A total of 191 hyperlipidemic patients with type II diabetes were divided into three groups: group A received pitavastatin 2 mg once daily (n = 64), group B received EPA 1800 mg daily (n = 55) and group C received both drugs (n = 72). PDMP and adiponectin were measured by ELISA at baseline and after 3 and 6 months of drug treatment. Thirty normolipidemic patients were recruited as healthy controls. PDMP levels prior to treatment in hyperlipidemic patients with diabetes were higher than levels in healthy controls (10.4 +/- 1.9 vs. 3.1 +/- 0.4 U/ml, p < 0.0001), and adiponectin levels were lower than controls (3.20 +/- 0.49 vs. 5.98 +/- 0.42 microg/ml, p < 0.0001). PDMP decreased significantly in group B (before vs. 6M, 10.6 +/- 2.0 vs. 8.0 +/- 1.7 U/ml, p < 0.01), but not in group A (before vs. 6M, 9.4 +/- 1.9 vs. 9.6 +/- 1.7 U/ml, not significant). In contrast, group A exhibited a significant increase in adiponectin levels after treatment (before vs. 6M, 3.29 +/- 0.51 vs. 4.16 +/- 0.60 microg/ml, p < 0.001). Furthermore, group C exhibited significant improvement in both PDMP and adiponectin levels after treatment (PDMP, before vs. 6M, 11.2 +/- 2.0 vs. 4.5 +/- 2.7 U/ml, p < 0.001; adiponectin, before vs. 6M, 3.24 +/- 0.41 vs. 4.02 +/- 0.70 microg/ml, p < 0.001). Reductions of PDMP in combined therapy were significantly greater than those observed with EPA alone (p < 0.05 by ANOVA). In addition, soluble CD40 ligand exhibited almost the same change as PDMP in all therapy groups. These results suggest that pitavastatin possesses an adiponectin-dependent antiatherosclerotic effect, and this drug is able to enhance the anti-platelet effect of EPA. The combination therapy of pitavastatin and EPA may be beneficial for the prevention of vascular complication in hyperlipidemic patients with type II diabetes.
[Show abstract][Hide abstract] ABSTRACT: Although brachial-ankle pulse wave velocity is a widely used index of arterial stiffness, there are several limitations of this method. The actual length of an artery used for measuring pulse wave velocity is estimated based on an anatomical correction value, and brachial-ankle pulse wave velocity is directly affected by systemic blood pressure or vascular occlusion. Thus, the aim of this study was to determine whether aortic wall strain rate as measured by tissue Doppler imaging is a more useful modality for evaluating regional arterial stiffness than brachial-ankle pulse wave velocity.
Seventy-two patients (18 to 78 years) with normal cardiac function and without large vessel complications were enrolled in this study.
A significant positive correlation was found between brachial-ankle pulse wave velocity and age, and brachial-ankle pulse wave velocity increased with age (r = 0.64, P < 0.0001).A significant negative correlation was found between strain rate and age, and strain rate decreased with age (r = -0.44, P < 0.05). A significant correlation was also found between brachial-ankle pulse wave velocity and systolic blood pressure (r = 0.45, P < 0.02), but not between strain rate and systolic blood pressure.There was no significant difference in brachial-ankle pulse wave velocity between hyperlipidaemic and normolipidaemic subjects. However, strain rate was lower in hyperlipidaemic than in normolipidaemic subjects (P < 0.05).
Strain rate on the ascending aortic wall is a novel and more accurate index of regional arterial stiffness than brachial-ankle pulse wave velocity.
