Pressure rinsing of coronary stents immediately before implantation reduces inflammation and neointimal hyperplasia.

OBJECTIVES: This study evaluates whether rinsing stents with high pressure immediately before implantation minimizes stent-induced inflammation and neointimal formation. BACKGROUND: Several reports indicate that manual stent manipulation before implantation results in foreign body contamination and increased neointimal hyperplasia. METHODS: A stent-cleaning chamber was developed to rinse stents at a sustained hydrodynamic pressure of 4 atm for 10 s. Commercial pre-mounted stents were examined with different levels of manipulation: 1) untouched stents: no stent manipulation before implantation; 2) handled stents: manual stent re-crimping on the balloon; 3) rinsed stents: pressure-rinsed with the stent-cleaning chamber. In vitro surface analysis was evaluated by scanning electron microscopy. Neointimal hyperplasia and inflammation around stent struts were also assessed in the pig in-stent restenosis model. RESULTS: In vitro analysis revealed fewer contaminants on rinsed stents compared with untouched (p = 0.01) and handled stents (p < 0.001). In vivo, neointimal thickness, neointimal area and vessel percent stenosis were significantly reduced in rinsed, compared with not-rinsed, stents (p = 0.002, p = 0.007, p = 0.008 respectively). In addition, a significant reduction in the inflammatory infiltrate around struts was observed in untouched, compared with handled, stents (p = 0.04) and in rinsed, compared with not-rinsed, stents (p < 0.001). Regression analysis accounting for injury and neointimal thickness showed significant differences in slopes between "handled + not-rinsed" and "handled + rinsed" stents (p = 0.004), and between "untouched + not-rinsed" and "untouched + rinsed stents" (p = 0.037). CONCLUSIONS: Rinsing stents under high pressure immediately before coronary implantation results in less inflammation around struts and thinner neointima at 28 days in this pig model.

Neointimal response following rotational atherectomy compared to balloon angioplasty in a porcine model of coronary in-stent restenosis.

In-stent restenosis remains a clinical therapeutic challenge. Rotational atherectomy (RA) is an attractive treatment option as it may cause less vascular injury than balloon angioplasty (BA) and, therefore, limit further neointimal response. In an animal model of coronary in-stent restenosis, thermal injury and stenting created neointima (old NI). The treatment of in-stent restenosis with either BA (n = 9) or RA (n = 11) also generated neointima (new NI). The average areas (mm2) of old NI in the BA and RA groups were similar (3.77 +/- 0.40 vs. 3.67 +/- 0.53; P = 0.32). However, new NI formed after treatment of in-stent restenosis was significantly less in the RA as compared to the BA group (0.33 +/- 0.12 vs. 0.73 +/- 36, P < 0.01). In this porcine coronary artery model of in-stent restenosis, treatment with rotational atherectomy resulted in significantly less recurrent neointimal hyperplasia than balloon angioplasty. This animal study, thus, provides a rationale for the clinical use of rotablation in the treatment of in-stent restenosis.

Selective ET(A) receptor antagonism reduces neointimal hyperplasia in a porcine coronary stent model.

BACKGROUND: As endothelin binds to ET(A) receptors, it stimulates vascular smooth muscle cell proliferation and may thus be pivotally involved in the pathogenesis of restenosis. This study assessed the ability of a potent and selective ET(A) antagonist to reduce neointimal hyperplasia in a porcine coronary artery stented injury model. METHODS AND RESULTS: Fifty-five pigs were randomized to receive placebo or the oral ET(A)-selective antagonist ABT147627 twice daily for 28 days in one of three doses: 0.75 mg/kg (low), 3.75 mg/kg (mid), and 10.0 mg/kg (high). Each underwent oversized stent deployment in two randomly assigned major epicardial coronary arteries. Three animals (5.5%) died as a consequence of stent thrombosis within 24 hours of the procedure. The remaining 52 animals (13 pigs per group) survived without complication until predetermined euthanasia at 28 days. In the placebo group, mean injury score was 1.73+/-0.80, with a mean neointimal response of 0.45+/-0.24 mm. By comparison, the low-dose group had a similar mean injury score of 1.79+/-0.75 with reduced neointimal response, 0.36+/-0.22 mm (P<0.01). Mean injury score in the mid-dose animals was significantly greater than in the placebo group (1.94+/-0.92; P<0.05). The neointimal hyperplasia associated with this injury was less than with placebo, although the difference did not reach statistical significance (0.40+/-0.25 mm; P=0.05). In the high-dose pigs, mean injury score was also significantly greater than in the placebo arm (1.93+/-0.73; P<0.05). Despite this, neointimal response was also significantly less (0.37+/-0.37 mm; P<0.01). CONCLUSIONS: Oral, selective ET(A) receptor antagonism significantly reduced neointimal hyperplasia forming over porcine coronary stented injuries in the first 28 days. This strategy may have clinical potential for the limitation and treatment of coronary restenosis after percutaneous revascularization.

