Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
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Acute Disease↗
Biomedical subjects
Kimihiro Komori
Publications and source records attributed to Kimihiro Komori.
Combination of in vivo angiopoietin-1 gene transfer and autologous bone marrow cell implantation for functional therapeutic angiogenesis.
OBJECTIVE: Autologous bone marrow mononuclear cell (BM-MNC) implantation into ischemic tissues promotes angiogenesis, but a large amount of marrow aspiration is required, which is a major clinical limitation. Angiopoietin-1 (Ang-1) is requisite for vascular maturation during angiogenesis. We examined the impacts of combinatorial Ang-1 gene transfer and low-dose autologous BM-MNC implantation on therapeutic angiogenesis in a rabbit model of hind limb ischemia. METHODS AND RESULTS: Rabbits were divided into 4 groups: phosphate-buffered saline (control), 500 microg Ang-1 plasmid (Ang-1), 1 x 10(6) autologous BM-MNCs (BMC), and Ang-1 plasmid plus BM-MNCs (combination). The Ang-1 group had a greater angiographic score and capillary density compared with the control (P<0.05), but the Ang-1 gene therapy alone did not improve transcutaneous oxygen pressure (TcO2) and skin ulcer score. However, the combination group showed a significant improvement in not only angiographic score and capillary density (P<0.05) but also TcO2 (P<0.05) and skin ulcer score. These efficacies were greater in the combination group compared with the BMC group. CONCLUSIONS: This Ang-1 gene and BM-MNC combination therapy enhances not only quantitative but also qualitative angiogenesis in ischemic tissues. Moreover, the combination therapy will enable a reduction in the amount of BM aspiration required for significant therapeutic angiogenesis.
Angiography↗
Bi-phasic activation of eNOS in response to uni-axial cyclic stretch is mediated by differential mechanisms in BAECs.
We investigated the signaling mechanism of stretch-induced NO (Nitric oxide) production in bovine arterial endothelial cells (BAECs). BAECs cultured on an elastic silicone chamber coated with fibronectin were subjected to uni-axial cyclic stretch (1 Hz, 20% in length) and the amount of produced NO was measured by a cGMP assay. NO production increased in a bi-phasic manner and peaked at 5 min and 20 min after stretch onset. Correspondingly, the activities of endothelial nitric oxide synthase (eNOS) and Akt/PKB (measured by phosphorylation at serine 1,177 and serine 473, respectively), showed two peaks over time. Application of Gd(3+), a potent SA channel blocker, and depletion of external Ca(2+) exclusively inhibited the first peaks of eNOS and Akt activity, but exerted little effect on the second peak. On the other hand, the PI3K inhibitors, Wortmannin, LY294002, almost completely inhibited the second peak but not the first. These results suggest that up-regulation of eNOS in response to cyclic stretch was mediated by two distinct pathways, [Ca(2+)](i) increases via the SA channel in an early phase (partially Akt/PKB), and PI3K-Akt/PKB pathways in a late phase.
Androstadienes↗
Current pathological and clinical aspects of Buerger's disease in Japan.
Since Buerger's disease was first described by Leo Buerger in 1908, many authors have discussed whether it indeed exists and, if so, is a definite clinical entity. Today, Buerger's disease is accepted as a definite vascular disease with a typical clinical picture, natural history, and histopathology; however, the diagnosis of Buerger's disease has been controversial, and the etiology of this vascular occlusive disease has remained unknown because many authors in different countries have their own criteria. Besides, patients with this disease have decreased in number even in Japan, while there has been no change in the number of arteriosclerosis obliterans patients. Currently, only one or two new patients per year are encountered at our outpatient clinic. The purpose of this review is to examine the current epidemiological, pathological, and clinical aspects of Buerger's disease in Japan based on the 222 patient files of our department between 1980 and 2000 and to discuss the pathogenesis, clinical presentation, and various treatment modalities.
