Prevention Of Arterial Restenosis Research Articles

Multifunctional CuBiS2 Nanoparticles for Computed Tomography Guided Photothermal Therapy in Preventing Arterial Restenosis After Endovascular Treatment.

Chronic inflammation mediated by artery infiltrated macrophages plays critical role in artery restenosis after endovascular therapy. Evidence has demonstrated the potential ability of photothermal therapy (PTT) in eliminating chronic inflammation by targeting inflammatory cells including macrophages. Recently, increasing attention has been payed to copper chalcogenide nanocrystals doped of radiocontrast agent, e.g., bismuth (Bi) for computed tomography (CT) guided PTT. However, the application of imaging guided PTT in preventing artery restenosis is lacking and limited. Herein, a novel multifunctional CuBiS2 nanoparticles (CuBiS2 NPs) were synthesized for CT imaging guided PTT in artery re-stenosis prevention. The optimum amount and other conditions of CuBiS2 NPs were optimized to exert the maximum ablation effect on macrophages with good biocompatibility. In vivo carotid injury model revealed that CuBiS2 NPs exhibited promising therapeutic effect on inhibition of artery stenosis by eliminating macrophages with excellent CT imaging ability. The recent study highlights a new cost-effective metal nanostructures-based nanotechnology in prevention of artery restenosis after endovascular therapy.

RhoA inhibitor-eluting stent attenuates restenosis by inhibiting YAP signaling

ObjectiveCurrent drug-eluting stent (DES) treatment is promising, but it still has the drawback of in-stent restenosis, which remains a clinically relevant problem. Efforts should be made to discover new signaling molecules and novel potential targets for the prevention of arterial restenosis. In this study, we fabricated a novel DES targeting the RhoA pathway and further examined this promising strategy in vitro and in a rabbit carotid model. MethodsActive RhoA expression is correlated with the synthetic smooth muscle phenotype, and the RhoA inhibitor rhosin suppresses this phenotypic modulation at both transcriptional and translational levels. We further demonstrated that the RhoA inhibitor rhosin might act through the YAP pathway in smooth muscle cell phenotype modulation by a gain-of-function assay. Moreover, we fabricated a RhoA inhibitor-eluting stent and tested it in a rabbit carotid model. ResultsCompared with a bare-metal stent, the RhoA inhibitor-eluting stent significantly attenuated neointimal formation at 6 months. However, overexpression of YAP by lentivirus blocked the antirestenosis effect of the RhoA inhibitor-eluting stent and repressed smooth muscle-specific genes. ConclusionsRhoA inhibitor-eluting stents attenuate neointimal formation through inhibition of the YAP signaling pathway. This novel DES may represent a potential strategy for the treatment of in-stent restenosis.