Fibrin-film stenting in a porcine coronary injury model: efficacy and safety compared with uncoated stents.

OBJECTIVES: This study was designed to test the efficacy and safety of a fibrin-film-covered stent compared with that of a bare metal stent in the porcine coronary injury model. BACKGROUND: Biodegradable stents are a potential method of achieving total lesion coverage and delivering local, lesion-specific drug therapy. METHODS: Two coronary arteries in each pig were randomly assigned to deployment of either a fibrin-film or a bare tantalum wire-coil stent. An oversized balloon injury, 1.15 to 1.30 times the reference vessel diameter, was induced in each coronary segment before stenting to simulate angioplasty injury. Thirty pigs were studied: group 1 for 28 days (15 pigs); group 2 for 90 days (5 pigs); group 3 for 6 months (5 pigs); group 4 for 1 year (5 pigs). RESULTS: Two pigs died of occlusion of the bare stent and one of occlusion of the fibrin stent (p > 0.99). There were no significant differences between the fibrin-stented and bare-stented coronary segments with regard to arterial injury. In group 1 (28 days, 14 pigs), the mean neointimal thicknesses in the fibrin-stented and bare-stented groups were 0.57+/-0.31 and 0.57+/-0.27 mm, respectively (p=0.89). In groups 2 to 4 (90 days, four pigs; 6 months, four pigs; 1 year, five pigs), the mean neointimal thicknesses for fibrin- and bare-stented coronary segments at the times studied were 0.48+/-0.26 versus 0.50+/-0.22 mm at 90 days; 035+/-0.04 versus 0.35+/-0.16 mm at 6 months; and 0.33+/-0.14 versus 0.30+/-0.14 mm at 1 year (p=0.98). CONCLUSIONS: Fibrin-film stents appear to be an excellent candidate for local drug delivery because they can completely and safely cover the stented coronary segment while degrading slowly over 1 to 3 months. This result is important when compared with the poor results of previous studies of synthetic polymer stents.

Short wave ultraviolet laser energy in porcine coronary arteries: medial cell death and neointimal formation.

BACKGROUND AND OBJECTIVE: Smooth muscle cell migration and proliferation from arterial media into the neointima are major factors in the restenosis process following coronary angioplasty. Because short wave ultraviolet (UV) radiation is cytotoxic for rat carotid artery smooth muscle cells, the aims of this study were to determine the effects of short wave UV irradiation on normal pig coronary arteries and to evaluate the efficacy of UV laser energy for reducing neointimal hyperplasia (NI). STUDY DESIGN/MATERIALS AND METHODS: In 13 pigs fed a normal diet, 37 coronary arteries were studied. UV laser light (275 nm) was applied in escalating doses from 0-16,353 mJ/cm2 via fiberoptic through a 20 mm PTCA balloon catheter. The pigs were euthanized at 21 days and histologic analysis performed. Arterial media was rendered acellular (ACM) in 20 of 33 irradiated coronary arteries (61%). The minimum UV energy density inducing ACM was 1348 mJ/cm2. The fraction of acellular media to internal elastic lamina length (ACM/IEL) was 0.79 +/- 0.29. RESULTS: No statistically significant difference was found between NI thickness at normal media sites (NM) vs. ACM sites (0.17 +/- 0.14 mm vs. 0.16 +/- 0.17 mm). No correlation was found between UV dose and NI formation (r = 0.307, P = 0.08). CONCLUSION: Short wave UV irradiation induces ACM in normal porcine coronary arteries. Induction of acellular media is not associated with a reduction of NI formation in this porcine coronary model.

Neointimal thickening after severe coronary artery injury is limited by a short-term administration of a factor Xa inhibitor. Results in a porcine model.

BACKGROUND: Fibrin- and platelet-rich thrombus formations occur as the initial event after percutaneous transluminal coronary angioplasty. We therefore tested the hypothesis that short-term administration of the recombinant tick anticoagulant peptide (rTAP), a factor Xa inhibitor, would reduce the thickness of neointima at 28 days after injury in a porcine coronary balloon angioplasty model. METHODS AND RESULTS: Continuous intravenous infusion of rTAP (average dose, 194 micrograms . kg-1 . min-1) or placebo (vehicle only) was given to the study pigs for 60 hours. The goal of anticoagulation was to maintain the activated clotting time at 200 seconds. A central venous catheter was inserted 2 days before the procedure. On the day of coronary injury, the animals were administered boluses of rTAP (6.5 mg) and then underwent injury with an oversized metallic coil by standard methods in the right, circumflex, or left anterior descending coronary artery. No significant difference in vascular injury between rTAP and vehicle control was observed after euthanasia at 28 days. Significantly less neointimal thickening occurred in the rTAP-treated animals (thickness, mean +/-SD: 0.30 +/-0.08 mm) compared with the control (0.48 +/- 0.12 mm, P< .001). CONCLUSIONS: The specific factor Xa inhibitor rTAP, when given in fully anticoagulant doses for a short duration after coronary artery injury in the porcine model, resulted in a long-term decrease in neointimal thickness. These results implicate thrombin generation in neointimal formation and suggest that administration of a potent antithrombotic for several days immediately after the procedure may influence the long-term outcome of the coronary injury with a decrease in neointimal formation.

