Effects of cytochalasin D-eluting stents on intimal hyperplasia in a porcine coronary artery model.

OBJECTIVE: To investigate whether cytochalasin D-eluting stents (CDES) suppress intimal hyperplasia in porcine coronary arteries and to compare the efficacy of paclitaxel and cytochalasin D as inhibitors of vascular smooth muscle cell (SMC) proliferation and platelet aggregation in vitro. METHODS: Rabbit platelet-rich plasma and SMC cultures derived from rabbit aortas were exposed to 10(-8)-10(-5) M cytochalasin D or paclitaxel. Stents directly coated with 2 microg cytochalasin D (low-dose CDES, n=12) and bare stents (n=12) were randomly deployed in the right and left coronary artery of 12 pigs. Six weeks later, neointima was studied using quantitative coronary angiography (QCA) and morphometry. To examine a ten-fold higher dose, polybutyl methacrylate/polyvinyl acetate-coated stents were loaded with 20 microg cytochalasin D. High-dose CDES (n=10) and polymer-only stents (n=11) were deployed in 11 pigs. RESULTS: After 7 days, cytochalasin D (IC(50) 9.9+/-0.4 10(-8) M) and paclitaxel (IC(50) 1.1+/-0.4 10(-8) M) inhibited SMC proliferation in vitro (n=4). In contrast, cytochalasin D (10(-6)-10(-5) M, n=5), but not paclitaxel, attenuated platelet shape change and aggregation induced by ADP. In vivo QCA showed less late lumen loss in low-dose CDES (0.08+/-0.07 vs. 0.32+/-0.08 mm, P=0.05), but morphometry demonstrated only a tendency toward a decreased intimal area. High-dose CDES inhibited both late lumen loss (0.31+/-0.08 vs. 0.91+/-0.06 mm, P<0.01) and intimal area (1.57+/-0.20 vs. 2.46+/-0.22 mm(2), P<0.01). Immunohistochemistry revealed that CDES suppressed peri-strut macrophage recruitment (CD68, P=0.04) and cell proliferation (Ki67, P=0.03) as compared to polymer-only stents without interfering with endothelial cell recovery or the density of alpha-SMC actin staining. Thromboses or edge effects were not observed in either study. CONCLUSIONS: CDES inhibited in-stent hyperplasia. The reduction (39%) with 20 mug CDES was equivalent to that reported for paclitaxel-eluting stents in pigs. Interference with platelet aggregation, SMC migration, SMC proliferation, and leukocyte recruitment could contribute to the benefit. The data indicate that targeting of actin microfilaments has a potential to suppress in-stent restenosis.

Cellular mechanisms of contractile dysfunction in hibernating myocardium.

Ischemic heart disease is a leading cause of chronic heart failure. Hibernation (ie, a chronic reduction of myocardial contractility distal to a severe coronary stenosis and reversible on revascularization) is an important contributing factor. The underlying cellular mechanisms remain however poorly understood. In young pigs (n=13, ISCH), an acquired coronary stenosis >90% (4 to 6 weeks) resulted in the development of hibernating myocardium. Single cardiac myocytes from the ISCH area were compared with cells from the same area obtained from matched normal pigs (n=12, CTRL). Myocytes from ISCH were larger than from CTRL. In field stimulation, unloaded cell shortening was reduced and slower in ISCH; relaxation was not significantly different. The amplitude of the [Ca2+]i transient was not significantly reduced, but reducing [Ca2+]o for CTRL cells could mimic the properties of ISCH, inducing a significant reduction of contraction, but not of [Ca2+]i. Action potentials were longer in ISCH. With square voltage-clamp pulses of equal duration in ISCH and CTRL, the amplitude of the [Ca2+]i transient was significantly smaller in ISCH, as was the Ca2+ current. Near-maximal activation of the myofilaments resulted in smaller contractions of ISCH than of CTRL cells. There was no evidence for increased degradation of Troponin I. In conclusion, cellular remodeling is a major factor in the contractile dysfunction of the hibernating myocardium. Myocytes are hypertrophied, action potentials are prolonged, and L-type Ca2+ currents and Ca2+ release are decreased. The steep [Ca2+]i dependence of contraction and possibly a reduction of maximal myofilament responsiveness further enhance the contractile deficit.

