Eiichi Geshi

Showa University, Shinagawa, Tōkyō, Japan

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Publications (78)100.07 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: Among the many factors related to bone marrow cell mobilization, local inflammation induced by cytokines may drive bone marrow cells to the vascular wall, resulting in a thickened neointima. However, the relationship between inflammatory reactions and bone marrow cell invasion has not yet been fully clarified. Methods: We inserted a large wire into the femoral artery in male balb/c(WT), interleukin (IL)-6-knockout(KO) and bone marrow-transplanted(BMT) mice that had received bone marrow cells from KO mice. Immunohistochemistry was performed to evaluate the degree of intimal hyperplasia and inflammation following vascular injury. Results: Three days after the vascular injury, the number of CD34/Sca-1-positive cells in the blood was higher in the KO mice. The numbers of apoptotic cells in the neointima was lower in the KO and BMT mice at two hours after injury. The morphometric analysis performed at one and four weeks after injury showed that the intima/media ratio was significantly lower in the KO and BMT mice, while CD34-positive cells were much more frequent in the WT mice. Furthermore, re-endothelialization appeared earlier in the KO and BMT mice than in the WT mice. No differences in the levels of vascular endothelial growth factor or hepatocyte growth factor were observed in the mice sera between the WT, KO and BMT mice after injury. The in vitro culture of bone marrow cells showed more differentiated smooth muscle-like cells in the WT mice than in the KO mice. Conclusions: IL-6 is involved in neointimal formation following vascular injury, possibly acting through inflammatory effects inducing the production of bone marrow cells.
    Journal of atherosclerosis and thrombosis 12/2013; · 2.93 Impact Factor
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    ABSTRACT: Nocturnal and early morning hypertension are both significant risk factors for cardiovascular events. It remains unclear whether anxiety disorder affects nocturnal blood pressure (BP), early morning BP, or BP pattern in hypertensive patients. One hundred and twenty consecutive hypertensive outpatients (77 men and 43 women; mean age, 66±11 years) were divided into 2 groups based on Hospital Anxiety and Depression Scale (HADS) score: a control group (n=78; HADS ≤10) and an anxiety group (42 patients; HADS ≥11). Nocturnal BP, early morning BP, morning BP surge (defined as BP rise ≥50 mmHg), and BP pattern (extreme-dipper/dipper/non-dipper/riser) were measured on ambulatory BP monitoring. Clinical characteristics and BP were also evaluated at physician check-up. There was no significant difference between the 2 groups for BP check-up, but nocturnal and early morning BP were significantly higher in the anxiety group (142±16 mmHg and 152±21 mmHg) than in the control group (126±14 mmHg and 141±18 mmHg). With regard to patients with morning BP surge, nocturnal and early morning BP were also significantly higher in the anxiety group. The relative risk of existing anxiety disorders in riser-type hypertension was 4.48-fold higher (95% confidence interval: 1.58-12.74; P<0.005) than in dipper-type hypertension. Anxiety disorder is associated with nocturnal and early morning hypertension, and may be a risk factor for cardiovascular events.
    Circulation Journal 04/2012; 76(7):1670-7. · 3.58 Impact Factor
  • Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2011; 57(14).
  • E Geshi, S Irie, T Katagiri
    Journal of Hypertension - J HYPERTENSION. 01/2010; 28.
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    ABSTRACT: Angiotensin-converting enzyme inhibitors (ACEI) reduce the mortality in the chronic phase of myocardial infarction (MI), and similar effects of angiotensin receptor blockers (ARB) have been reported. However, these effects of ARB have not yet been established in Japanese patients. A multicenter randomized study was designed for the present study to examine the effect of valsartan as compared to that of ACEI against left ventricular dysfunction after MI. Patients with acute MI were randomly allocated to either the valsartan group (n=120; mean age 63 +/-1.0) or the ACEI group (n=121; mean age 62.9 +/-1.0) and followed up until 6 months. Left ventriculography was performed during hospital admission and at 6 months. The blood pressure was similar in the 2 groups throughout the study. The incidences of cardiovascular events and target vessel revascularization were similar, although that of adverse events was significantly higher in the ACEI (12.4%) than in the valsartan group (3.3%; P<0.05). There were no differences in left ventricular ejection fraction and left ventricular end-diastolic volume index between the groups. Valsartan exhibits similar efficacy effective to that of ACEI in preventing left ventricular dysfunction in Japanese patients with acute MI, and is, in addition, better tolerated than ACEI.
