Restenotic Changes Research Articles

頚部頚動脈狭窄症の治療方針 頚部頚動脈狭窄病変に対する外科的治療指針―現時点でのＣＥＡの問題点と対策―

We focused on complicated carotid lesions in 324 of our carotid endarterectomies (CEAs) to clarify controversies in carotid surgeries. Carotid lesions extented to the C2 level in over 20% of lesions. Bilateral stenotic lesions were operated in 22 cases without problems. Nine of 15 contralateral occlusion cases were supported with STA-MCA anastomosis indicated by the CBF. In near-occlusion cases, distal sites of lesions were detected by IVUS. Restenosis was observed in 9 cases. Only 1 restenotic case was symptomatic and 4 restenotic cases were reoperated with patch graft. Hemashield patch grafts were used in 18 cases and no restenotic changes were observed. Intracranial aneurysm was seen in 12 cases and 7 cases were clipped before CEA. Hyperperfusion syndrome was seen in 6 cases. Two cases showed intracerebral hemorrhage resulting in postoperative neurological deficits. Symptomatic occlusive coronary lesions were seen in 62 cases and surgical or intravascular treatment or both were performed in 30 cases. Guidelines for CEA have been established by randomized controlled trails, but some cases have very complicated clinical features such as multiple lesions. For these cases, safer and more effective strategies should be established by collaborative studies.

Stress and vascular responses: anti-inflammatory therapeutic strategy against atherosclerosis and restenosis after coronary intervention.

Atherosclerosis and restenosis after percutaneous coronary interventions have become major issues in public health in Western countries. Recent studies have revealed that inflammation plays an important role in pathogenesis of cardiovascular diseases. Vascular injury may involve an inflammatory response, which accelerates the recruitment and activation of monocytes through monocyte chemoattractant protein-1 (MCP-1). MCP-1 expression has been shown to be increased in atherosclerotic lesions and balloon injured arteries. Recently, we have devised a new strategy for anti-MCP-1 gene therapy by transfecting mutant MCP-1 gene into skeletal muscle. This mutant MCP-1 has been shown to work as a dominant-negative inhibitor of MCP-1. We here demonstrate that this strategy limited progression of pre-existing atherosclerotic lesions and improved the lesion composition into a more stable phenotype in the hypercholesterolemic mice. This strategy also suppressed monocyte infiltration/activation in the injured site and markedly inhibited restenotic changes (neointimal hyperplasia) in the carotid artery in rabbits, rats, and monkeys after balloon injury or stent implantation. Therefore, MCP-1-mediated monocyte infiltration is essential in the development of restenotic changes as well as atherosclerosis progression. MCP-1 can be a practical therapeutic target for human restenosis and atherosclerosis.

Anti-monocyte chemoattractant protein-1 gene therapy inhibits restenotic changes (neointimal hyperplasia) after balloon injury in rats and monkeys.

Prevention of restenosis after coronary intervention is a major clinical challenge, which highlights the need of new therapeutic options. Vascular injury may involve inflammatory responses that accelerate the recruitment and activation of monocytes through the activation of chemotactic factors, including monocyte chemoattractant protein-1 (MCP-1). However, there is no definitive evidence supporting the role of MCP-1 in restenosis. We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. We demonstrate here that this strategy suppressed monocyte infiltration/activation in the injured site and markedly inhibited restenotic changes (neointimal hyperplasia) after balloon injury of the carotid artery in rats and monkeys. This strategy also suppressed the local production of MCP-1 and inflammatory cytokines. Therefore, monocyte infiltration and activation mediated by MCP-1 are essential in the development of restenotic changes after balloon injury. This strategy may be a useful form of gene therapy against human restenosis.

Essential role of monocyte chemoattractant protein-1 in development of restenotic changes (neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits.

Renarrowing of dilated arterial sites (restenosis) hampers the clinical benefits of coronary angioplasty. Infiltration and activation of monocytes in the arterial wall mediated by monocyte chemoattractant protein-1 (MCP-1) might be a major cause of restenosis after angioplasty. However, there is no direct evidence to support a definite role of MCP-1 in the development of restenosis. Methods and Results- We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. We used this strategy to investigate the role of MCP-1 in the development of restenotic changes after balloon injury in the carotid artery in hypercholesterolemic rabbits. Intramuscular transfection of the mutant MCP-1 gene suppressed monocyte infiltration/activation in the injured arterial wall and thus attenuated the development of neointimal hyperplasia and negative remodeling. MCP-1-mediated monocyte infiltration is necessary in the development of restenotic changes to balloon injury in hypercholesterolemic rabbits. This strategy may be a useful and practical form of gene therapy against human restenosis.