[Show abstract][Hide abstract] ABSTRACT: Although stem cell transplantation (SCT) is being used for hematopoietic reconstitution following high-dose chemotherapy for malignancy, it involves certain serious transplant-related complications such as graft-versus-host disease (GVHD). Angiopoietins play important roles in angiogenesis. However, the role of angiopoietins after SCT is poorly understood. In this study, 52 patients underwent SCT; 26 patients received allogeneic SCT, while the remaining 26 received autologous SCT. In 48 of 52 patients, levels of angiopoietins, cytokines, and soluble factors were measured by enzyme-linked immunosorbent assay. Soluble Fas ligand (sFasL) and endothelial cell-derived microparticle (EDMP) exhibited significant elevation in the early phase (2-3 weeks) after SCT. In addition, the elevation of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and sIL-2 receptor (sIL-2R), which are GVHD markers after allogeneic SCT was observed. The level of angiopoietin (Ang)-2 in allogeneic SCT continued to increase for up to 4 weeks, although the level of Ang-1 did not show significant changes. The patients with high Ang-2 exhibited significant increase of sFasL and EDMP compared with those with low Ang-2. In addition, the patients with high-grade GVHD exhibited a significant increase in Ang-2 compared to patients with low-grade GVHD. In the in vitro experiment using endothelial cells, the suppressive effect of Ang-1 on EDMP generation by TNF-alpha was partially inhibited by the addition of Ang-2. Furthermore, multivariate regression analysis showed that EDMP and sFasL were significant factors in Ang-2 elevation. Our results suggest that Ang-2 generation after allogeneic SCT relates to GVHD.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 08/2008; 14(7):766-74. DOI:10.1016/j.bbmt.2008.04.005 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We analyzed the association between platelet activation, adiponectin, insulin resistance and oxidative stress in aging. In addition, we included American football (AB) players to investigate whether this association is modulated by exercise. Eighty-six old age patients (> or = 65 years old) hospitalized at the nursing institution and 62 AB players were recruited as study subjects. Reactive oxygen metabolites (ROM), soluble CD40 ligand (sCD40L) and adiponectin were estimated with these patients. In comparison to old age, plasma adiponectin levels in AB players were significantly low. In addition, the adiponectin values of elder group (> 80 years) in old age were significantly increased higher than those for younger group (< or = 80 years). There were no differences of sCD40L in two groups. Levels of ROM in AB players were also significantly lower than that in old age. However, the ROM values of younger group in old age were significantly increased higher than those for elder group. The sCD40L also exhibited the same results. There were no significant differences in ROM and adiponectin levels between the high homeostasis model assessment-insulin resistance (HOMA-IR) (> 2.0) and the low HOMA-IR (< or = 2.0). In contrast, in the old age, the sCD40L and ROM levels in the high HOMA-IR group were significantly higher than those in the low HOMA-IR group. In addition, the adiponectin level in the high HOMA-IR group was significantly lower than that in the low HOMA-IR group. Our results suggest that platelet activation, adiponectin and oxidative stress are the very important factors for aging, and the maintenance of exercise could prevent the occurrence of metabolic syndrome or insulin resistance.
Archives of gerontology and geriatrics 05/2008; 49(1):13-6. DOI:10.1016/j.archger.2008.04.004 · 1.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Seventy-five hyperlipidemic patients with and without type 2 diabetes were enrolled to receive pitavastatin 2 mg daily. Cell adhesion molecules (sCD40L, sP-selectin, sE-selectin, and sL-selectin), chemokines (MCP-1 and RANTES) and adiponectin were measured at baseline and after 3 and 6 months of pitavastatin treatment. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the LDL-cholesterol (LDL-C) decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with type 2 diabetes exhibited a significant increase in adiponectin levels after pitavastatin treatment (before vs. 3 months, 6 months, 2.81+/-0.95 vs. 3.84+/-0.84 microg/ml (p<0.01), 4.61+/-1.15 mug/ml (p<0.001)). Furthermore, hyperlipidemic diabetics exhibited significant decreases in sE-selectin and sL-selectin levels after 6 months of pitavastatin treatment (sE-selectin, before vs. 6 months, 74+/-21 vs. 51+/-10 ng/ml, p<0.05; sL-selectin, before vs. 6 months, 896+/-141 vs. 814+/-129 ng/ml, p<0.05). In addition, adiponectin showed significant correlation with sE-selectin and sL-selectin in diabetic hyperlipidemia. However, MCP-1, RANTES and sCD40L did not exhibit any differences before or after pitavastatin administration. These results suggest that pitavastatin possesses an adiponectin-dependent anti-atherosclerotic effect in hyperlipidemic patients with type 2 diabetes in addition to its lowering effects on total cholesterol and LDL-C.
Thrombosis Research 01/2008; 122(1):39-45. DOI:10.1016/j.thromres.2007.08.013 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Some factors play pathogenic roles in the development of restenosis after percutaneous coronary intervention (PCI). We measured and compared the ratio of elevated levels of monocytic chemotactic peptide-1 (MCP-1), regulated on activation normally T-cell expressed and secreted (RANTES), soluble (s) P-selectin, sE-selectin and adiponectin after PCI.
