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Coronary artery stenting is currently the most frequently performed percutaneous coronary intervention for the treatment of coronary artery disease. The endothelium is a single layer of endothelial cells lining the vascular wall and plays an integral part in maintaining vascular homeostasis. Stenting however causes significant injury to the vascular wall and endothelium, resulting in inflammation, repair and the development of neointimal hyperplasia. The ability of the endothelium to repair itself depends on both the migration of surrounding mature endothelial cells, and the attraction and adhesion of circulating endothelial progenitor cells (EPCs) to the injured region, which then differentiate into endothelial-like cells. Current therapies with drug-eluting stents interrupt the natural response to damage. Accelerating the reendothelialization of the damaged arterial segment following stent implantation is an attractive form of therapy as it is seen as hastening the natural process of repair. It potentially has the benefit of reducing the amount of neointimal hyperplasia and stent thrombosis. Studies have been performed to identify agents that augment the mobilisation and recruitment of EPCs to the injured area (statins, exercise, estrogen and cytokines). Other studies have looked at seeding stents with endothelial cells or EPCs. The most current approach is to coat anti-CD34 antibodies on a stent surface to attract circulating EPCs to the stent which then differentiate into endothelial-like cells. This approach is currently being tested in safety and feasibility clinical studies.

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The aim of the study was to determine the safety and efficacy of the second-generation ACS Multi-Link Duet coronary stent system for the treatment of single, symptomatic, de novo, native coronary artery lesions. Between February and June 1998, 427 patients (69.3% male, 51.5% class 3 or 4 angina, 20.1% diabetic, 43.6% hyperlipidemia) were included at 38 centers in this prospective observational study. All patients received ticlopidine 500 mg/day for 1 month and aspirin > or =100 mg/day. The Duet stent was available in 8, 18, and 28 mm length and 3.0, 3.5, and 4.0 mm diameter. After adequate predilatation, stents were successfully implanted, at up to 16 atm, in 99.3% of patients. Mean vessel diameter by core laboratory quantitative coronary angiography was 3.0 +/- 0.53 mm and postprocedural minimum luminal diameter was 2.79 +/- 0.43 mm (12% +/- 9.3% diameter stenosis). At 30 days, 96.7% of patients were event-free and at 6 months 88.1% remained free of major adverse cardiac events. The restenosis rate was 18.1%. The ACS Duet stent was safely implanted in >99% of target lesions by a diverse group of international investigators. With late outcomes at least comparable to the best published results, this stent platform provides safe and effective percutaneous treatment of obstructive coronary artery disease. Cathet Cardiovasc Intervent 2001;54:25-33.

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PURPOSE: Endovascular radiation therapy is a promising strategy for the prevention of restenosis. Radiation prevents proliferation of vascular smooth muscle cells, thereby reducing the incidence of restenosis, but may also affect the remaining endothelial cells. For this reason, a comparison was made between irradiated and nonirradiated endothelial cells and their effects on the proliferation of vascular smooth muscle cells in a coculture system was evaluated. MATERIALS AND METHODS: A coculture system was used, in which both endothelial cells and vascular smooth muscle cells were grown on opposite sides of a semipermeable membrane. After a period of growth arrest, the proliferation of vascular smooth muscle cells was measured during four subsequent days. RESULTS: The presence of endothelial cells stimulated the proliferation of vascular smooth muscle cells during the first days of analysis but had an inhibitory effect during the subsequent days (P <.5). gamma-irradiation of endothelial cells resulted in a complete blockage of the proliferation of these cells. However, irradiated endothelial cells affected the proliferation of vascular smooth muscle cells in coculture in a fashion comparable to nonirradiated endothelial cells (P >.5). CONCLUSION: The results suggest that, in endovascular radiation therapy, irradiation of endothelial cells does not change their effects on the proliferative behavior of vascular smooth muscle cells.