Invited commentary

Neointimal hyperplasia (NIH) is the proliferation and migration of vascular smooth muscle cells primarily in the intima, resulting in the thickening of the arterial wall and decreased arterial lumen. NIH is a significant problem after revascularization that can lead to significant graft and stent failures. Novel research investigating pathways that are responsible for NIH may provide insight into the pathophysiologic process and effective treatment options. There are currently drug-eluting stents based on paclitaxel and sirolimus, which are designed to inhibit smooth muscle cell proliferation. Although they are effective at reducing NIH, in-stent restenosis and thrombosis continue to occur. This may be due to the nonspecific effects of the drug to the target pathways/cells or incomplete inhibition of the pathways responsible for NIH. In this very important study, the authors investigate the inhibition of Rho GTPase, specifically RhoA and its effect on Hippo pathway-related genes and YAP transcription coactivator. YAP (Yes-associated protein) is a protein that acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing apoptotic genes. Initially, the study demonstrated that active RhoA expression affects the smooth muscle cell synthetic phenotype and decreases the contractile phenotype. Inhibition of RhoA by rhosin decreased cell proliferation but had no effect on apoptosis. The inhibition of RhoA-guanosine triphosphate involved the knockdown of cyclin D and affected the majority of cells in the S phase of the cell cycle. Next, the authors demonstrated that YAP plays an important role in the regulation of smooth muscle cell phenotypic modulation and is affected by RhoA, whereby RhoA inhibition reduces the expression of both cytoplasmic and nuclear YAP. Finally, the authors tested whether inhibition of RhoA in a carotid rabbit model would decrease NIH, using rhosin jelly-coated stents to inhibit RhoA. Compared with bare-metal stents, the rhosin-coated stents had less NIH, and cellular analysis demonstrated that the smooth muscle cell contractile phenotype was induced and the synthetic phenotype was suppressed. These effects were mitigated when active YAP lentivirus was instilled into the RhoA-inhibited stent carotid section for 30 minutes, indicating the involvement of YAP in switching the smooth muscle cell phenotype from contractile to synthetic, with increased NIH. In summary, the data demonstrated that the RhoA inhibitor-eluting stent attenuated in-stent restenosis through the YAP signaling pathway evaluated at 6 months. These novel mechanistic discoveries of RhoA and YAP involved in NIH in the context of arterial stents offer an exciting and promising area for clinical trials using RhoA inhibitor drug-eluting stents. Further work is necessary to validate the in vitro and in vivo animal studies from this study, to translate the basic scientific research of RhoA inhibition and decreased NIH, and to determine the effectiveness and durability in human trials. The opinions or views expressed in this commentary are those of the author and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery or the Society for Vascular Surgery. RhoA inhibitor-eluting stent attenuates restenosis by inhibiting YAP signalingJournal of Vascular SurgeryVol. 69Issue 5PreviewCurrent drug-eluting stent (DES) treatment is promising, but it still has the drawback of in-stent restenosis, which remains a clinically relevant problem. Efforts should be made to discover new signaling molecules and novel potential targets for the prevention of arterial restenosis. In this study, we fabricated a novel DES targeting the RhoA pathway and further examined this promising strategy in vitro and in a rabbit carotid model. Full-Text PDF Open Archive

Mesenchymal Stem Cell Sheets Exert Antistenotic Effects in a Rat Arterial Injury Model

Restenosis after catheter or surgical intervention substantially affects the prognosis of arterial occlusive disease. Mesenchymal stem cells (MSCs) may have antistenotic effects on injured arteries. MSC transplantation from the adventitial side of an artery is safer than endovascular transplantation but has not been extensively examined. In this study, a rat model of femoral artery injury was used to compare the antistenotic effects of transplanted cell sheets and transplanted cell suspensions. Rat adipose-derived stem cells (ASCs) were used as the source of MSCs. For both cell sheets and suspensions, 6 × 106 MSCs were transplanted on the day of arterial injury. MSC sheets attenuated neointimal hyperplasia more than MSC suspensions (intima-to-media ratio in hematoxylin/eosin-stained sections: 0.55 ± 0.13 vs. 1.14 ± 0.12; p < 0.05). Cell engraftment (assessed by immunohistochemistry or bioluminescence imaging of luciferase-expressing cells), arterial re-endothelialization (evaluated by immunohistochemical staining for rat endothelial cell antigen-1), and restriction of vascular smooth muscle cell proliferation in the neointima (double-staining of alpha-smooth muscle actin and phospho-histone H3) were greater when MSC sheets were applied than when MSC suspensions were used. In conclusion, MSC sheets exhibited better antistenotic and cell engraftment properties than MSC suspensions. MSC sheet transplantation from the adventitial side is a promising therapy for prevention of arterial restenosis.