Defining the transmurality of a chronic myocardial infarction by ultrasonic strain-rate imaging: implications for identifying intramural viability: an experimental study.

BACKGROUND: In a correlative functional/histopathologic study, we investigated the regional deformation characteristics of both chronic nontransmural and transmural infarctions before and after a dobutamine challenge. METHODS AND RESULTS: After stenosing copper-coated stent implantation to produce circumflex artery endothelial proliferation, 18 pigs were followed up for 5 weeks. Posteuthanasia histology showed 10 to have a nontransmural and 8 a transmural infarction. Eight nonstented animals served as controls. Regional radial function was monitored by measuring ultrasound-derived peak systolic strain rates (SR(SYS)) and systolic strains (epsilon(SYS)) (1) before stent implantation and (2) at 5 weeks, at baseline (bs) and during an incremental dobutamine infusion. In controls, dobutamine induced a linear increase in SR(SYS) (dobutamine: bs, 4.8+/-0.4 s(-1); 20 microg x kg(-1) x min(-1), 9.9+/-0.7 s(-1); P<0.0001) and an initial increase of epsilon(SYS) at low dose (bs, 58+/-5%; at 5 microg x kg(-1) x min(-1), 78+/-6%; P<0.05) but a subsequent decrease during higher infusion rates. In the nontransmural group, bs SR(SYS) and epsilon(SYS) were significantly lower than prestent values (SR(SYS), 2.9+/-0.5 s(-1) and epsilon(SYS), 32+/-6%, P<0.05 versus prestent). During dobutamine infusion, SR(SYS) increased slightly at 5 microg x kg(-1) x min(-1) (4.7+/-0.6 s(-1), P<0.05) but fell during higher infusion rates, whereas epsilon(SYS) showed no change. For nontransmural infarctions, transmural scar extension correlated closely with epsilon(SYS) at bs (r=0.88). For transmural infarctions, SR(SYS) at bs was significantly reduced and epsilon(SYS) was almost not measurable (SR(SYS), 1.8+/-0.3 s(-1); epsilon(SYS), 3+/-4%). Both deformation parameters showed no further change during the incremental dobutamine infusion. CONCLUSIONS: Ultrasonic deformation values could clearly differentiate chronic nontransmural from transmural myocardial infarction. The transmural extension of the scar could be defined by the regional deformation response.

Inhibition of restenosis with a paclitaxel-eluting, polymer-free coronary stent: the European evaLUation of pacliTaxel Eluting Stent (ELUTES) trial.

BACKGROUND: The use of a stent to deliver a drug may reduce in-stent restenosis. Paclitaxel interrupts the smooth muscle cell cycle by stabilizing microtubules, thereby arresting mitosis. METHODS AND RESULTS: On the basis of prior animal studies, the European evaLUation of the pacliTaxel Eluting Stent (ELUTES) pilot clinical trial (n=190) investigated the safety and efficacy of V-Flex Plus coronary stents (Cook Inc) coated with escalating doses of paclitaxel (0.2, 0.7, 1.4, and 2.7 microg/mm2 stent surface area) applied directly to the abluminal surface of the stent in de novo lesions compared with bare stent alone. The primary efficacy end point was angiographic percent diameter stenosis at 6 months. At angiographic follow-up, percent diameter stenosis was 33.9+/-26.7% in controls (n=34) and 14.2+/-16.6% in the 2.7-microg/mm2 group (n=31; P=0.006). Late loss decreased from 0.73+/-0.73 to 0.11+/-0.50 mm (P=0.002). Binary restenosis (> or =50% at follow-up) decreased from 20.6% to 3.2% (P=0.056), with no significant benefit from intermediate paclitaxel doses. Freedom from major adverse cardiac events in the highest (effective) dose group was 92%, 89%, and 86% at 1, 6, and 12 months, respectively (P=NS versus control). No late stent thromboses were seen in any treated group despite clopidogrel treatment for 3 months only. CONCLUSIONS: Paclitaxel applied directly to the abluminal surface of a bare metal coronary stent, at a dose density of 2.7 microg/mm2, reduced angiographic indicators of in-stent restenosis without short- or medium-term side effects.