Plasma levels of chemokines and soluble markers were measured before and 30 days after PCI in 96 patients (69 males and 27 females, aged 63 +/- 9 years) who underwent PCI and who had repeated angiograms at a 6-month follow-up. In addition, we carried out the basic study of the tissue factor expression on monocytic cell line (THP-1) by MCP-1.
Restenosis occurred in 33 (34.4%) patients. A significant and time-dependent increase in MCP-1 was observed in the restenosis group. However, there were no significant differences in RANTES, sP-selectin, and sE-selectin levels with or without restenosis. Adiponectin levels in patients with coronary artery disease were significantly lower than levels in normal controls. However, adiponectin levels were no different at baseline between patients with or without restenosis. MCP-1 did not induce the expression of tissue factor on THP-1. However, the recombinant sCD40 ligand-induced expression of tissue factor on THP-1 was enhanced by the addition of MCP-1.
These findings suggest that restenosis development after PCI in patients with coronary artery disease may involve the participation of MCP-1 after PCI, and adiponectin incompletely prevent this MCP-1-dependent restenosis.
Journal of Thrombosis and Thrombolysis 01/2008; 24(3):267-73. DOI:10.1007/s11239-007-0042-8 · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study used a small-sized collagen bead column system to investigate platelet functions under high shear stress in 28 patients with effort angina and 15 healthy controls. Soluble P-selectin and soluble L-selectin were also evaluated. Patients underwent stent insertion, followed by treatment with aspirin (100 mg/day) and ticlopidine (200 mg/day). High-shear-dependent platelet function was measured using small-sized collagen beads. The retention rate of platelets from patients with angina was higher than that in healthy controls (10.9% +/- 3.9% versus 5.6% +/- 1.7%, P < .01). Soluble P-selectin and soluble L-selectin levels of patients with angina significantly increased after passage through the columns. Levels of soluble P-selectin and L-selectin in healthy controls did not exhibit significant changes with passage through the columns. These results suggested that high shear stress caused abnormal activation of leukocytes or adhesive proteins in patients with effort angina, and ticlopidine failed to suppress hyperaggregability of platelets in these patients.
[Show abstract][Hide abstract] ABSTRACT: Our objective was to examine the influence of leg muscle weakness and body mass index (BMI) on ultrasonography (US) of the knee joint in middle-aged women. US and measurements of leg muscle strength and BMI were performed at the beginning of the study and after 6 months. Subjects with US abnormalities at the first examination were excluded from the study. Muscle strength and BMI were compared between subjects with normal US findings at the beginning of the study and after 6 months (N) and those in whom initially normal US findings became abnormal after 6 months (A). Analysis was performed for 20 knees with a mean age of 52.9 years old. In Group N, there were no significant changes in muscle strength and BMI between the initial results and those after 6 months. Significant changes in muscle strength occurred in Group A, but there was no significant change in BMI. There were significant differences between Groups N and A in the changes after 6 months; however, there was no significant difference in the change in BMI between the two groups. We conclude that abnormal knee joint findings in US of the knee are associated with leg muscle weakness in middle-aged women.
[Show abstract][Hide abstract] ABSTRACT: We investigated the mechanism of exercise-induced late cardioprotection against ischemia-reperfusion (I/R) injury. C57BL/6 mice received treadmill exercise (60 min/day) for 7 days at a work rate of 60-70% maximal oxygen uptake. Exercise transiently increased oxidative stress and activated endothelial isoform of nitric oxide synthase (eNOS) during exercise and increased expression of inducible isoform of NOS (iNOS) in the heart after 7 days of exercise. The mice were subjected to regional ischemia by 30 min of occlusion of the left coronary artery, followed by 2 h of reperfusion. Infarct size was significantly smaller in the exercised mice. Ablation of cardiac sympathetic nerve by topical application of phenol abolished oxidative stress, activation of eNOS, upregulation of iNOS, and cardioprotection mediated by exercise. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine during exercise also inhibited activation of eNOS, upregulation of iNOS, and cardioprotection. In eNOS(-/-) mice, exercise-induced oxidative stress was conserved, but upregulation of iNOS and cardioprotection was lost. Exercise did not confer cardioprotection when the iNOS selective inhibitor 1400W was administered just before coronary artery occlusion or when iNOS(-/-) mice were employed. These results suggest that exercise stimulates cardiac sympathetic nerves that provoke redox-sensitive activation of eNOS, leading to upregulation of iNOS, which acts as a mediator of late cardioprotection against I/R injury.