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OBJECTIVES: To evaluate the effectiveness of electively placed heparin-coated stents in the treatment of coronary saphenous vein bypass grafts with de novo lesions less than 15 mm in diameter in a prospective study with all eligible consecutive patients presenting to Middelheim Hospital, Antwerp, Belgium between September 1997 and August 1998. PATIENTS AND METHODS: Fifty patients with 53 lesions were studied. Anginal class, risk factors, quantitative coronary angiographic measurements pre- and postprocedure, procedural outcome, in-hospital events, clinical status on discharge, and six-month clinical and angiographic follow-up (in 48 patients) were recorded. All patients received acetylsalicylic acid and ticlopidine, unless known intolerance was present. RESULTS: On average, 1.1 stents/patient were placed in very old saphenous vein grafts (11. 7+/-3.9 years). Procedural success was 98%. Only two non-Q wave myocardial infarctions (MIs) occurred, with no Q-wave MIs and no deaths during hospital stay. Length of hospital stay was short (2. 4+/-1.7 days), and 96% of patients were free of angina on discharge. At six-months' follow-up, two patients had died, one of whom died of a noncardiac cause. One patient suffered a non-Q wave MI. At six months, 86% of patients were free from angina. Minimal luminal diameter decreased from 1.14 mm before to 3.33 mm after stenting and to 2.52 mm at six months. Restenosis was present in 22% of patients (21.6% of lesions). CONCLUSIONS: In a selected population with coronary saphenous vein bypass graft disease, Wiktor heparin-coated stents can be delivered with an excellent periprocedural outcome. Six-month outcome appears favourable with a low recurrence of angina (18%) and a low rate of angiographic restenosis (21.6%).

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While quantitative coronary angiography (QCA) remains the standard used to assess new interventional therapies, intracoronary ultrasound (ICUS) is gaining interest. The aim of the study was to determine the relationship between QCA and quantitative coronary ultrasound (QCU) measurements after stenting. Sixty-two consecutive patients with both QCA and QCU analysis after stent implantation were included in the study. The mean luminal diameter (QCU vs. QCA) were 2.74 +/- 0.46 mm and 2.41 +/- 0.49 mm (P < 0.0001), the minimal luminal diameter (MLD) 2.08 +/- 0.44 mm and 1.62 +/- 0.42 mm (P < 0. 0001), and the projected QCU MLD 1.90 +/- 0.42 mm (P < 0.0001 with respect to QCA). Percentage obstruction diameter (QCU vs. QCA) were 41.53% +/- 10.78% and 43.15% +/- 12.72% (P = NS). The stent diameter (QCU vs. QCA) were 3.54 +/- 0.65 mm and 3.80 +/- 0.37 mm (P = 0. 0004). Stent length measured by QCU were longer at 31.11 +/- 13.54 mm against 28.63 +/- 12.75 mm, P < 0.0001 with respect to QCA. In conclusion, while QCA and QCU appear to be comparable tools for measuring corrected stent diameters and stent lengths, smaller luminal diameters were found using QCA. This is of particular relevance to quantitative studies addressing absolute changes in vascular or luminal diameters. Cathet. Cardiovasc. Intervent. 48:133-142, 1999.

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Percutaneous therapy of coronary bifurcated lesions is associated with greater risk of acute complications and late restenosis. Numerous innovative techniques using various stent types have been proposed. We report the first clinical use of a truly bifurcated stent (Bard XT Carina). The implantation procedure, favorable medium-term angiographic and 1-year clinical follow-up of the first human use in a 43-year-old female are illustrated with angiography and intravascular ultrasound. As a single prosthesis that effectively covers the bifurcation, this stent presents appealing alternative for the treatment of coronary bifurcation lesions when compared to methods that involve multiple-stent implantation. Cathet. Cardiovasc. Intervent. 47:361-369, 1999.