    Circulation Journal 04/2009; 73(5):918-24. · 3.58 Impact Factor
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    ABSTRACT: Recent evidence suggests that small dense low-density lipoprotein (sd-LDL) particles are more atherogenic than large-LDL in spite of their lower cholesterol content. This study aimed to determine whether sd-LDL-cholesterol (sd-LDL-C) is superior to LDL-C as a biomarker of coronary heart disease (CHD). LDL particle size determined by gradient gel electrophoresis and sd-LDL-C concentrations quantified by heparin-magnesium precipitation were compared between 482 stable CHD patients and 389 non-diabetic subjects without CHD who were not receiving any lipid-lowering drugs. Both male and female CHD patients had significantly smaller LDL particles and lower large-LDL-C concentrations (estimated by subtracting the sd-LDL-C concentration from the LDL-C concentration), and significantly higher sd-LDL-C concentrations than the control subjects. LDL-C concentrations were modestly higher and sd-LDL-C concentrations were significantly higher in 258 patients with angiographically documented severe CHD than in the patients with mild CHD irrespective of treatment by LDL-lowering drugs and history of myocardial infarction and/or coronary revascularization. Large-LDL-C concentrations, in contrast, were similar between the two groups. Multivariate logistic regression analysis revealed that sd-LDL-C levels were significantly associated with severe CHD independently of LDL-C. sd-LDL-C levels are more powerful than LDL-C levels for the determination of severe stable CHD.
    Journal of atherosclerosis and thrombosis 11/2008; 15(5):250-60. · 2.93 Impact Factor
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    ABSTRACT: Granulocyte-colony stimulating factor (G-CSF) affects injured arteries through early endothelialization. Some reports, however, have cautioned that the restenosis rate may increase after G-CSF injection. In the present study, high-dose G-CSF was administered to mice with vascular injury to clarify its effect. Mice were received daily subcutaneous injections of saline or a high dose (300 microg/kg) of G-CSF for 5 days after vascular injury. In the FACS analysis, CD34-/Sca-1-positive progenitor cells were more abundant in the G-CSF group (p<0.05). Neointimal hyperplasia was more evident in the G-CSF group at 1 week (p<0.05), whereas at 4 weeks it was more evident in the control group (p<0.01). TUNEL-positive cells in the arterial wall were more numerous in the G-CSF group at day 1 (p<0.01). CD34-positive cells were observed in the G-CSF group at 1 week. Re-endothelialization appeared earlier in the G-CSF group (at 4 weeks; p<0.01). An increased number of 1A4-positive smooth muscle cells were found in bone marrow cell culture treated with G-CSF. High-dose G-CSF induced neointimal proliferation through excessive inflammation and bone marrow cell mobilization in the early phase. In the late phase, however, it induced early re-endothelialization and thereby inhibited neointimal hyperplasia.