[Show abstract][Hide abstract] ABSTRACT: Inflammation plays a pathogenic role in the development of restenosis after percutaneous coronary intervention (PCI). We measured and compared the ratio of elevated levels of regulated on activation normally T-cell expressed and secreted (RANTES), monocytic chemotactic peptide-1 (MCP-1), soluble (s) P-selectin and sL-selectin after PCI. Plasma levels of chemokines and soluble markers were measured before, 1, 3 and 7 days after PCI in 52 patients (43 males and nine females, aged 63 +/- 10 years) who underwent PCI and who had repeated angiograms at a 6-month follow-up. Restenosis occurred in 16 (31%) patients. A significant and time-dependent increase in sL-selectin was observed in the restenosis group. However, there were no significant differences in MCP-1 levels with or without restenosis. sP-selectin levels in the restenosis group exhibited a transient elevation at 3 days after PCI. RANTES levels were no different at baseline between patients with or without restenosis. However, a significant and time-dependent decrease in RANTES levels were observed in the non-restenosis group, and patients with restenosis compared with patients without restenosis had a statistically significant ratio of elevated levels of RANTES. These findings suggest that restenosis development after PCI in patients with effort angina pectoris may involve leukocyte activation at an early period after PCI. In addition, platelet-derived chemokine RANTES may be a sign of restenosis after PCI in patients with stable angina pectoris.
[Show abstract][Hide abstract] ABSTRACT: It has been demonstrated that the haemoglobin (Hb) level is associated with the prognosis of congestive heart failure (CHF). Correction of anaemia has improved CHF outcomes even in patients without anaemia. Lower Hb level may play a more important role in left ventricular (LV) dysfunction than previously recognized. This study aimed to evaluate the association of Hb level with plasma brain natriuretic peptide (BNP) level as a marker of LV function adjusted for known determinants of BNP.
Association of Hb level with plasma BNP level was studied in 279 outpatients of cardiology (mean age 61 +/- 16, 54% men) using multivariate regression analysis. Mean Hb level was 13.7 +/- 1.5 g/dl and 14% of patients had anaemia. Median BNP level was 28 pg/ml (range < 4 to 580 pg/ml). In total subjects, the multivariate model adjusted for age, sex, history of CHF, atrial fibrillation, serum creatinine level, LV wall motion abnormality, end-diastolic LV dimension, LV mass index, and cardiovascular risk factors showed that a lower Hb level was significantly associated with higher BNP level (p = 0.0243). In "normal" subjects who did not have a history of CHF, atrial fibrillation, LV wall motion abnormality, LV dilatation, valvular abnormality, or LV hypertrophy, a lower Hb level was significantly associated with a higher BNP level (p = 0.0012) after adjustment for age, sex, serum creatinine level, and cardiovascular risk factors.
Lower Hb levels are associated with higher plasma BNP levels independent of age, sex, serum creatinine level, LV wall motion abnormality, LV hypertrophy, history of CHF, atrial fibrillation, and cardiovascular risk factors.
[Show abstract][Hide abstract] ABSTRACT: We measured and compared the levels of plasma soluble (s) P-selectin, sCD40L, platelet-derived microparticles (PDMP), monocyte-derived microparticles (MDMP), and anti-oxidized LDL antibody, to obtain a better understanding of their potential contribution to vascular complications in acute coronary syndrome (ACS). The concentrations of sP-selectin, sCD40L, PDMP, and MDMP in ACS patients were significantly higher than those in normal controls and patients with stable angina. When levels of these markers were compared with differences in concentration of anti-oxidized LDL antibody, all markers were significantly higher in ACS patients with a high level of anti-oxidized LDL antibody. Next, a monocytic cell line (THP-1) was incubated with high shear stress-induced platelet aggregates and PDMP. After incubation,THP-1 cells generated tissue factor-expressing MDMPs. This finding was particularly significant in the presence of oxidized LDL. These findings suggest that elevated levels of MDMPs may be a sign of atherosclerotic development in ACS patients, particularly those who exhibit anti-oxidized LDL antibodies.