Identification of acutely ischemic myocardium using ultrasonic strain measurements. A clinical study in patients undergoing coronary angioplasty.

OBJECTIVES: The goal of this study was to investigate whether the changes in myocardial deformation measured with ultrasonic strain could accurately identify acutely ischemic myocardium during coronary angioplasty. BACKGROUND: Early identification of acute myocardial ischemia has important clinical implications. The accuracy of ultrasonic strain for the detection of acute myocardial ischemia has been validated in animal experiments but has not been investigated in the clinical setting. METHODS: In 73 patients (64 +/- 12 years), either radial or longitudinal strain values were monitored in the "at-risk" segments before, during, and early after right, circumflex, and left anterior descending coronary angioplasty. Based on the visual wall motion assessed before the angioplasty, segments were divided into normokinetic (group I) and hypo/akinetic (group II). Strain data in the "at-risk " segments were compared with values derived from the adjacent nonischemic segments and normal values in 20 controls. RESULTS: Coronary occlusion induced a marked reduction in the systolic strain both in the radial (from 49 +/- 6.9% to 23 +/- 4.6% in group I and from 21.9 +/- 11% to 11.3 +/- 8.4% in group II, p < 0.001) and longitudinal directions. Concomitantly, postsystolic strain increased (from 3.8 +/- 3.1% to 14.6 +/- 9.5% in group I, and from 4.4 +/- 3.7% to 11.3 +/- 7.8% in group II in radial direction, p < 0.001). Upon reperfusion, all deformation parameters returned to near preocclusion values. In comparison with control, baseline, and reperfusion data, the systolic and postsystolic strain parameters measured during total coronary occlusion identified acutely ischemic myocardium with a sensitivity of 86% to 95% and a specificity of 83% to 89%. CONCLUSIONS: In this model of acute ischemia, ultrasonic strain indexes differentiate acutely ischemic segments from both normal and dysfunctional myocardium. This should be a promising new approach to the bedside monitoring of acute ischemic changes in regional myocardial function.

Direct stenting versus direct stenting followed by centered beta-radiation with intravascular ultrasound-guided dosimetry and long-term anti-platelet treatment: results of a randomized trial: Beta-Radiation Investigation with Direct Stenting and Galileo in Europe (BRIDGE).

OBJECTIVES: We sought to assess the efficacy of vascular brachytherapy (VBT) combined with stenting for the primary prevention of restenosis. BACKGROUND: Intravascular brachytherapy after stent implantation for de novo lesions has been abandoned for the present. We revisited this procedure by optimizing all procedural steps-the use of glycoprotein IIb/IIa blockers, direct stenting, adequate radiation coverage, avoidance of edge damage, source centering, intravascular ultrasound-guided dosimetry, and continuation of a dual anti-platelet regimen for one year. METHODS: The Beta-Radiation Investigation with Direct stenting and Galileo in Europe (BRIDGE) study is a multicenter, randomized controlled trial evaluating the long-term efficacy of VBT with P-32 (20 Gy at 1 mm in the coronary wall) after direct stenting. The primary end point was angiographic intra-stent late loss; secondary end points were six months binary restenosis and neo-intimal hyperplasia. Patients (n = 112) with de novo lesions (2.5 to 4.0 mm in diameter up to 15 mm long) were randomized to either VBT or no-VBT. RESULTS: At six months, intra-stent loss was 0.43 and 0.84 mm (p < 0.001) in the irradiated and control groups, respectively. Intra-stent neo-intimal volume was reduced from 36 mm3 to 10 mm3. However, in the irradiated group there were six late occlusions as well as eight restenoses outside the stented and peri-stented area at the fall-off dose edges of the irradiated area. Accordingly, the target vessel revascularization and major adverse cardiac and cerebrovascular events rates at one year in the VBT group (20.4% and 25.9%, respectively) were higher than in the control group (12.1% and 17.2%, respectively). CONCLUSIONS: Despite the optimization of pre-, peri-, and post-procedural factors and despite the relative efficacy of the brachytherapy for the prevention of the intra-stent neo-intimal hyperplasia, the clinical outcome of the irradiated group was less favorable than that of the control group.