Adolescent↗
Long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits.
BACKGROUND: Rho kinase plays an important role in vascular smooth muscle cell (VSMC) contraction and other cellular functions, such as proliferation, migration, and apoptosis. Recent studies have demonstrated that long-term inhibition of Rho kinase suppresses coronary artery spasm and vascular lesion formation after arterial injury. In the cardiovascular surgery field, intimal thickening in vein grafts is the major cause of late graft failure, for which no effective treatment has yet been developed. In this study, we examined whether long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits. METHODS: Male rabbits were randomly divided into two groups and received normal chow (control group) or a special chow containing 0.09% fasudil (fasudil group). After oral administration, fasudil is metabolized to a specific Rho kinase inhibitor, hydroxyfasudil. Each group underwent reversed autologous vein graft surgery with the internal jugular vein into the left common carotid artery. At 1, 2, and 4 weeks after the operation, we examined the extent of intimal thickening of the graft and VSMC proliferation and apoptosis. RESULTS: The intimal thickening was significantly suppressed in the fasudil group compared with the control group at 2 and 4 weeks after the operation. In the fasudil group, VSMC proliferation was suppressed at 1 and 2 weeks after the operation, whereas VSMC apoptosis was enhanced at 2 weeks after the procedure. CONCLUSIONS: These results indicate that Rho kinase is substantially involved in the pathogenesis of intimal thickening of vein grafts and that it is an important therapeutic target for the prevention of graft failure.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Controlled release of small interfering RNA targeting midkine attenuates intimal hyperplasia in vein grafts.
OBJECTIVE: Intimal hyperplasia is a major obstacle to patency after vein grafting. Despite of a diverse array of trials to prevent it, a satisfactory therapeutic strategy for clinical use has not been established. However, sufficient inhibition of early stages of intimal hyperplasia may prevent this long-term progressive disease. Midkine (MK) is a heparin-binding growth factor that was originally discovered as the product of a retinoic acid-responsive gene. We previously demonstrated that MK-deficient mice exhibit a striking reduction of neointima formation in a restenosis model, which is reversed on systemic MK administration. In this study, we evaluated a strategy of using small interfering RNA (siRNA) targeting MK as a therapy for vein graft failure. METHODS: We first made a highly effective siRNA to rabbit MK. Jugular vein-to-carotid artery interposition vein grafts, which are applied to a low flow condition, were made in Japanese white rabbits. Small interfering RNA mixed with atelocollagen was administrated to the external wall of grafted veins. Cy3-conjugated stabilized siRNA was used to confirm its stability and successful transfer into the vein graft wall. Neointimal hyperplasia was evaluated 4 weeks after the operation. The proliferation index and leukocyte infiltration were determined. RESULTS: MK expression was induced and reached the maximum level 7 days after operation. Fluorescence of Cy3-labeled siRNA could be detected in the graft wall even 7 days after operation. Knockdown of the gradually increasing expression was achieved by perivascular application of siRNA using atelocollagen. The intima-media ratio and the intima thickness at 28 days after grafting were both reduced >90% by this treatment compared with controls. This phenomenon was preceded by significant reductions of inflammatory cell recruitment to the vessel walls and subsequent cell proliferation in MK siRNA-treated grafts. CONCLUSIONS: These results suggest that midkine is a candidate molecular target for preventing vein graft failure. Furthermore, for clinical applications of siRNA, a single intraoperative atelocollagen-based nonviral delivery method could be a reliable approach to achieve maximal function of siRNA in vivo. This strategy may be a useful and practical form of gene therapy against human vein graft failure.
Animals↗
Clinical protocol for angiogenesis by intramyocardial injection of autologous bone marrow mononuclear cells in patients with severe coronary artery disease: TACT-NAGOYA-HEART.