    Circulation Journal 10/2008; 72(11):1885-93. · 3.58 Impact Factor
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    ABSTRACT: Recent studies have suggested that granulocyte colony-stimulating factor (G-CSF) may improve cardiac function after acute myocardial infarction (AMI) by accelerating angiogenesis or cardiomyogenesis, but negative results and side effect of G-CSF have also been reported. However, no previous studies have used large animal models of ischemia/reperfusion to investigate the effect and side effect of G-CSF after AMI. The diagonal branch of the left anterior descending coronary artery of swine was balloon-occluded for 1 h and then reperfused. The animals of the G-CSF group were injected with G-CSF subcutaneously (5.0 microg/kg/day) for 6 days after MI and then sacrificed after 4 weeks. The control group received the same volume of saline. There were no differences between the groups in the rate of thrombotic obstruction or progression of stenosis lesion in coronary angiography. The ejection fraction and end-diastolic volume in the G-CSF group were not significantly improved over the control values. The fibrotic area was significantly smaller in the G-CSF group than in the controls (P<0.05), and the numbers of vessels counted in anti-von Willebrand factor and anti-alpha-smooth muscle actin-stained sections were significantly larger (P<0.005 and P<0.05, respectively). The expression of collagen III mRNA was significantly lower in the G-CSF group than in the control in the infarct (P<0.0005) and border areas (P<0.005), and TGF-beta mRNA was significantly lower in the G-CSF group in the border area (P<0.05). G-CSF could modify the healing process after AMI by accelerating angiogenesis in a swine ischemia/reperfusion model. At the dose administered, however, G-CSF did not seem to improve the global cardiac function.
    International journal of cardiology 07/2008; 127(2):166-73. · 6.18 Impact Factor
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    ABSTRACT: Carboxylesterase 1 (CES1) is involved in metabolic activation of a variety of prodrugs into active derivatives and plays an important role in pharmacokinetics. We previously reported that a single nucleotide polymorphism (SNP), -816A/C of the CES1A2 gene associates with the responsiveness to an angiotensin-converting enzyme (ACE) inhibitor, imidapril, whose activity is achieved by CES1. To identify relevant functional polymorphisms, we re-sequenced the CES1A2 promoter region ( approximately 1kb) in 100 Japanese hypertensive patients. Altogether 10 SNPs and one insertion/deletion (I/D) were identified, among which seven SNPs and one I/D residing between -62 and -32 were in almost complete linkage disequilibrium (D'=1.00, r2=0.97). They consisted a minor and a major haplotype, the allele frequencies of which were 22% and 74%, respectively. The minor haplotype possessed two putative Sp1 binding sites while the major haplotype did not have any Sp1 binding site. The minor haplotype had a higher transcription and Sp1 binding activities than the major haplotype, invitro. The original -816A/C was in high linkage disequilibrium with these haplotypes (D'=0.92, r2=0.85), and well agreed with the efficacy of imidapril medication. These results suggest that the Sp1 binding site variation in the CES1A2 promoter is functional, and are good candidates for the pharmacogenetic studies of CES1-activated drugs.
    Biochemical and Biophysical Research Communications 06/2008; 369(3):939-42. · 2.28 Impact Factor
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    ABSTRACT: Low-density lipoprotein (LDL) particles are heterogeneous with respect to their size, density, and lipid composition, and the size of LDL particles is chiefly determined by their lipid contents. Small dense LDL particles have been suggested to be highly atherogenic compared to large buoyant LDL. Our case-control studies have shown that the LDL particle size determined by gradient gel electrophoresis was remarkably smaller in patients with coronary heart disease (CHD), irrespective of the presence of diabetes and the differences in clinical situation and severity of CHD. In addition, small dense LDL-cholesterol concentration evaluated by heparin magnesium precipitation was significantly higher in severe stable CHD and acute coronary syndrome compared with non-CHD subjects and patients with mild CHD, while large LDL-cholesterol estimated by subtracting the small dense LDL-cholesterol concentration from the LDL-cholesterol concentration, were somewhat lower in stable CHD compared with healthy subjects. Further more, reduced LDL particle size and elevated small dense LDL-cholesterol levels were significantly associated with metabolic dyslipidemia in Metabolic syndrome. These suggest that the predominance of small dense LDL and high levels of small dense LDL-cholesterol are very promising risk marker for CHD.