Stent-mediated methylprednisolone delivery reduces macrophage contents and in-stent neointimal formation.

OBJECTIVE: Corticosteroids have a wide range of biological effects. Stent-based methylprednisolone delivery could effectively suppress peri-strut inflammation and neointima induced by a polymer matrix. We tested the safety and efficacy of local stent-mediated methylprednisolone delivery using a biological coating on in-stent neointimal formation in a porcine coronary stent model. METHODS: Stainless steel coronary stents were dip-coated in a biological polymer/ methylprednisolone solution, resulting in total load of 530 mug methylprednisolone per stent. In-vitro drug release was performed. Stainless steel bare stents, polymer-only and methylprednisolone-coated stents (MP) were implanted in coronary arteries of pigs with a stent/artery ratio of 1.2 : 1. Histopathologic evaluation, morphometry and immunohistochemistic staining were analyzed at 4-week follow-up. RESULTS: In-vitro drug release studies showed sustained release up to 10 weeks. In vivo the vascular response of polymer-only-coated stents was comparable with the bare stents. No increased peri-strut inflammation and neointimal hyperplasia were observed. The in-stent neointimal formation of methylprednisolone-coated stents was significantly reduced compared with the bare and polymer-only-coated stents (bare, 1.92+/-0.73; polymer-only, 2.14+/-1.50; MP, 1.01+/-0.47 mm, P=0.019). The macrophage content of methylprednisolone-coated stents (bare, 30.74+/-48.67; polymer-only, 19.55+/-24.60; MP, 1.16+/-3.33/mm, P=0.072) was dramatically decreased. However, there were no significant difference among the three group in terms of the proliferating cells expressed by proliferation cell nuclear antigens. CONCLUSION: Stent-based local methylprednisolone delivery could effectively decrease both vascular macrophage infiltration and in-stent neointimal hyperplasia.

Use of a tacrolimus-eluting stent to inhibit neointimal hyperplasia in a porcine coronary model.

In-stent restenosis remains an unresolved problem which occurs in 5-20% of patients undergoing coronary stenting within the first 3-6 months. Neointimal formation is the main contributor to in-stent restenosis. Stent-induced arterial injury and peri-strut inflammation are involved in the process of neointimal formation by activating cytokines and growth factors which induce smooth muscle cell dedifferentiation, migration, and proliferation. Histopathological studies found that neointimal hyperplasia is principally composed of smooth muscle cells, inflammatory cells, and extracellular matrix. Stent-based delivery of anti-proliferative and/or anti-inflammatory agents have shown beneficial effects on neointimal hyperplasia in experimental studies and clinical trials. Tacrolimus (FK506) is a water-insoluble macrolide immunosuppressant discovered in 1984. It has been widely used in reducing the incidence and severity of allograft rejection after organ transplantation. It has also been used to treat other inflammatory conditions such as atopic dermatitis. In this study, we evaluated the efficacy of stent-based delivery of tacrolimus on inflammation and neointimal formation in an overstretched coronary stent model.

Comparison of neointimal formation in polymer-free paclitaxel stents versus stainless stents (from the ASPECT and ELUTES randomized clinical trials).

The investigators examined 326 pairs of angiograms from 2 randomized dose-finding (0.2 to 3.1 microg paclitaxel/mm(2) of stent surface area) clinical trials of polymer-free paclitaxel-eluting stents in de novo lesions (the ASian Paclitaxel-Eluting stent Clinical Trial [ASPECT] and the European evaLUation of Taxol Eluting Stent [ELUTES]). A dose-dependent effect was observed: the largest dose of paclitaxel in the 2 trials resulted in a significantly larger proportion of lesions at follow-up with <10% diameter stenosis (54% vs 16%, p = 0.00012 in ASPECT; 53% vs 21%, p = 0.013 in ELUTES) and with minimal luminal diameter located outside the stent compared with control stents (62% vs 20% in ASPECT, 48% vs 18% in ELUTES; p <0.05). Also, significantly shorter lesion lengths at 6-month follow-up were observed for the doses of 0.7 to 3.1 microg/mm(2) (p <0.03) relative to their respective lengths before the procedure compared with control stents.