BACKGROUND: Despite recent improvements in the treatments of coronary artery disease (CAD), there are a considerable number of patients who can not receive complete revascularization because of severe or total arterial occlusion. Intramyocardial injection of autologous bone marrow mononuclear cells (ABMMCs) has been shown to induce neovascularization of ischemic myocardium. METHODS AND RESULTS: The study will investigate the safety and feasibility of intramyocardial injections of ABMMCs and test the hypothesis that this treatment would promote neovascularization and improve left ventricular (LV) global and/or regional function in patients with severe CAD who have no other option. ABMMCs (approximately 10(6) cells) will be injected into the area of ischemic myocardium where the coronary artery is not graftable, in combination with bypass surgery to the other coronary branches. Myocardial perfusion and LV global and regional function will be evaluated, based on the micromanometer-tipped catheter method, single-photon emission tomography, and myocardial enhanced and color tissue Doppler echocardiography at baseline and during 12 month follow-up. CONCLUSIONS: This project will demonstrate that intramyocardial injection of ABMMCs with or without coronary artery bypass surgery could be a safe and effective method for therapeutic neovascularization, resulting in an improvement of cardiac function in patients with severe CAD.
Bone Marrow Cells↗
Therapeutic angiogenesis with intramuscular injection of low-dose recombinant granulocyte-colony stimulating factor.
OBJECTIVE: In vivo administration of granulocyte colony-stimulating factor (G-CSF) has been shown to facilitate regeneration of cardiovascular tissues. However, G-CSF causes marked leukocytosis that potentially induces adverse cardiovascular events. Earlier studies showed that G-CSF had direct stimulatory actions on mature endothelial cells, resulting in promotion of angiogenesis. We thus examined whether low doses of recombinant human G-CSF (rhG-CSF) locally injected into ischemic tissues would stimulate angiogenesis without inducing severe leukocytosis. METHODS AND RESULTS: Reverse-transcription polymerase chain reaction (PCR) revealed expression of G-CSF receptor in human umbilical vein endothelial cells (HUVECs). rhG-CSF (100 ng/mL) enhanced migration and tube formation but not proliferation of HUVECs in vitro. We then examined the effects of rhG-CSF on angiogenesis in a rat model of hindlimb ischemia. Nude rats received in their ischemic skeletal muscles either rhG-CSF (2, 10, 20 microg/kg per day) or saline (control) for 6 days. Laser Doppler blood flowmetry (LDBF) revealed an augmented ischemic/normal limb LDBF ratio and an increased capillary density in the rhG-CSF-treated groups compared with the control at days 14, 21, and 28 (P<0.05). These doses of rhG-CSF induced only mild leukocytosis ( approximately 1.4-fold increases versus baseline). CONCLUSIONS: rhG-CSF promoted endothelial migration and tube formation in vitro. Local injection of low doses rhG-CSF effectively augmented ischemia-induced angiogenesis in vivo. This treatment regimen of low-dose rhG-CSF may become a new and safe modality for therapeutic angiogenesis.
Animals↗
Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury.
Restenosis is the major clinical problem of angioplasty. We have previously shown that neointima formation is strikingly suppressed in midkine (MK)-deficient mice. Neointima formation is restored if MK protein is administrated to the deficient mice. MK is a heparin-binding growth factor and implicated in the migration of inflammatory cells and vascular smooth muscle cells. Consistently, the suppression of neointima formation in the deficient mice is accompanied by suppression of recruitment of inflammatory cells into the vascular wall. Here, we evaluated the potential of MK antisense oligodeoxyribonucleotide (ODN) for the prevention of restenosis. We cloned the cDNA of rabbit MK, which showed a strongly conserved sequence in mammals. The balloon injury induced MK expression, with the maximum level occurring 7-14 days after angioplasty, in the rabbit carotid artery. Two antisense ODNs suppressed the production of MK in a rabbit kidney cell line, RK13 cells, one of which was then transfected into the arterial wall by means of lipofection immediately after balloon treatment. The antisense ODN suppressed MK induction in vivo and consequently suppressed neointima formation to 60% of the control level. These results suggest that MK is a candidate molecular target for the therapy for vascular restenosis.