Invited commentary

The purpose of this experimental animal study was to test the hypothesis that a 14-day course of intravenous human urinary kininogenase (HUK, 0.02 paranitroaniline unit) would attenuate balloon-injured carotid neointimal formation in New Zealand White rabbits fed a high-fat diet. The results were strongly positive: treatment with intravenous HUK inhibited the formation of arterial neointima by >50%, with accompanying reductions in macrophage infiltration, tumor necrosis factor-α, interleukin-1β, and transforming growth factor-β1 message and expression of transforming growth factor-β1 and p-Smad2/3 protein. So convinced were the investigators that they even demonstrated the effect angiographically after 2 months, a rarity for animal studies of this kind. The search for a safe and effective systemic method for the inhibition of neointimal proliferation after vascular or endovascular intervention has been both arduous and futile. Although significant strides have been made in controlling thrombotic and access complications, and drug-eluting stents and balloons inhibit restenosis on a local level, no systemic pharmacologic therapy has yet been shown to safely and effectively attenuate vascular proliferation. Many classes of agents have been tested, including lipid lowering drugs, antihypertensives, antiproliferatives, antiflammatories, antithrombotics, and antioxidants, but to date, none have consistently proven useful in the clinical arena. HUK represents a potentially new agent for the prevention of restenosis after vascular intervention. Made from fresh human urine, it is a tissue kallikrein with profound effects on multiple cellular processes such as inflammation, cytokine release, cellular proliferation, and membrane stabilization. Intravenous treatment with HUK has been found to reduce neurologic impairment and improve long-term outcomes after stroke; in fact, it has recently been approved in China for this indication using a dose similar to that used in this experimental study. Hopefully, the clinical safety profile of HUK will ultimately prove mild enough to also be considered for the postprocedural prevention of arterial restenosis. Human urine kininogenase attenuates balloon-induced intimal hyperplasia in rabbit carotid artery through transforming growth factor β1/Smad2/3 signaling pathwayJournal of Vascular SurgeryVol. 64Issue 4PreviewEffective treatments against restenosis after percutaneous transluminal angioplasty and stenting are largely lacking. Human tissue kallikrein gene transfer has been shown to be able to attenuate neointima formation induced by balloon catheter. As a tissue kallikrein in vivo, human urinary kininogenase (HUK) is widely used to prevent ischemia-reperfusion injury. However, the effects of HUK on neointima formation have not been explored. We therefore investigated whether HUK could alleviate balloon catheter-induced intimal hyperplasia in rabbits fed with high-fat diets. Full-Text PDF Open Archive

Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research.

Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

Binding of an intravascular delivery vehicle for prevention of arterial restenosis is contingent on tertiary structure

CONCLUSIONS: These data suggest that TXA decreases the time to initial clot formation and increases the rate of clot propagation indicating its procoagulant effects beyond fibrinolysis, which are relevant to both potential benefit as well as safety. Thus, it is imperative to confirm a diagnosis of pathologic fibrinolysis prior to treatment with TXA to avoid exposure of a patient to a potentially thrombogenic drug.

Prevention of Restenosis: Medical Treatment and Procedures for Iliac Occlusive Disease

The treatment of occlusive vascular disease has evolved considerably over the past decades, with management strategies shifting from open surgical approaches toward less-invasive endovascular solutions or hybrid open and endovascular therapies. The treatment of aortoiliac occlusive disease has followed a similar pattern, with a more aggressive, minimally invasive approach being used even for long-segment iliac artery occlusions. Regardless of the type of treatment, however, optimal results are still limited by restenosis. This is also true in virtually all locations undergoing treatment of arterial occlusive disease. The current review seeks to explore the medical therapy and treatment options available for preventing restenosis in the iliac artery following intervention. Here we include data regarding prevention of restenosis in other arterial locations. Finally, novel therapies not currently available for iliac artery use but showing promise in prevention of arterial restenosis are reviewed.

A targeted systemic therapy for the prevention of arterial restenosis

A targeted systemic therapy for the prevention of arterial restenosis

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD.

Ticagrelor to Prevent Restenosis

Neointimal proliferation after stent implantation remains a concern even if local delivery of various antimitotic drugs has led to a significant reduction in smooth cell proliferation and a subsequent reduction in the rate of target vessel revascularization. The prevention of arterial restenosis in those treated by percutaneous coronary intervention using such new-generation stents fails in approximately 10% of patients, contributing to recurrent ischemic events and new revascularization procedures. Thus far, the systemic approach with statins, pioglitazone, angiotensin-converting enzyme inhibitors, and various antiproliferative drugs has not been successful in further reducing in-stent stenosis, raising the question of whether the aim included the right targets. See accompanying article on page 2385 Histopathologic studies in humans have demonstrated that after coronary stent placement, thrombus formation and acute inflammation are followed by vascular smooth cell proliferation, resulting in neointimal growth and leading to restenosis.1,2 Platelets play a key role in early thrombus generation and in the late neointima formation that results from arterial injury, such as after percutaneous coronary intervention or as a consequence of vessel wall inflammation, as occurs with atherosclerosis. Indeed, once recruited to or in the proximity of the vessel wall and exposed to thrombin, collagen, or thromboxane A2, platelets may release or express a plethora of growth factors …