    12/2007: pages 115-123;
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    ABSTRACT: Recent studies suggest that neointimal cells in atherosclerotic lesions are partly derived from bone marrow (BM) cells. However, studies with large animal models have not yet clarified how BM cells contribute to neointimal formation in restenotic lesions. We examined the expression of CD34, a hematopoietic stem cell marker, in the neointima after coronary stent implantation in porcine. Pigs underwent balloon injury in the coronary arteries followed by stent implantation. The arteries were harvested at 3, 7, and 28 days after the stenting. The samples were used for immunohistochemistry for CD34, smooth muscle embryo (SMemb), alpha-smooth muscle cell actin (alpha-SMA), macrophage, c-kit, and AC133 antibodies. In morphometric analysis, each layer of vascular wall was calculated in the sections. At 3 days, the expressions of CD34 and SMemb were minimal, and many macrophages were seen around the stent struts. At 7 days, co-expression of CD34 and SMemb was observed around the struts, and 11.5% of the neointimal cells were stained by CD34. In addition, c-kit positive cells and AC133 positive cells are detected in neointimal area. At 28 days, the neointima had thickened and expressed alpha-SMA rather than SMemb, and a few CD34-positive cells were detected. In morphometric analysis, luminal area/total vascular area was significantly smaller and intimal area/total vascular area was significantly bigger in 7 and 28 days than in the day of implantation. BM cells of possibly hematopoietic origin partially contributed to neointimal formation after coronary stent implantation in a large animal model.
    International journal of cardiology 10/2007; 121(1):44-52. · 6.18 Impact Factor
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    ABSTRACT: Tumor necrosis factor (TNF)-alpha is linked to the pathogenesis of cardiovascular diseases, but how it affects myocardial infarction (MI), so the present study examined the effects of TNF-alpha and the involvement of intercellular adhesion molecule (ICAM)-1 on MI. Left coronary arteries of C57BL/6 wild type (WT) and TNF-alpha knockout (KO) mice were ligated and the mice were killed 1, 3, and 7 days later. Fractional shortening on echocardiography of the KO mice was significantly higher than that of the WT mice from day 1 to 7 (p<0.01). The ICAM-1 mRNA in the infarcted area of the KO mice was significantly lower than that of the WT from day 1 (p<0.01) to 7. In immunohistochemistry, the expression of ICAM-1 was weaker in the KO than in the WT mice. The number of neutrophils in the KO mice peaked at day 1, but even this peak level failed to reach the levels in the infarcted (p<0.01) and peri-infarcted areas (p<0.05) in the WT. The number of macrophages in the KO mice peaked at day 7, but this peak level failed to reach the levels in the infarcted (p<0.01) and peri-infarcted areas (p<0.05) in the WT. In a permanent occlusion model of MI TNF-alpha decreased cardiac function and ameliorated myocardial remodeling through the induction of ICAM-1.
    Circulation Journal 01/2007; 70(12):1635-42. · 3.58 Impact Factor
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    ABSTRACT: Background: Recent studies suggest that bone marrow cells contribute to neointimal formation after vascular injury. However, the relationship between the inflammatory reactions and bone marrow cell invasion has not been clarified. Method and Results: We insert a large wire (0.38 mm in a diameter) into the femoral arteries of 6–8 week-old male balb/c (WT) and TNF-α Knockout (KO) mice. In imunohistochmistry using CD34 at 1 week, positive cells possibly containing bone marrow derived cells, were hardly observed in KO, but some were observed in WT in neointima. At 4 weeks, CD45 positive cells were rarely seen, and α-smooth muscle actin positive cells were main component of thickened neointima in both groups. In morphometric analysis at 4 weeks after the injury, developed neointimal area was smaller in KO. Furthermore, re-endothelialization appeared earlier in KO than WT. Conclusion: TNF-α is involved in neointimal formation after vascular injury, possible through its inflammatory effects to induce bone marrow cells.