Amino Acid Sequence↗
Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition.
BACKGROUND: Recent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro. METHODS: In the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 micromol/L and 30 micromol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis. RESULTS: We demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 +/- 3.5 microm vs control group, 64.0 +/- 7.1 microm; n = 7; P < .05) and suppressed cell proliferation and apoptosis in the neointima 2 weeks after implantation. In addition, we found that pravastatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human umbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells. CONCLUSIONS: These novel findings clearly demonstrate that a hydrophilic statin can suppress intimal hyperplasia of the vein graft in vivo and also show endothelial cell-tropic inhibition of Rho-kinase in vitro. Furthermore, these results strongly support the clinical use of hydrophilic statins to prevent intimal hyperplasia of the vein graft after bypass grafting. CLINICAL RELEVANCE: Late graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of pravastatin on the development of vein graft intimal hyperplasia. In addition, we demonstrate that pravastatin showed endothelial cell-tropic benefits through both the inhibition of Rho-kinase activity and acceleration of eNOS expression in vitro. Because the clinical benefits and safety of pravastatin have been established to a certain extent through long-term clinical usage, pravastatin may soon become standard treatment after vein bypass grafting.
Animals↗
Ex vivo electroporation as a potent new strategy for nonviral gene transfer into autologous vein grafts.
Gene transfer to vein grafts has therapeutic potential to prevent late graft failure; however, certain issues, including efficacy and safety, have hindered the clinical application of this treatment modality. Here, we report the successful and efficient gene transfer of plasmid DNA via ex vivo electroporation into veins as well as into vein grafts. Two approaches were used: one involved transluminal in situ gene transfer using a T-shaped electrode (the "Lu" method), and the other was an adventitial ex vivo approach using an electroporation cuvette followed by vein grafting (the "Ad" method). The Lu method was carried out at 10 V, with optimal gene transfer efficiency in the in situ jugular veins of rabbits, and transgene expression was observed primarily in endothelial cells. However, when these veins were grafted into the arterial circulation, no luciferase activity was detected; this effect was probably due to the elimination of the gene-transferred cells as a result of endothelial denudation. In contrast, optimal and satisfactory gene transfer was obtained with the vein grafts subjected to the Ad method at 30 V, and transgene expression was seen primarily in adventitial fibroblasts. Gene transfer of endothelial nitric oxide synthase cDNA to the vein graft via the Ad method successfully limited the extent of intimal hyperplasia, even under hyperlipidemic conditions, at 4 wk after grafting. We thus propose that the Ad method via ex vivo electroporation may provide a novel, safe, and clinically available technique for nonviral gene transfer to sufficiently prevent late graft failure.
Animals↗
Autologous peripheral blood mononuclear cell implantation for patients with peripheral arterial disease improves limb ischemia.
BACKGROUND: Implantation of bone marrow mononuclear cells, including endothelial progenitor cells, into ischemic limbs has been shown to improve collateral vessel formation. In the present study the safety and feasibility of autologous peripheral blood mononuclear cells (PBMNCs) implantation after granulocyte-colony stimulating factor (G-CSF)-induced mobilization was investigated in patients with severe peripheral arterial disease. METHODS AND RESULTS: Six cases were enrolled: 5 of thromboangitis obliterans and 1 of arteriosclerosis obliterans. Following administration of G-CSF (10 microg . kg(-1) . day(-1)), PBMNCs were harvested and injected intramuscularly (5 legs and 1 arm) for 2 days for the patients with ischemia of the legs. No serious adverse events related to G-CSF administration, harvest or implantation were observed during this study period. Improvement in the ankle - brachial pressure index (ABI: >0.1) was seen in 4 patients at 4 weeks and ischemic ulcers improved in 3 of 3 patients. The mean maximum walking distance significantly increased from 203 m to 559 m (p=0.031) at 4 weeks and was sustained for 24 weeks. Significant improvement was seen in physiological functioning subscale of Short Form-36. CONCLUSION: Implantation of PBMNCs collected after G-CSF administration could be an alternative to therapeutic angioplasty in patients with severe peripheral arterial disease.