In Vitro Photodynamic Therapy with Chlorin e6 Leads to Apoptosis of Human Vascular Smooth Muscle Cells

Percutaneous coronary intervention has become the most common and widely implemented method of heart revascularization. However, the development of restenosis remains the major limitation of this method. Photodynamic therapy (PDT) recently emerged as a new and promising method for the prevention of arterial restenosis. Here the efficacy of chlorin e6 in PDT was investigated in vitro using human vascular smooth muscle cells (TG/HA-VSMCs) as one of the cell types crucial in the development of restenosis. PDT-induced cell death was studied on many levels, including annexin V staining, measurement of the generation reactive oxygen species (ROS) and caspase-3 activity, and assessment of changes in mitochondrial membrane potential and fragmentation of DNA. Photosensitization of TG/HA-VSMCs with a 170 μM of chlorin e6 and subsequent illumination with the light of a 672-nm diode laser (2 J/cm2) resulted in the generation of ROS, a decrease in cell membrane polarization, caspase-3 activation, as well as DNA fragmentation. Interestingly, the latter two apoptotic events could not be observed in photosensitized and illuminated NIH3T3 fibroblasts, suggesting different outcomes of the model of PDT in various types of cells. The results obtained with human VSMCs show that chlorin e6 may be useful in the PDT of aerial restenosis, but its efficacy still needs to be established in an animal model.

Mutant Parathyroid Hormone-Related Protein, Devoid of the Nuclear Localization Signal, Markedly Inhibits Arterial Smooth Muscle Cell Cycle and Neointima Formation by Coordinate Up-Regulation of p15Ink4b and p27kip1

Arterial expression of PTH-related protein is markedly induced by angioplasty. PTH-related protein contains a nuclear localization signal (NLS). PTH-related protein mutants lacking the NLS (DeltaNLS-PTH-related protein) are potent inhibitors of arterial vascular smooth muscle cell (VSMC) proliferation in vitro. This is of clinical relevance because adenoviral delivery of DeltaNLS-PTH-related protein at angioplasty completely inhibits arterial restenosis in rats. In this study we explored the cellular mechanisms through which DeltaNLS-PTH-related protein arrests the cell cycle. In vivo, adenoviral delivery of DeltaNLS-PTH-related protein at angioplasty markedly inhibited VSMC proliferation as compared with angioplastied carotids infected with control adenovirus (Ad.LacZ). In vitro, DeltaNLS-PTH-related protein overexpression was associated with a decrease in phospho-pRb, and a G(0)/G(1) arrest. This pRb underphosphorylation was associated with stable levels of cdks 2, 4, and 6, the D and E cyclins, p16, p18, p19, and p21, but was associated with a dramatic decrease in cdk-2 and cdk4 kinase activities. Cyclin A was reduced, but restoring cyclin A adenovirally to normal did not promote cell cycle progression in DeltaNLS-PTH-related protein VSMC. More importantly, p15(INK4) and p27(kip1), two critical inhibitors of the G(1/S) progression, were markedly increased. Normalization of both p15(INK4b) and p27(kip1) by small interfering RNA knockdown normalized cell cycle progression. These data indicate that the changes in p15(INK4b) and p27(kip1) fully account for the marked cell cycle slowing induced by DeltaNLS-PTH-related protein in VSMCs. Finally, DeltaNLS-PTH-related protein is able to induce p15(INK4) and p27(kip1) expression when delivered adenovirally to primary murine VSMCs. These studies provide a mechanistic understanding of DeltaNLS-PTH-related protein actions, and suggest that DeltaNLS-PTH-related protein may have particular efficacy for the prevention of arterial restenosis.