Acute changes in systolic and diastolic events during clinical coronary angioplasty: a comparison of regional velocity, strain rate, and strain measurement.

Ultrasound-derived natural strain rate and strain are new Doppler myocardial imaging (DMI) parameters, which can measure local deformation independently of overall heart motion and thus could better characterize local contractility than DMI velocities alone. This study was undertaken to evaluate the relative benefits of regional velocity, strain rate, and strain measurements in detecting the range of acute changes in regional myocardial function in the "at-risk" zone during coronary angioplasty. Sixty-one patients (aged 63 +/- 12, 18 women) with stable angina pectoris were studied before, at the end of, and during recovery from a 60-second percutaneous transluminal coronary angioplasty (PTCA) balloon occlusion. High frame rate (147 fps) color DMI regional velocity data were derived from basal posterior (parasternal view) and mid, apical septal (apical view) "at-risk" segments as well as from the corresponding segments in healthy subjects and analyzed offline for velocity (VEL), strain rate (SR), and strain (epsilon) measurements. Coronary occlusion resulted in the reduction in VEL(SYS), SR(SYS), and epsilon(SYS) values for both radial (RCA/CX occlusion) and longitudinal data (LAD occlusion) in all segments analyzed. Velocity parameters alone failed to distinguish between baseline and occlusive measurements in the "at-risk" segments with visually abnormal baseline function. SR(SYS) and epsilon(SYS) had a higher diagnostic accuracy (sensitivity 75%, 80% and specificity 80%, 82%, respectively) than VEL(SYS) velocity alone (sensitivity 68%, specificity 65%,) for identifying acute ischemia in either baseline normal and abnormal segments. DMI-derived indexes can identify and quantify the spectrum of acute systolic and diastolic ischemic changes induced during clinical PTCA. The quantitation of regional deformation rather than motion would appear to be more appropriate in detecting and quantifying acute ischemic changes in myocardial function, especially in segments with pre-existing abnormal function.

Can strain rate and strain quantify changes in regional systolic function during dobutamine infusion, B-blockade, and atrial pacing--implications for quantitative stress echocardiography.

BACKGROUND: We investigated the ability of ultrasonic strain rate (SR) and strain (epsilon) to quantify the changes in normal myocardial function at varying inotropic states and heart rates (HR) in an attempt to determine whether these new regional function indices are potentially robust enough to quantitate stress echocardiography. METHODS AND RESULTS: Twenty closed-chest pigs underwent incremental atrial pacing (AP: 120-180/min, n = 7), dobutamine infusion (DI: 2.5-20 microg/kg/min, n = 7) or esmolol infusion with subsequent pacing (EI: 0.5 +/- 0.15 mg/kg/min with pacing 120-180/min, n = 6). Radial deformation of the left ventricular posterior wall was interrogated using the parasternal short-axis view to derive regional systolic SR and epsilon values. At baseline SR and epsilon averaged 5.0 +/- 0.4 s(-1) and 60% +/- 4%, respectively. SR remained unchanged during AP and increased linearly with DI (at 2.5 microg/kg/min = 6.2 +/- 0.3 s(-1), P <.05 vs baseline; at 20 microg/kg/min = 9.9 +/- 0.7 s(-1), P <.0001 vs baseline), whereas EI resulted in a constant decrease of 30% +/- 4% in SR (P <.05). SR and left ventricular dP/dt(MAX) correlated linearly over the induced change in inotropic states and HR (r = 0.82; P <.0001). Conversely, epsilon values decreased during AP (at 180/min = 36% +/- 2%, P <.001). During DI, epsilon initially increased at 2.5 and 5 microg/kg/min (at 5 microg/kg/min = 77% +/- 6%, P <.05) and decreased for higher doses because of increasing HR. EI resulted in a decrease of 30% +/- 4% in epsilon with a further decrease during subsequent pacing. epsilon correlated linearly with left ventricular ejection fraction (r = 0.87; P <.0001). CONCLUSION: Both SR and epsilon can quantify the changes in myocardial function during a range of inotropic challenges and over the range of physiologic HRs encountered during clinical stress echocardiography. SR may reflect regional contractile function, whereas epsilon reflects changes in ventricular geometry. This study would suggest that for quantitative stress echocardiography SR is better in quantification of changes in contractile function being relatively independent of HR.