Adult↗
Molecular evaluation of endothelial progenitor cells in patients with ischemic limbs: therapeutic effect by stem cell transplantation.
OBJECTIVE: Although some patients with limb ischemia have recently undergone therapeutic angiogenesis by cell transplantation, their angiogenic potential has not been well characterized. It is also important to evaluate endothelial progenitor cell (EPC) contents in different stem cell sources to choose the best material for therapeutic angiogenesis. METHODS AND RESULTS: We quantitated the mRNA expression of EPC-specific molecules (eg, Flk-1, Flt-1, CD133, VE-cadherin, etc) in bone marrow-derived or peripheral blood-derived mononuclear cells obtained from patients with ischemic limbs, using real-time reverse-transcription polymerase chain reaction technique. The mRNA expression level of EPC markers was significantly lower in the patients than in healthy controls, which was consistent with results of flow cytometric analysis. However, the implantation of autologous bone marrow mononuclear cells increased the circulating EPCs in the peripheral blood of patients. We furthermore revealed the different expression pattern of EPC markers in possible sources for stem cell transplantation, including normal bone marrow, peripheral blood obtained from recombinant granulocyte colony-stimulating factor-treated donor, and umbilical cord blood. CONCLUSIONS: Patients with peripheral obstructive arterial diseases may have lower angiogenic potential because of decreased expression of EPC specific molecules in their marrow and blood. Therapeutic angiogenesis by transplantation of autologous marrow mononuclear cells increased circulating EPCs in the patients and improved ischemic symptoms.
AC133 Antigen↗
Near-infrared spectroscopy with treadmill exercise to assess lower limb ischemia in patients with atherosclerotic occlusive disease.
PURPOSE: We used near-infrared spectroscopy (NIRS) to measure exercise-induced ischemia in patients with intermittent claudication, and compared these results with those obtained by ankle-brachial pressure index (ABPI) analysis. METHODS: Sixty-two patients with intermittent claudication caused by atherosclerotic occlusive disease exercised on a treadmill until reaching the maximal tolerated walking distance. We measured the ABPI at rest and after exercise until it returned to the baseline value. A NIRS probe was positioned on the patient's calf, which allowed the continuous monitoring of oxygen saturation (StO2), oxygenated hemoglobin (Oxy Hb), and deoxygenated hemoglobin (Deoxy Hb) in the calf muscles before, during, and after exercise. During exercise, the StO2 and Oxy Hb decreased, and the Deoxy Hb increased. The time taken for each measurement to return to the baseline value was defined as the recovery time. The recovery times obtained by NIRS and ABPI were compared. RESULTS: The recovery time for ABPI correlated well with that for StO(2 (rhos = 0.73), Oxy Hb (rhos = 0.63), and Deoxy Hb (rhos = 0.65); however, the recovery times measured by NIRS were shorter than the recovery time for the ABPI. CONCLUSIONS: Near-infrared spectroscopy is a reliable method for monitoring peripheral circulation during and after exercise, although the data generated provided slightly different information than the results obtained by ABPI.
Adult↗
Subcutaneous tissue release of amikacin from a fibrin glue/polyurethane graft.