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BACKGROUND: The non-uniform extent and distribution of atherosclerotic plaque at bifurcations have been described by necropsy studies and they are related to local blood-flow disturbances. Systematic evaluation of plaque extent and distribution upstream and downstream of major coronary side-branches has not yet been evaluated in vivo. METHODS: We used intravascular ultrasound imaging in 41 patients with atherosclerotic disease to study the region of 73 major coronary side-branches at 2 mm increments proximal and distal to the side-branch (657 images: 73 at origin of side-branch; 292 proximal; 292 distal). The maximum (MXT) and minimum (MINT) plaque thickness and the plaque burden percentage (% PB) were measured in all the segments. The angle of distribution of maximum plaque thickness with respect to the origin of the side-branch was determined in each cross-section and assigned to S1 when located on the semicircle in the direction of the origin of the side-branch and to S2 when located on the opposite wall. RESULTS: The mean value of maximum plaque thickness and the plaque burden percentage were similar at the origin and in the two adjacent segments proximal and distal to the side-branch (1.0 +/- 0.48 mm, 1.06 +/- 0.48 mm and 0.98 +/- 0.48 mm; 45 +/- 19%, 46 +/- 19% and 44 +/- 18%). In distal sites of analysis, the plaque was more frequently eccentric in comparison to proximal sites (presence of an arc of plaque-free wall: 79% versus 62% in very distal and in very proximal sites respectively; p < 0.05). The prevalence of maximum plaque in S2 was higher at the origin (84%) and in adjacent distal segments (86%) as compared with the adjacent proximal segments (60%; p < 0.0001). CONCLUSIONS: The distribution of plaque is influenced by the origin of a major coronary side-branch in patients with coronary atherosclerosis: in distal sites the location of maximum plaque is almost always eccentrically distributed on the wall opposite the take-off.

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A novel approach of cell seeding of stents using xenotransplanted endothelium is proposed. The advantages of this approach are that these doubly transgenic animals will provide a limitless supply of endothelial cells producing controllable levels of active compound. These foreign cells will act as Trojan horses, graciously accepted at face value by the host organism, but capable of modifying the pathophysiological response to vessel damage, typified by the process of restenosis. Once implanted, the production of the bioactive compound is under exogenous control by means of 'designer' genes coding for modified cell surface receptors, which are introduced with the transgene to provide controllable levels of compound. Interaction of an orally administered compound with the modified cell receptor will switch on the transgene, while in its absence the transgene remains dormant. We have been able to show the feasibility this type of approach has for other animal species, and it shows great potential for application to humans.

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BACKGROUND: Demonstration and quantification of site-specific intracoronary administration of compounds has been confined thus far to the experimental animal laboratory. The aim of this study was to describe a scintigraphic method to demonstrate site-specific intracoronary drug delivery in humans. The methods allow on-line visualization and off-line quantification of site-specifically infused gamma-emitting compounds. METHODS AND RESULTS: In 12 patients after balloon angioplasty, 99mTc-labeled heparin was administered at the site of dilatation by use of a coil balloon. Both the infusion period and the washout period after the end of infusion were monitored with a gamma-camera. A curve of counts per pixel as a function of time was derived that showed an accumulation phase during infusion followed by washout phase after the end of infusion. Both phases were fitted by regression analysis and showed a linear accumulation pattern and a biexponential washout pattern. After correction for background counts, 99mTc decay, and body attenuation, peak heparin amount and regional bioavailability were calculated. Peak amount was defined as the initial point of the slow washout component of the biexponential curve (elimination component), and regional bioavailability was defined as the area under the curve of accumulation and washout phase. Half-life and retention time, define as seven half-lives, were obtained by use of the elimination component after correction for 99mTc decay. Mean peak delivered amount was 45 +/- 44 IU (236 +/- 228 micrograms), corresponding to an efficiency of delivery ranging from 1% to 8% of the totally infused dose. Total regionally bioavailable heparin reached 244 +/- 194 IU.h (1.28 +/- 1.01 mg.h). Retention time varied from 12 to 90 hours (mean, 50:33 +/- 22:50 hours:minutes). CONCLUSIONS: Site-specific intracoronary heparin delivery after angioplasty by means of the coil balloon was demonstrated in humans, and regional pharmacokinetics was quantified by use of a radioisotopic technique.