Long-term biocompatibility evaluation of a novel polymer-coated stent in a porcine coronary stent model.

BACKGROUND: Polymer coatings have been used to modify the surface of stents and to serve as a matrix for local drug delivery. METHODS: Bare stainless steel stents or poly-bis-trifluorethoxy phosphazene (PTFEP) dip-coated stents (Coroflex, Germany) were randomly implanted into porcine coronary arteries with a balloon-to-artery ratio of 1.1-1.2 : 1. Scanning electron microscopy (SEM), repeat quantitative coronary angiography (QCA) and histomorphometric analysis were performed at 5 days, 6 weeks and 6 months. RESULTS: At 5 days, complete endothelial cell coverage with fibrin strands was detected in both the bare and the coated stents with SEM. Late loss, determined by QCA, of coated and bare stents was identical at all time points. Histomorphometric analysis showed that coated and bare stents elicited a similar tissue response at 5 days. At 6 weeks, the coated stents showed a moderate peri-strut inflammatory response, resulting in increased neointimal hyperplasia. Compared to the bare stents, however, no significant differences were observed. At 6 months, peri-strut inflammation was minimal and similar in the coated and the bare stent groups. Neointimal hyperplasia of the coated and bare stent groups was also comparable (1.37+/-0.44 compared with 1.15+/-0.40 mm2, P=0.213) and decreased compared to the 6-week response. CONCLUSION: This PTFEP stent coating showed a long-term biocompatibility in a porcine coronary stent model. Because no increased proliferative response was observed up to 6 months, this phosphazene coating may serve as a vehicle for local drug delivery.

Addition of cytochalasin D to a biocompatible oil stent coating inhibits intimal hyperplasia in a porcine coronary model.

BACKGROUND: Polymer-based, drug-eluting stents, are currently under extensive investigation in the conquest against in-stent restenosis. Concern remains, however, about potential long-term lack of biocompatibility of the polymers used in these studies. Therefore, this study aimed to evaluate in porcine coronary arteries (1) the in vivo biocompatibility of a new natural, eicosapentaenoic acid oil stent-coating and (2) the efficacy of this coating in preventing in-stent restenosis when cytochalasin D--an inhibitor of actin filament formation, that interferes with cell proliferation and migration--was added. METHODS AND RESULTS: To assess in vivo biocompatibility of the oil coating, 15 bare and 15 oil-coated stents were randomly deployed in coronary arteries of 15 pigs. No difference in tissue response, regarding inflammation or proliferation, was seen between both groups at five days or at four weeks follow-up. To evaluate the efficacy of the coating in preventing in-stent restenosis by adding a potential anti-restenotic drug, stents were dip-coated in 20 mg cytochalasin D/ml oil solution, resulting in 93 +/- 18 microg cytochalasin D/stent load (n = 3). In vitro drug release studies showed sustained release up to four weeks. Next, 11 oil-coated and 11 cytochalasin D-loaded stents were randomly implanted in coronary arteries of 11 pigs. At four weeks, a 39% decrease in neointimal hyperplasia (p < 0.05, ANCOVA, with injury as covariate) was found in cytochalasin D-loaded stents compared to oil-coated stents. CONCLUSIONS: This new natural oil stent-coating shows excellent biocompatibility to vascular tissue. Local cytochalasin D delivery from this stent-platform significantly inhibits neointimal hyperplasia in a porcine coronary model.

In-vivo biocompatibility evaluation of stents coated with a new biodegradable elastomeric and functional polymer.