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    ABSTRACT: Exuberant smooth muscle cells hyperplasia is the major cause of postangioplasty restenosis. We suggested that circulating smooth muscle progenitor cells might contribute to lesion formation after vascular injury. We extensively investigated the cellular constituents during neointimal formation after mechanical injury. A large wire was inserted into the mouse femoral artery. At 2 hours, the injured artery remained dilated with a thin media containing very few cells. One week after the injury, CD45 positive hematopoietic cells accumulated at the luminal side. Those CD 45 positive cells gradually disappeared, whereas neointimal was formed with alpha smooth muscle actin positive cells. Bone marrow cells and peripheral mono-nuclear cells differentiated into alpha smooth muscle cells in the presence of PDGF and basic FGF. These results suggest that early accumulation of hematopoietic cells may play a role in the pathogenesis of smooth muscle cells hyperplasia under certain circumstances.
    12/2006: pages 67-74;
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    ABSTRACT: [Case Report] A 47-year-old man with Buerger’s disease was admitted with complaints of progressive ulcer of left planta pedis and resting pain of the left leg. The ulcer was not healed under medical therapy nor lumbar sympathetic ganglion block, and angioplasty or bypass surgery was not applicable. All his toes showed cyanotic and left third and fifth toes were gangrene, as well as ulcer in left planta pedis. Angiography showed arterial occlusion in the crus and formation of corkscrew like changes. Although ankle-brachial index was kept in almost normal range, transcutaneous oxygen pressure (TcO2) was decreased. Leg pain was not relieved with medication and he could not walk for pain due to his ulcer. We performed bone-marrow mononuclear cell implantation to his inferior limbs to achieve therapeutic angiogenesis. After aspirating the bone marrow (600 ml) from the ileum, the bone-marrow mononuclear cells were sorted. The separated cells were implanted into the ischemic legs by intramuscular injection. Reduction of leg pain was observed as early as 3 days, and completely disappeared at rest after 4 weeks. Improvement of TcO2 was observed at 1 week, and the ulcer of planta pedis was almost healed 4 weeks after the therapy. [Conclusion] Bone-marrow mononuclear cell implantation is very effective in patients with Buerger’s disease, even they have large severe ulcer.
    12/2006: pages 95-100;
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    ABSTRACT: [Background] Efficacy of autologous bone marrow-mononuclear cell (BM-MNC) implantation as therapeutic angiogenesis has been reported in patients with severe peripheral artery disease. In addition to containing CD34 positive-cells, sorted BM-MNCs contain an abundance of CD34-negative cells. No studies have yet elucidated which types of CD34-negative cells influence the clinical appearance in BM-MNC implantation. We investigated the correlations of morphologically classified cell types of sorted BM-MNCs with changes in the ankle brachial index (ABI) and transcutaneous oxygen pressure (TcO2). [Material and Methods] Seven patients with severe peripheral arterial disease who were not candidates for angioplasty or surgical operation underwent BM-MNC implantation. The sorted BM-MNCs using a cell separator were classified on the basis of May-Giemsa staining, and CD34-positive cells were counted. ABI and TcO2 were performed before and after BM-MNC implantation. [Results] Mean ABI (p<0.05) and mean TcO2 (p<0.005) from baseline to 4 weeks after the implantation were significantly increased. The numbers of total injected cells and CD34-positive cells were not correlated with Δ TcO2 from before to 4 weeks. Among the cell types analyzed, ΔTcO2 showed significant negative correlations with the percentage of mature neutrophils (p<0.01) and significant positive correlations with the percentage of erythroblasts (p<0.05). [Conclusions] Neutrophils could be an inverse regulator and erythroblasts could be a positive regulator in clinical BM-MNC implantation.