Cryoplasty for the Prevention of Arterial Restenosis

Restenosis after percutaneous transluminal angioplasty remains the limiting factor for the long-term benefit of endovascular therapies of peripheral arterial occlusive disease. Despite a variety of modifications and adjuncts to angioplasty such as bare metal stents, covered stents, and drug-eluting stents as well as a number of new technologies like laser angioplasty and cutting balloon angioplasty, restenosis rates have not been significantly affected and remain inferior to those for surgery for long lesions in the femoropopliteal segment. Cryoplasty, which combines balloon angioplasty with the application of cryothermal energy to the vessel wall, was suggested as a promising approach to prevent the formation of neointimal hyperplasia after angioplasty procedures. This review discusses the basic principles of cryoplasty, summarizes the current data on restenosis rates after cryoplasty treatment, and evaluates cryoplasty as a new treatment method to solve the problems associated with restenosis development. The results of the clinical studies suggest that cryoplasty is a feasible and safe technique in the treatment of femoropopliteal disease, however, they have failed to prove any superiority of cryoplasty over conventional angioplasty.

The role of NF-kB and I-kB in intimal proliferation following balloon catheter-induced injury in the rat carotid artery

The aim of our study was to gain insight into the molecular and cellular mechanisms of post-angioplasty restenosis using balloon catheter-induced injury model in the rat carotid artery. SD rats were subjected balloon catheterization at one side carotid artery as study group and another side as control group. Six rats were killed on the 6 h, and 3rd, 7th, 14th, 28th day after balloon-induced injury respectively. The intimal thickness and the expression of NF-kappa B and I-kappa B were detected by HE-staining, gel electrophoretic mobility shift assay (EMSA) and Western-blot methods. The results showed that: (1) The thickening of intima was observed on the 3rd day after balloon-induced injury, and it became more significant on the 7th, 14th and 28th day. The area ratio of intima/media was increased significantly (P<0.05); (2) The expression of NF-kappa B was not detectable in the control group, however, in study group, the expression of NF-kappa B was detected on the 6th h after balloon-induced injury, reached the peak on the 14th day, and on 28th day, strong expression of NF-kappa B was observed; (3) The expression of I-kappa B protein was reduced after balloon-induced injury, and there were significant differences between the study group and the control group (P<0.05). It was concluded that the alteration of NF-kappaB/I-kappa B system might play an important role in aberrant proliferation within the intima and vascular remodeling following vascular injury. To block NF-kappa B activation and its role in arterial restenosis initiation may potentially provide a novel therapeutic tool for the treatment and prevention of arterial restenosis.

Porphyrin-Photosensitized Processes: Their Applications in the Prevention of Arterial Restenosis

Photodynamic therapy (PDT) is based on the use of a photozensitising compound which is accumulated by rapidly proliferating cells. Subsequent irradiation with light wavelengths specifically absorbed by the photosensitiser promotes the generation of reactive short-lived oxygen species which cause an irreversible and selective damage. Endovascular interventions to correct obstructive arterial disease have been developed worldwide with excellent short term results. However, long term patency is still limited by the onset of restenosis, due to subsequent intimal hyperplasia (IH). IH is characterized by proliferation and migration of smooth muscle cells (SMC) and extracellular matrix production. Targeting of SMC by photozensitisers can be efficiently achieved by taking advantage of the receptors for low density lipoproteins (LDL) expressed by such cells. Thus, preference is given to hydrophobic compounds which readily partition in the lipid matrix of LDL. We developed a liposomal formulation of a highly hydrophobic photozensitising agent, Zn(II)-phthalocyanine (ZnPc). The liposome-delivered ZnPc was readily taken up by cultured SMC cells and preferentially localized in the Golgi apparatus. Red light irradiation of incubated SMC induced cell death. Extension of these investigations to an in vivo rabbit model showed that ZnPc mainly accumulated in the media layer, where PDT induces the main damage through cellular depletion due to apoptosis of SMC, changes in the extracellular matrix with generation of a barrier to cellular migration, and acceleration of re-endothelization. Initial clinical applications showed that PDT safely and effectively prevents restenosis after angioplasty up to a 6 month follow-up.