BACKGROUND: In-stent restenosis may be prevented by impregnating an antiproliferative agent in a polymer from a stent platform. This approach requires both an antiproliferative agent effective in small doses and a biocompatible polymer. METHODS: A series of new biodegradable elastomeric poly(ester-amide)(co-PEA) polymers having functional carboxyl groups for drug conjugation were synthesized from non-toxic building blocks. The in-vivo biocompatibility was tested in porcine coronary arteries, by comparing the polymer-coated stents with bare metal stents in 10 pigs. RESULTS: All animals survived until sacrifice 28 days later and follow-up angiography prior to sacrifice revealed identical diameter stenosis (21 +/- 23%) in both groups. Histology confirmed similar injury scores (0.34 +/- 0.34 compared with 0.34 +/- 0.32), inflammatory reaction (1.18 +/- 0.38 compared with 1.11 +/- 0.32) and area stenosis (26 +/- 17% compared with 28 +/- 22%). CONCLUSIONS: This study suggests that the newly developed copoly(ester-amide) elastomers may be suitable for stent-based local drug delivery.

Dexamethasone-eluting stent: an anti-inflammatory approach to inhibit coronary restenosis.

The long-term efficacy of percutaneous coronary interventions is still hampered by restenosis. Restenosis is the result of a complex pathophysiological process, which is thought to be caused by an exaggerated healing response induced by the vascular injury caused by the percutaneous coronary interventions and the implantation of a foreign body (the stent). There is increasing evidence that inflammation plays an important role in the initiation and development of neointimal hyperplasia and subsequent restenosis. Dexamethasone (Decadron, Merck Sharpe and Dohme Ltd) is a glucocorticoid with well-known potent anti-inflammatory and antiproliferative properties. Early studies using either systemic or local delivery of dexamethasone have shown limited beneficial effects on restenosis. The dexamethasone-eluting stent (Dexamet, Abbott Vascular Devices Ltd) is one of the first generation of drug-eluting stents for local drug delivery to prevent restenosis. Preclinical studies demonstrated that implantation of dexamethasone-loaded coronary stents was safe and had a beneficial effect on stent implantation-related inflammation. A pilot trial suggested a beneficial effect on restenosis. Large randomized trials are underway to confirm these findings. This article reviews the potential role of inflammation in the pathogenesis of restenosis and the efficacy of dexamethasone in the prevention of restenosis.

Arterial wall temperature following coronary stent implantation in pigs: the role of post-stent inflammation.

BACKGROUND: The purpose of this study was to investigate in vivo the arterial wall temperature after coronary stent implantation in pigs. METHODS: We performed cardiac catheterization in 20 pigs with normal coronary arteries. Arterial wall temperature was studied with a thermography system that uses a 4-thermistor sensor tip. A segment was selected in the proximal right coronary artery. Temperature was mapped in this segment by means of a continuous catheter pullback. A stent was then implanted in the middle of this area, and the temperature scan was repeated. Pigs were randomized in two groups (10 + 10 pigs) for arterial temperature scanning: group A to be re-scanned after 5 days and then sacrificed, and group B to be re-scanned after 8 days and then sacrificed. RESULTS: The temperature of the arterial wall before stent implantation was equal to the adjacent areas. Immediately after stent implantation, the stented area had lower temperature than the adjacent areas (p < 0.001). Five days after implantation, the stented area was significantly warmer than the adjacent areas (p < 0.001); histopathology showed the highest macrophage population at the place of the stent. Eight days after implantation, the temperature differences were reduced to non-significant levels (p = NS) and the macrophage population was significantly lower. CONCLUSION: Stent implantation results in an immediate temperature decrease at the stented arterial segment, followed by a significant temperature increase around day 5 after stent implantation. These findings can be correlated with the peri-strut inflammation that follows the stent implantation.

Optimization of local methylprednisolone delivery to inhibit inflammatory reaction and neointimal hyperplasia of coated coronary stents.