ナノテクノロジーとＤＤＳ ナノ診断・ナノ治療が開く新しい薬物治療

Restenosis after coronary intervention still remains a serious problem in clinical cardiology. Recent advances in nanotechnology have enabled us to selectively deliver an antiproliferative drug to the balloon-injured artery. Here we report our results with NK911 that is a doxorubicin containing nanocapsule and is characterized to selectively accumulate in vascular lesions with increased permeability. We first confirmed by Evans-blue staining that in the rat carotid artery, vascular permeability was markedly increased at least for one week after balloon injury. We then examined the inhibitory effect of NK911 on the restenotic changes 4 weeks after the injury either in the normal artery (single injury protocol) and in the arteriosclerotic artery that had been induced by a previous balloon injury (double injury protocol). NK911 was intravenously administered only three times (immediately after, and 3 and 6 days after the injury) at three different doses (0.1, 1.0 and 10 mg/kg). Corresponding doses of doxooruhicin alone (0.016, 0.16, 1.6 mg/kg) were also administered in the same manner. In both protocols. NK911 dose-dependently suppressed neointimal formation (P<0.001, n=6 each). Immunohistochemical examination demonstrated that the inhibitory effect of NK911 was mainly due to suppression of vascular smooth muscle proliferation. Measurement of vascular concentrations of doxorubicin demonstrated that NK911 effectively delivered the drug to the balloon-injured carotid arteries. Finally, NK911 was well tolerated without any systemic adverse effects. Thus, the treatment with nanocapsules containing antiproliferative agents may be a novel and promising strategy for the prevention of restenosis after balloon angioplasty.

Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs.

Restenosis after angioplasty still remains a major problem for which neointimal formation appears to play an important role. Recent studies in vitro suggested that Rho kinase, a target protein of Rho, is important in various cellular functions. We thus examined whether Rho kinase is involved in the restenotic changes after balloon injury. In vivo gene transfer was performed immediately after balloon injury in both sides of the porcine femoral arteries with adenoviral vector encoding either a dominant negative form of Rho kinase (AdDNRhoK) or beta-galactosidase (AdLacZ) as a control. One week after the transfer, immunohistochemistry confirmed the successful gene expression in the vessel wall, whereas 2 wk after the transfer, Western blotting showed the functional upregulation of Rho kinase at the AdLacZ site and its suppression at the AdDNRhoK site. Angiography showed the development of a stenotic lesion at the AdLacZ site where histological neointimal formation was noted, whereas those changes were significantly suppressed at the AdDNRhoK site. These results indicate that Rho kinase is involved in the pathogenesis of neointimal formation after balloon injury in vivo.

Local adenovirus-mediated transfer of C-type natriuretic peptide suppresses vascular remodeling in porcine coronary arteries in vivo

OBJECTIVEThis study was designed to examine whether or not adenovirus-mediated gene transfer of C-type natriuretic peptide (CNP) can prevent coronary restenotic changes after balloon injury in pigs in vivo.BACKGROUNDGene therapy to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) might be useful but requires a method applicable for in vivo gene delivery into the coronary artery as well as the efficient vector encoding a potent antiproliferative substance. We tested whether the adenovirus-mediated gene transfer of CNP by use of an infiltrator angioplasty balloon catheter (IABC) might prevent the coronary restenotic changes after balloon injury.METHODSBalloon angioplasty was performed in the left anterior descending and the left circumflex coronary artery in pigs. Immediately after the balloon injury, adenovirus solution encoding either CNP (AdCACNP) or β-galactosidase (AdCALacZ) gene was injected with IABC into the balloon-injured coronary segments. Expression of CNP was assessed by immunohistochemical staining and cyclic guanosine 3′,5′-monophosphate (cGMP) measurement. Coronary restenotic changes were evaluated by both angiographic and histological examinations.RESULTSCNP was highly expressed in the media and the adventitia of the coronary artery at the AdCACNP-transfected but not at the AdCALacZ-transfected segment. In the AdCALacZ-transfected segment, vascular cGMP levels tended to be reduced as compared with the untreated segment, whereas in the AdCACNP-transfected segment, vascular cGMP levels were restored. Angiographic coronary stenosis was significantly less at the AdCACNP-transfected than at the AdCALacZ-transfected segment. Histological examination revealed that this was achieved primarily by the marked inhibition of the geometric remodeling of the coronary artery by the CNP gene transfer.CONCLUSIONSAdenovirus-mediated CNP gene transfer with the IABC system may be a useful gene therapy to prevent restenosis after PTCA in vivo.

Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo.

This study was designed to examine whether or not intramural delivery of ST638 (a specific tyrosine kinase inhibitor) with biodegradable stent can suppress the restenotic changes of the coronary artery in vivo. Clinical and animal studies demonstrated that restenosis after coronary intervention results from a combined effect of neointimal formation and geometric remodeling (decrease in total cross-sectional area). Thus, the most effective strategy to prevent the restenosis appears to inhibit both the neointimal formation and geometric remodeling by antiproliferative agent and stent, respectively. We have previously shown that ST638 markedly suppresses the restenotic changes of the porcine coronary artery when applied from the adventitial site. A poly-L-lactic acid biodegradable stent was coated with either ST638 (0.8 mg) or equimolar of its inactive metabolite, ST494. A pair of these stents were implanted alternatively in the left anterior descending or circumflex coronary artery in pigs (n=6). Three weeks after the procedure, coronary stenosis was assessed by angiography followed by histological examination. Coronary stenosis was significantly less at the ST638 stent site than at the ST494 stent site (47+/-5% vs. 25+/-4%, p < 0.01). Histological examination also showed that the extent of neointimal formation and that of geometric remodeling were significantly less at the ST638 stent site than at the ST494 stent site (p < 0.05). These results indicate that intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent overcomes the proliferative stimuli caused by balloon injury, the stent itself, and the drug coating on the stent, resulting in the suppression of the restenotic changes of the coronary artery in vivo. This strategy might also be useful in the clinical setting in humans.

2D-TOF MRA Follow-up Study of Percutaneous Transluminal Angioplasty for Severely Stenotic Cervical Internal Carotid Artery

Percutaneous transluminal angioplasty (PTA) for severe arteriosclerotic stenosis in the cervical internal carotid artery (ICA) was successfully carried out in 23 cases between December 1994 and August 1996. In order to analyze the condition of the cervical ICA in the early stage after PTA, 12 stenotic lesions of 11 cases were exposed to follow-up study of stenotic cervical ICA after PTA with magnetic resonance angiography (MRA) 1 to 150 days postoperatively. In six lesions, the diameter of the cervical ICA was dilated sequentially. In another four lesions, the diameter of the cervical ICA was decreased in the first three weeks and dilated over the next three weeks. Angiographically, these lesions had a small intimal flap at the balloon dilated portion, which was speculated to cause the turbulent flow in the first stage. In the remaining 2 lesions, restenotic changes in cervical ICAs were observed within three weeks after PTA. Follow-up angiography was performed over three months after PTA in five cases of this series and compared with MRA. Consequently, the diameters of the cervical ICA between angiography and MRA were closely correlated. The evaluation of the lesion after PTA of the cervical ICA demonstrated that MRA is beneficial, but within three weeks after PTA, caution should be paid for underestimation of the small intimal flap on MRA.

頚部頚動脈内膜剥離術（ＣＥＡ）の術後ｆｏｌｌｏｗ‐ｕｐにおける超音波断層法（Ｂモード）の検討 ｖｅｉｎ ｐａｔｃｈの有用性について

High-resolution B-mode ultrasonography was used for postoperative evaluation of 72 carotid arteries in 65 patients after carotid endarterectomy (CEA) . The intima-media complex (IMC) and the dilative parameter (d-CEA/d-CCA) were measured. The IMC of the VP-A group (operated on with a vein patch, within 4 years of follow-up, N=30) (mean±SD: 0.85±0.51 mm) was relatively thinner than that of the NON-VP-A group (operated on without a vein patch, within 4 years of follow-up, N=25) (1.13±0.73 mm) . The d-CEA/d-CCA of the VP-A group (1.65±0.42) was significantly higher than that of the NON-VP-A group (1.24±0.24) . In conclusion, CEA with a vein patch led to smooth dilatation of the treated carotid artery and seemed to be effective for reducing restenotic changes in endarterectomized arteries.