Ionizing Radiation to Prevent Arterial Intimal Hyperplasia At the Edges of the Stent: Induces Necrosis and Fibrosis

Although ionizing radiation has been proposed for the prevention of intimal hyperplasia in coronary and peripheral arteries in multicenter clinical trials, information is lacking on how irradiation affects arterial histology after stenting and especially how it affects the edges of the stent. We investigated intimal hyperplasia recasting with histological changes in arterial wall at the edges of the stent after arterial stenting followed by adequate external radiation for the prevention of intimal hyperplasia in pigs. The aorta was experimentally stented in 30 pigs who were then assigned to two groups: irradiation with 20 Gy and a control group with no irradiation. The aorta was resected for morphometric and histological studies 6 weeks after procedure. Intimal thickness was reduced and the intima/media ratio was significantly lower in irradiated groups than in control pigs. In the irradiated group histological examination at the edges of the stent showed thin neointimal proliferation with an intact endothelium. In all sections analyzed in the 20-Gy irradiated group the vascular media at 45 days contained necrotic areas and fibrosis with calcifications. After arterial injury, adequate ionizing radiation effectively reduces neointimal thickening. Irradiation-induced histological changes include previously undetected recasting with necrosis and fibrosis at the arterial edges of the stent. The parietal recasting we observed in animal arteries irradiated at high doses is unclear and a cause of concern especially after clinical spontaneous dissection was recently reported. The use of ionizing radiation for the prevention of arterial restenosis awaits confirmation with a long-term follow-up including specific experimental histological analyses.

Inactivation of vascular smooth muscle cells photosensitised by liposome-delivered Zn(II)–phthalocyanine

Photodynamic therapy is a promising approach for the prevention of arterial restenosis, which frequently occurs after balloon angioplasty, largely owing to abnormal proliferation of vascular smooth muscle cells (VSMC) and their migration from the media to the intima, where they originate intimal hyperplasia (IH). We investigated the efficacy of Zn(II)–phthalocyanine-photosensitised processes in promoting the inactivation of VSMC. This liposome delivered phthalocyanine is readily taken up by VSMC, largely partitions in the Golgi apparatus, and upon photoactivation causes >95% cell mortality using mild irradiation conditions (e.g. 5 min irradiation at 1 μM ZnPc). Cell death occurs through the parallel development of random necrotic and apoptotic processes.

Experimental study of Salvia Miltiorrhiza on the prevention of restenosis after angioplasty

For evaluating the possibility of Salvia miltiorrhiza (SM) on the prevention of arterial restenosis after angioplasty, we investigated the effect of SM on the intimal thickening of air-injured carotid artery of rats. The results showed that the maximal intimal thickness of the injured arteries was much thinner in the treatment group than that in the control group, indicated that SM could prevent experimental restenosis in rat model. Furthermore, we examined the effect of SM on the proliferation of the isolated rabbit arterial smooth muscle cells (SMC) cultivated in vitro. The results showed that SM inhibited the 3H-TdR take-up and proliferation of SMC in a dose-dependent manner. The study raised the possibility that SM could be used to prevent arterial restenosis after angioplasty.

Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double-blind, placebo-controlled trial. Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism Study (CARPORT).

GR32191B is a novel thromboxane A2-receptor antagonist with potent antiagregational and antivasoconstrictive properties. We have conducted a randomized, double-blind placebo-controlled trial to study its usefulness in restenosis prevention. Patients received either GR32191B (80 mg orally before angioplasty and 80 mg/day orally for 6 months) or 250 mg i.v. aspirin before angioplasty and placebo for 6 months. Coronary angiograms before angioplasty, after angioplasty, and at 6-month follow-up were quantitatively analyzed. Angioplasty was attempted in 697 patients. For efficacy analysis, quantitative angiography at follow-up was available in 522 compliant patients (261 in each group). Baseline clinical and angiographic parameters did not differ between the two treatment groups. The mean difference in coronary diameter between postangioplasty and follow-up angiogram (primary end point) was -0.31 +/- 0.54 mm in the control group and -0.31 +/- 0.55 mm in the GR32191B group. Clinical events during 6-month follow-up, analyzed on intention-to-treat basis, were ranked according to the highest category on a scale ranging from death (control, six; GR32191B, four) to nonfatal infarction (control, 22; GR32191B, 18), bypass grafting (control, 19; GR32191B, 22) and repeat angioplasty (control, 52; GR32191B, 48). No significant difference in ranking was detected. Six months after angioplasty, 75% of patients in the GR32191B group and 72% of patients in the control group were symptom free. Long-term thromboxane A2-receptor blockade with GR32191B does not prevent restenosis and does not favorably influence the clinical course after angioplasty.