    12/2006: pages 57-65;
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    ABSTRACT: [Purpose] Recent studies have suggested that granulocyte colony-stimulating factor (G-CSF) may accelerate angiogenesis or cardio-myogenesis. No previous studies, however, have used large animal models to investigete how clinical doses of G-CSF affect cardiac function after acute myocardial infarction (AMI). [Methods] Diagonal branch of the left anterior descending coronary artery of domestic swine was balloon-occluded for 1-hour and then reperfused. The G-CSF group received a subcutaneous injection of G-CSF at a dose of 5.0/µg/kg/day for 6 days after MI. Left ventriculography was performed 4 weeks after Ml. The number of vessels in the infarcted area were calculated using sections stained by anti-α-smooth muscle actin (SMA) and anti-von Willebrand factor (vWF). Reverse transcription polymerase chain reactions for collagen I, collagen III, and transforming growth factor (TGF)-β were also examined. [Results] The G-CSF group showed a significantly higher ejection fraction and lower end-diastolic volume in left ventriculography. The numbers of α-SMA- and vWF-positive vessels in the G-CSF group were significantly larger. The expression of collagen III mRNA was significantly lower in the G-CSF group in the infarct and border areas. The expression of TGF-β mRNA was significantly lower in the G-CSF group in the border area. [Conclusions] The administration of clinical doses of G-CSF improved cardiac function after reperfusion in AMI. G-CSF confers its effects by accelerating angio-genesis and modifying the wound-healing process.
    12/2006: pages 101-109;
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    ABSTRACT: Although angiotensin-converting enzyme inhibitors (ACEIs) have been shown to reduce left ventricular remodeling after acute myocardial infarction (AMI), the effects of angiotensin receptor blockers have yet to be established. This study was conducted to examine the effects of candesartan on left ventricular remodeling after AMI. Consecutive AMI patients were assigned to a candesartan group or ACEI group after successful coronary intervention. The patients in the candesartan group (n = 77, mean age, 62.8 +/- 1.3) received candesartan and the patients in the ACEI group (n = 80, mean age, 63.3 +/- 1.2) received lisinopril, enalapril, or trandolapril. Four mg was the most frequent dose in the candesartan group at 6 months. Lisinopril, enalapril, and trandolapril were administered to 52%, 27%, and 21% of the patients in the ACEI group, respectively. No significant differences in the incidences of cardiac death, nonfatal MI, or hospitalization for heart failure (P = NS) were found between the groups. The candesartan group exhibited a somewhat higher percent increase in left ventricular ejection fraction and significantly lower percent increases in left ventricular end-diastolic volume index and left ventricular end-systolic volume index compared to the ACEI group (P < 0.05, P < 0.05, respectively). Candesartan is more effective than ACEI in preventing left ventricular remodeling after AMI.
    International Heart Journal 09/2006; 47(5):715-25. · 1.23 Impact Factor
  • European Journal of Clinical Investigation 02/2006; 36(1):65-6. · 3.37 Impact Factor
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    ABSTRACT: Constrictive remodeling is thought to be more important than neointimal formation in coronary restenosis after balloon angioplasty. The inhibition of Rho-kinase prevents neointimal proliferation, but now this inhibition that affects constrictive remodeling remains unknown. To explore this issue further, we investigated whether a specific Rho-kinase inhibitor, Y-27632, could suppress restenosis after coronary balloon angioplasty in a porcine model. Balloon angioplasty with local administration of Y-27632 (Y group) or vehicle (C group) was performed at 2 and 3 weeks after overstretch injury in a porcine coronary artery. Quantitative coronary angiography (QCA) and quantitative coronary ultrasound (QCU) were performed to assess the coronary lesion segment. A morphometrical analysis was performed in a histological study. Proliferative cells and p27(Kip1)-positive cells were evaluated in the arterial wall using immunohistochemistry. QCA and QCU demonstrated that the minimal lumen diameter and minimal lumen area were greater, and % stenosis was less in the Y group than in the C group. The QCU analysis also revealed a significant inhibition in the increase of the intimal area and a prevention of constrictive remodeling by Y-27632. In the histological study, the intimal, adventitial and collagen areas were significantly smaller in the Y group than in the C group. The Y group also exhibited significantly less proliferative activity and a significantly higher percentage of cells expressing p27(Kip1) in the arterial wall. Local delivery of Y-27632 suppressed constrictive remodeling as well as neointimal formation after coronary balloon angioplasty in pigs.
    International Journal of Cardiology 02/2006; 106(1):103-10. · 6.18 Impact Factor