Thrombosis and Haemostasis 02/2004; 91(1):146-54. DOI:10.1267/THRO04010146 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: EN-RAGE is a ligand for the receptor for advanced glycation end products (RAGE) and may be involved in the development of diabetic macro- and micro-angiopathy. This study is designed to investigate the regulation of EN-RAGE gene expression in human macrophages. The amounts of EN-RAGE mRNA were measured in cultured human THP-1 macrophages after treatment with various stimuli known to modulate atherosclerosis. First, interleukin-6 (IL-6), a proinflammatory cytokine, increased the level of EN-RAGE mRNA by approximately 2-fold in a time- and a dose-dependent fashion. EN-RAGE protein was detected in the cultured medium and increased significantly by the addition of IL-6. The induction was abolished by pretreatment with the JAK kinase inhibitor and cycloheximide, but not with the MEK kinase inhibitor. Second, pioglitazone (PIO), a thiazolidinedione, decreased the level of EN-RAGE mRNA by approximately 25% of the basal in a time- and a dose-dependent fashion. Pioglitazone also inhibited the induction of EN-RAGE mRNA by IL-6. These results indicate the production of EN-RAGE is induced by IL-6 through de novo protein synthesis via the JAK-STAT kinase pathway and inhibited by the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) in human macrophages.
[Show abstract][Hide abstract] ABSTRACT: The levels of platelet-derived microparticles (PDMPs), platelet activation markers (P-selectin, CD63, and PAC-1 on activated platelets), and C-C chemokines (monocyte chemotactic peptide [MCP]-1 and regulated on activation normally T-cell expressed and secreted [RANTES] were measured and compared in patients with acute myocardial infarction (AMI) or stable pectoris angina. These substances are thought to paricipate in the development of complications in patients with AMI. The percentage binding of anti-P-selectin, CD63, and PAC-1 antibody to platelets, and the levels of PDMPs (per 10(4) platelets) were higher in the patients with AMI than in those with stable pectoris angina (P-selectin, 23.1% +/- 2.1% vs. 10.3% +/- 1.2%, p < 0.001; CD63, 24.6% +/- 3.3% vs. 11.2% +/- 3.1%, p < 0.01; PAC-1, 14.1% +/- 1.7% vs. 9.3% +/- 2.1%, p < 0.05; PDMPs, 613 +/- 71 vs. 413 +/- 55, p < 0.01). There were no differences in platelet levels of GPIIb/IIIa and GPIb between groups. Levels of MCP-1 and RANTES were higher in the patients with AMI than in patients with stable pectoris angina (MCP-1, 430 +/- 35 vs. 265 +/- 23, p<0.01; RANTES, 175 +/- 32 vs. 88 +/- 29, p<0.001). The effects of percutaneous transluminal coronary angioplasty (PTCA) on the levels of these agents in patients with AMI were studied. Platelet activation markers were significantly decreased in patients with AMI after PTCA. RANTES level was also significantly decreased after treatment, but MCP-1 level was not changed. In addition, this tendency was clearer in STENT patients. These findings suggest that in patients with AMI PTCA, particularly STENT, may prevent the development of complications in which activated platelet and RANTES participate.
[Show abstract][Hide abstract] ABSTRACT: Background: We investigated the effects of a platelet-activating-factor antagonist TCV-309, an antagonist of metabolites of ischemia, on arrhythmias and functional recovery during in-situ reperfusion in dogs.
Methods: Open-chest anesthetized dogs were subjected to ligation of the left anterior coronary artery. Ischemia was maintained for 20 min after which reperfusion was allowed. A cardiac surface ECG was recorded continuously with the II limb lead. Monophasic action potential, left ventricular segment shortening measured by sonomicrometer, and left ventricular pressure were recorded simultaneously under atrial pacing (group A, n =14). In a second group of dogs, TCV-309 (1 mg/kg) was administered before coronary artery occlusion (group B, n = 12). The hearts were constantly paced through the right atrium at 120beats/min throughout all experiments. Measurements were continuously obtained from before drug administration to 30 min after reperfusion.
Results: The 90% repolarization time of monophasic action potentials in group B revealed significant recovery compared with group A until the fifth minute after reperfusion (P<0.02). Reduction of severe ventricular arrhythmias was observed during reperfusion in group B (P<0.05). The percentage segment shortening and left ventricular pressure did not differ significantly between the groups.
Conclusion: The platelet-activating-factor antagonist had beneficial effects on arrhythmias but not on functional recovery during reperfusion after brief coronary artery occlusion in situ in dogs.
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