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The use of 2-dimensional intravascular ultrasound (2-D IVUS) to improve the outcome of coronary stenting has gained clinical acceptance, and recently 3-D IVUS has been introduced to clinical practice. However, there have been no comprehensive studies comparing the measurements of the coronary dimensions after stenting obtained by the different approaches of IVUS and quantitative coronary angiography. We examined the minimal luminal cross-sectional area of 38 stents using 2-D IVUS, 3-D IVUS, and 2 standard methods of quantitative coronary angiography, edge detection (ED) and videodensitometry (VD). Correlations between 2-D IVUS and ED (r = 0.72; p < 0.0001), VD (r = 0.87; p < 0.0001), and 3-D IVUS (r = 0.81; p < 0.0001) were higher than the correlations seen between 3-D IVUS and ED (r = 0.58; p < 0.0005) and VD (r = 0.70; p < 0.0001). The measurements by 2-D and 3-D IVUS (8.32 +/- 2.50 mm2 and 8.05 +/- 2.66 mm2) were larger than the values obtained by the quantitative angiographic techniques ED and VD (7.55 +/- 2.22 mm2 and 7.27 +/- 2.21 mm2). Thus, concordance was seen among all of the 4 techniques, confirming the validity of using IVUS for determination of the minimal luminal cross-sectional area after coronary stenting. A particularly good correlation was found between VD and IVUS, perhaps because measurement of the luminal area is the basic quantification approach of both techniques, whereas the lower correlations of ED with IVUS and VD may be explained by the dependence of ED on the angiographic projections used, which is especially important in eccentric stent configurations.

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Stent use has been increasing steadily over the last 5 years and might be viewed as the "second wind" of angioplasty. A large number of different stents are now available, and many trials have been designed to assess their safety and efficacy. But do comparisons of the various stents serve a useful purpose-i.e., do they address real medical questions? Many issues remain unresolved, such as who should and should not be stented, what the actual costs are of this modality, and what the future holds in terms of multifunctional devices. In addition, research is under way to explore such areas as techniques for stent guidance, the role of anticoagulation and adjunctive therapies, treatment of patient subsets (e.g., those with ischemic syndromes or challenging coronary anatomy), and synergistic approaches (e.g., directional atherectomy, radiotherapy, laser angioplasty). The results of such studies are likely to change the face of interventional cardiology.

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Coronary artery restenosis remains the major limitation of balloon angioplasty and occurs in 30-50% of initially successful procedures. Our current understanding of pathophysiology of restenosis suggests that it involves three inter-related phases; (1) acute effects of thrombosis, (2) neointimal proliferation, and (3) acute recoil and chronic remodelling. In an attempt to prevent vessel restenosis both systemic and site-specific pharmacotherapy have been investigated. Although successful in animal models, systemically administered pharmacological agents for the prevention of restenosis in humans have not been effective. The local administration of compounds such as heparin, anti-thrombin agents, colchicine, angiopeptin, antineoplastic agents, calcium antagonists, nitrates, forskolin, cytochalasin B, protein kinase inhibitors and dexamethasone have been shown to reduce neointimal formation in animal models of restenosis. Clinical trials have demonstrated the feasibility of the local administration of heparin using both InfusaSleeve and Dispatch drug delivery catheters. Preliminary results on long-term prevention of restenosis by heparin appear promising using the Dispatch delivery device. In addition, a multicentre trial investigating the effectiveness of cytochalasin B delivered using the Microporous Infusion Catheter for the prevention of restenosis is currently underway. Rapid progress in our understanding of the complex pathophysiology of restenosis and the development of more effective pharmacological agents and atraumatic site specific delivery modalities ensure a promising future for local delivery strategies.