We investigated whether fibrin glue (FG) might be useful as a carrier of amikacin (AMK) for prevention of local graft infection. After AMK (4.0 mg)-treated FG (AMK-FG) polyurethane grafts were implanted subcutaneously in the anterior abdominal region of Sprague-Dawley rats, AMK concentrations in tissues surrounding the implantation sites were compared over time with concentrations at the same sites in rats given an intravenous injection of AMK (4.0 mg). In the injection group, AMK concentrations in serum were detectable only for 4 h, whereas AMK released from AMK-FG grafts remained detectable over 24 h. Until 4 h after implantation, AMK concentrations in tissues near implantation sites were significantly higher in the AMK-FG graft group than in the injection group; peak local concentrations during that time were 210 times higher for the AMK-FG graft group than for the injection group. Areas under the tissue concentration-time curve (AUC) for AMK were 171 microg x h/g and 1.35 microg x h/g in the AMK-FG graft and injection groups, respectively. FG therefore was considered to control release of AMK and to maintain a high AMK concentration in tissues surrounding the implantation site. Thus, AMK-FG polyurethane graft delivery may be useful in preventing local infection by local delivery of AMK.
Abdomen↗
External iliac venous aneurysm in a pregnant woman: a case report.
We report an external iliac venous aneurysm in a young pregnant woman who was diagnosed incidentally by ultrasound scanning. The aneurysm was successfully treated by tangential aneurysmectomy and lateral venorrhaphy. Primary iliac venous aneurysm is a rare vascular abnormality. The clinical significance of the disease is unknown. However, embolism, rupture, and thrombosis might occur as they can occur with popliteal venous aneurysm. In fact, three of four reported patients with iliac venous aneurysms had a thromboembolic event. For those reasons, prophylactic treatment is indicated. This is the first patient with an iliac venous aneurysm to be diagnosed without complication.
Adult↗
Intramuscular gene transfer of FGF-2 attenuates endothelial dysfunction and inhibits intimal hyperplasia of vein grafts in poor-runoff limbs of rabbit.
We previously demonstrated that sustained disturbance of endothelium-dependent vasorelaxation and poor distal runoff in ischemic limbs were critical factors affecting the neointimal development of autologous vein grafts (VGs). Also, we recently showed the superior therapeutic potential of basic fibroblast growth factor (bFGF/FGF-2) boosted by the recombinant Sendai virus (SeV) for severe limb ischemia compared with that of vascular endothelial growth factor. Here, the effect of FGF-2 on neointimal hyperplasia of VGs was examined in a rabbit model of poor-runoff limbs. Two weeks after initial surgery for the induction of poor-runoff, SeV-expressing human FGF-2 (SeV-hFGF2) or that encoding firefly luciferase (109 plaque-forming units/head) was injected into the thigh and calf muscle. At that time, the femoral vein was implanted in the femoral artery in an end-to-end manner in some groups. FGF-2 gene-transferred limbs demonstrated significantly increased blood flow assessed not only by laser Doppler flow image but also by ultrasonic transit-time flowmeter (USTF). USTF also showed a significant increase in the blood flow ratio of the deep femoral artery to external iliac artery, indicating that collateral flow was significantly restored in the thigh muscles (P < 0.01). Reduction of neointimal hyperplasia was also observed in the VGs treated by SeV-hFGF2; these grafts demonstrated significant restoration of endothelium-dependent vasorelaxation. These findings thus extend the indications of therapeutic angiogenesis using SeV-hFGF2 to include not only limb salvage but also prevention of late graft failure.
Acetylcholine↗
Buerger's disease in a 19-year-old woman.
A 19-year-old female college student had numbness and the sensation of coldness of her left toes. She had a 3-year smoking history. Gangrene of the left foot developed rapidly. Angiography revealed peripheral arterial occlusion of both legs and arms. Detailed laboratory examination excluded collagen disease, a hypercoagulable state, and juvenile atherosclerosis. Below-knee amputation of the left leg was performed. Typical histologic findings of Buerger's disease were observed in the crural arteries and saphenous veins. The clinical course was uneventful after the patient stopped smoking. This is the second case report of Buerger's disease in a woman in the second decade of life. It is important that a correct diagnosis of Buerger's disease be established, because the disease process is benign, compared with collagen disease, if the patient stops smoking.
Adolescent↗