Polymer coating can optimize the surface characteristics of metallic coronary stents and serve as a vehicle for local drug delivery. Major problems, however, include the lack of biocompatibility of the polymers used and the limited amount of drug that can be loaded onto the stent. Stainless-steel stents were spray-coated or spray-coated combined with a barrier coating using a fluorinated polymethacrylate PFM-P75 impregnated with different methylprednisolone concentrations. When spray-coated with highly concentrated methylprednisolone ( 33%) fluorinated polymethacrylate PFM-P75, the surface became progressively more rough. Adding a barrier coating, however, could decrease these surface irregularities of methylprednisolone-loaded PFM-P75 spray-coated stents. In vitro, most of the methylprednisolone was released in the first 48 hours. A barrier coating could dramatically slow down the drug release from 80% to 13% during the first 48 hours. Histomorphometric analysis showed that the inflammatory response and neointimal hyperplasia of methylprednisolone-loaded stents were lower than in control stents. Neointimal hyperplasia of methylprednisolone-loaded PFM-P75 stents spray-coated with a barrier coating was decreased compared to the non-barrier-coated methylprednisolone-loaded stents. In conclusion, spray coating enables the use of high methylprednisolone concentrations. A barrier coating could significantly slow down the methylprednisolone release. Methylprednisolone-loaded PFM-P75-coated stents could significantly inhibit the inflammatory response and neointimal hyperplasia. The response to methylprednisolone was related to the dose used and the release time of the drug.

Two-year clinical results of a polymer-free, paclitaxel-eluting stent: the ELUTES trial.

AIMS: The ELUTES Study was a dose-finding trial to determine clinical safety and angiographic efficacy of a polymer-free, paclitaxel-eluting stent. The aim of this paper is to present the longer term follow-up. METHODS AND RESULTS: 192 patients with de novo lesions were randomised to either control or one of four doses of paclitaxel directly applied to a Cook Incorporated V-Flex Plus stent without polymer. The six-month data has been previously published and showed a dose-response effect on diameter stenosis, late loss and binary stenosis, with the highest dose density achieving benefit for late loss and diameter stenosis. Binary restenosis was 3% in this group vs. 21% in controls.Clinical follow-up data has been obtained in 152 patients (79%) to 24 months and shows sustained effects with no evidence of late stent thrombosis, suggesting drug-eluting non-polymer stents are clinically safe. CONCLUSIONS: Non-polymer, paclitaxel-coated stents effectively inhibited angiographic parameters of restenosis. The stent system appeared safe with no recorded late stent thrombosis.

Stent-based tempamine delivery on neointimal formation in a porcine coronary model.

BACKGROUND: Tempamine is one of new class of antioxidant agents, the nitroxides, which have shown a wide range of biological effects like suppressing free radical driven reactions to maintain cell functions. The objectives of this study were to evaluate the effect of a biodegradable polymer coated stent loaded with tempamine on in-stent neointimal formation. METHODS: Stainless steel stents were dip coated in biodegradable elastomeric poly (ester-amide) (co-PEA) or in polymer solution mixed with 50% (wt%) and 100% (wt%) tempamine. One group 100% (wt%) tempamine loaded stents were further dip coated in co-PEA polymer to form a top layer. Stainless steel bare, polymer-only, and different doses tempanine coated stents were implanted into porcine coronary arteries with a stent to artery ratio 1.2:1. Histomorphometric analysis was performed at 5 days and 6 weeks respectively. RESULTS: Histomorphometric analysis showed that the bare, polymer-only and tempamine-coated stents elicited a similar tissue response at 5 days. At 6 weeks, the peri-strut inflammation and neointimal hyperplasia of polymer-only stents were comparable to the bare stents. Compared to the bare stents, 50% tempanine coated stents had a trend to decrease the arterial injury (0.62 +/- 0.41 versus 0.34 +/- 0.18, P = 0.075) and neointimal hyperplasia (1.80 +/- 0.77 versus 1.27 +/- 0.39 mm2, P = 0.085). However, 100% tempanine coated showed significantly increased inflammatory response and neointimal formation. CONCLUSION: These co-PEA polymer coatings showed a biocompatible performance. Loaded with 50% tempamine had a trend to decrease neointimal hyperplasia. The 100% tempamine for stent-based delivery may have potential cytotoxic effects to arterial wall. Using a co-PEA polymer topcoat could effectively abolish these side effects.