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Cholesterol oxidase (3 beta-hydroxy-steroid oxidase) catalyzes the oxidation of cholesterol to 4-cholesten-3 one and other oxidized cholesterol derivatives. The purpose of the present study was to investigate its effects on cultured vascular smooth muscle cells. Cultured rabbit aortic smooth muscle cells were morphologically altered after exposure to cholesterol oxidase in the presence of culture medium containing 10% fetal calf serum. If fetal calf serum was absent, cells were unaffected by the treatment. The extent of morphological change of the smooth muscle cells was dependent upon the time of exposure to the enzyme and the concentration of cholesterol oxidase employed. After moderate treatment with cholesterol oxidase, cells excluded trypan blue. Further, a specific mitochondrial marker DASPMI (dimethyl aminostyryl-methyl-pyridiniumiodine) which was used as a fluorescent index of cell viability, revealed that cell viability was unchanged after moderate cholesterol oxidase treatment. Nile red, a hydrophobic probe which selectively stains intracellular lipid droplets, was applied to detect the cellular lipid content after treatment with cholesterol oxidase. Cellular nile red fluorescence intensity increased linearly with the time and concentration of cholesterol oxidase treatment. These results demonstrate that cholesterol oxidase alters lipid deposition in the cell and changes cell morphology. The primary site of action of cholesterol oxidase appears to be independent of the cell membrane itself and instead is dependent upon the lipid content in the surrounding culture media. These changes occur prior to the cytotoxic effects of extensive oxidation. Because oxidized cholesterol may play an important role in the pathogenesis of atherosclerosis, our results have implications for intracellular accumulation of lipids in smooth muscle cells during the atherosclerotic lesion.

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It has been proposed that low density lipoprotein (LDL) must undergo oxidative modification before it can participate in atherosclerosis. The present paper studied the effect of cholesterol oxidation in LDL on cultured vascular smooth muscle cells. LDL was oxidized by cholesterol oxidase (3-beta-hydroxy-steroid oxidase) which catalyzes the oxidation of cholesterol to 4-cholesten-3 one and other oxidized cholesterol derivatives. Cholesterol oxidase treatment of LDL did not result in lipid peroxidation. Cultured rabbit aortic smooth muscle cells were morphologically changed following exposure to cholesterol oxidized LDL. Nile red, a hydrophobic probe which can selectively stain intracellular lipid droplets, was applied to detect the cellular lipid content after treatment with oxidized or non-oxidized LDL cholesterol. LDL which did not undergo oxidation of its cholesterol had no effect on the cells. However, cellular nile red fluorescence intensity was increased as the pre-incubation time of cholesterol oxidase with LDL increased. This was supported by HPLC analysis which revealed that the oxidized cholesterol content of treated cells increased. These findings suggest that cholesterol oxidation of LDL can alter lipid deposition in the cells and change cell morphology. The oxidation of cholesterol in vivo may play an important role in the modification of LDL which could contribute to the generation of the lipid-laden foam cells.

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Oxygen free radicals have the ability to oxidize cholesterol. However, nothing is known about the effects of cholesterol oxidation on ion transport in isolated myocardial membranes. The purpose of the present study was to investigate the effects of in situ oxidative modification of sarcolemmal cholesterol on Ca2+ flux. Cholesterol oxidase was used to oxidatively modify membrane cholesterol. After incubation of cardiac sarcolemmal vesicles with cholesterol oxidase, cholest-4-en-3-one (cholestenone) was the predominant species of oxidated cholesterol produced. Cholesterol oxidase inhibited sarcolemmal Na(+)-Ca2+ exchange in a concentration-dependent manner. Both the Vmax and Km of the reaction were altered after cholesterol oxidase treatment. Extensive treatment of the sarcolemmal membranes with cholesterol oxidase increased the passive permeability characteristics of the membrane. Passive Ca2+ efflux from the sarcolemmal vesicles was stimulated by increasing the concentration of cholesterol oxidase. ATP-dependent Ca2+ uptake was also inhibited after cholesterol oxidase treatment, but it was not as sensitive as the Na(+)-Ca2+ exchange. Conversely, passive Ca2+ binding to sarcolemmal vesicles was strikingly stimulated by cholesterol oxidase treatment. The results demonstrate that oxidative modification of sarcolemmal membrane cholesterol can directly affect ionic interactions with the sarcolemmal vesicle and provide potentially important mechanistic information for the molecular basis of the effects of free radicals on ion flux and function in the heart.

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The effects of platelet-activating factor (PAF) on Na(+)-dependent calcium uptake in myocardial sarcolemmal vesicles were examined in order to clarify its mechanism of inotropic action on the heart. PAF (40 and 20 microM) significantly inhibited Na(+)-Ca2+ exchange by 61% and 37%, respectively. Both initial rate of exchange and maximal exchange were inhibited. The Km for the reaction was not altered but Vmax was lowered 55% by PAF. Lyso-PAF inhibited Na(+)-Ca2+ exchange to a similar degree as PAF. CV-3988, a specific PAF receptor antagonist, failed to diminish the inhibitory effect of PAF on Na(+)-Ca2+ exchange, suggesting that the effect of PAF on Na(+)-Ca2+ exchange is not via a receptor mechanism. The passive permeability of sarcolemmal vesicles to Ca2+ was markedly elevated after PAF treatment. However, this effect could not account for the decrease in Na(+)-Ca2+ exchange. Interestingly, passive Ca2+ binding to cardiac sarcolemma was increased by 40 microM PAF. This study indicates that a depression of Na(+)-Ca2+ exchange probably does not play a role in the negative inotropic effect of PAF on the myocardium under physiological conditions. Its mechanism of action on Na(+)-Ca2+ exchange is discussed.

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Calcium exchange was measured in enzymatically isolated, cultured smooth muscle cells from the rabbit thoracic aorta. Cells were grown to confluence in monolayer on scintillator discs which were then inserted into a modified flow cell/spectrometer to measure 45Ca exchange in a continuous, on-line manner. This also allowed us to measure rapid movements of cellular Ca2+ without solubilizing the cells. Two components of Ca2+ exchange were detected: a La3+-displaceable, rapidly exchangeable fraction (t 1/2 = 15.6 s) and a slowly exchangeable fraction (t 1/2 = 34.5 min). The La3+ displaceable, rapidly exchangeable Ca2+ fraction represented 57 to 61% of the total exchangeable Ca2+. Multiple passaging of cells did not after the Ca2+ flux characteristics. Low Na+ perfusion increased smooth muscle cell Ca2+ flux by 6.71 mmol/kg dry weight. This increase was localized to both the rapidly and slowly exchangeable Ca2+ compartments. Ouabain, an inhibitor of the plasmalemmal Na+ -K+ pump, also increased net uptake of 45Ca. The results demonstrate that approximately 60% of exchangeable Ca2+ of smooth muscle cells is very rapidly exchangeable (t 1/2 less than 16 s). The results stress the importance of measuring 45Ca2+ movements in an on-line, continuous manner in order to ensure detection of the majority of total exchangeable Ca2+ in smooth muscle cells.

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The purpose of the present study was to examine the effects on cataractogenesis of daily sc administration of the Ca2+ antagonist drug verapamil to diabetic rats. Streptozotocin-induced diabetic rats were given verapamil half-way through the 8-week experimental period or during the full 8 weeks of diabetes. Verapamil administration had no effect on the high blood glucose values, low circulating insulin levels, or elevated triglyceride and cholesterol concentrations in the diabetic rats. Untreated diabetic rats had a 90% incidence of cataracts. Four weeks of verapamil administration reduced this incidence to 41%, and a full 8 weeks of drug treatment further lowered the incidence to 20%. Diltiazem, another Ca2+ antagonist, lowered the incidence of cataracts in the diabetic rats to a similar extent. Verapamil administration to the diabetic animals also partially protected against the presence of retinal microangiopathy in the diabetic animals. Lenticular hydration and lipid accumulation were only indirectly related to cataractogenesis in the diabetic rats and its protection by verapamil treatment. Lenticular electrolyte imbalance, particularly Ca2+, in the diabetic animals was closely correlated with cataract formation, and verapamil significantly reduced the alterations in these ion concentrations. The present results demonstrate the efficacy of verapamil as a protective agent against cataractogenesis and some retinal damage in diabetic animals. Most importantly, this occurs in the absence of any change in the glycemic status of the diabetic animals. The findings strongly support a role for lenticular Ca2+ imbalance in cataract development in diabetes and provide initial evidence to suggest its clinical use in the diabetic population at risk for blindness.

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