The effects of lovastatin on neointimal hyperplasia following injury in a porcine coronary artery model.

OBJECTIVE: To assess the effectiveness of lovastatin, an HMGCoA reductase inhibitor, in the inhibition of coronary arterial restenosis post-balloon angioplasty. DESIGN: Randomized single-blind study comparing the degree of restenosis in a control and lovastatin group of animals with similar degree of arterial injury. ANIMALS: Seventeen domestic cross-bred pigs received either oral lovastatin (11 animals) or no lovastatin (six animals). INTERVENTIONS: The pigs received 20 mg of oral lovastatin twice daily or no drug. All pigs received acetylsalicylic acid and verapamil preprocedure. One or more coronary arteries were injured by deployment of tantalum wire stents delivered on oversized percutaneous transluminal coronary angioplasty balloons. The balloons were intentionally overexpanded to create arterial injury. The animals were sacrificed at 28 days. The arteries were cross-sectioned and evaluated blindly by quantitative histomorphometry. The amounts of arterial injury and neointimal thickening were quantitated. A series of linear regression models was used to control for the degree of injury. MAIN RESULTS: The reduction of neointimal thickness for the lovastatin group compared with the control animals was 0.08 mm, a statistically significant result (P < 0.05). CONCLUSIONS: Although lovastatin produced a statistically significant decrease in neointimal thickness post-balloon angioplasty, when extrapolated to angiographical end-points, the differences would not be clinically significant. These data suggest that lovastatin may be of marginal use in humans for limiting restenosis.

Polymeric stenting in the porcine coronary artery model: differential outcome of exogenous fibrin sleeves versus polyurethane-coated stents.

OBJECTIVES: In a porcine coronary model, fibrin film soaked for 3 h in heparin was used as a circumferential coating on a tantalum stent to assess the effect of this naturally occurring biopolymer on arterial healing. The results were compared with those obtained with medical grade polyurethane-coated stainless steel stents. BACKGROUND: Thrombus plays an important role in healing after arterial injury and may affect the development of neointimal hyperplasia. Manipulation of the initial thrombus may alter the healing response. To study this, we placed a template of fibrin in a porcine coronary artery restenosis model. METHODS: Thirty-four fibrin film stents were delivered in 20 swine. Oversizing was avoided, to prevent deep arterial injury, by placement of optimally sized stents. Initial patency of the stented vessel was confirmed by angiography. RESULTS: Three fibrin-stented swine died within 48 h; in each, the stent was occluded with a fibrin/red blood cell mass. In two of these three, a portion of the exogenous fibrin had become detached from the stent and partially occluded the lumen. Of the remaining 31 stents, all were patent at elective sacrifice at 28 days. Eighty-four percent had a diameter stenosis < 50%, and the mean (+/- SD) diameter stenosis was 32.3 +/- 13%. There was no evidence of significant foreign-body giant-cell reaction. These results contrasted with the medical grade polyurethane-coated stents placed according to the same protocol without oversizing. Twelve of these stents were placed; six swine died of thrombotic occlusion within the 1st 48 h. At elective sacrifice at 28 days, the remaining polyurethane-coated stents were occluded by marked neointimal hyperplasia. CONCLUSIONS: Fibrin film-coated stents seem promising as a template for modifying the local response to arterial injury and for potentially decreasing restenosis rates.

Differential neointimal response to coronary artery injury in pigs and dogs. Implications for restenosis models.

Neointimal hyperplasia occurs in the coronary arteries after percutaneous revascularization procedures and is a reparative response that frequently causes recurrent stenosis. Prior animal studies have shown that neointimal tissue thickness is proportional to the depth of arterial injury. Because animal models are increasingly used to test therapeutic strategies against restenosis, the purpose of this study was to evaluate the degree of neointimal thickening formed in the coronary arteries of pigs compared with dogs in response to severe injury. Fourteen coronary arteries in six mongrel dogs and 18 coronary arteries in nine pigs underwent severe arterial injury using tantalum metal coils delivered on oversized angioplasty balloons. Animals were killed after 4 weeks, and all coronary arteries were pressure perfusion fixed. Mean histological injury scores and neointimal thicknesses for dogs were 1.9 +/- 0.3 and 0.30 +/- 0.11, respectively, compared with 2.1 +/- 0.7 and 0.71 +/- 0.36 for pigs. Thus, there was significantly less neointimal thickening in dogs compared with pigs (P < .001) despite no differences in injury (P = NS). The neointimal thickening differences translated into significantly different percent area stenoses: 55 +/- 24% for pigs versus 27 +/- 13% for dogs (P < .001). Linear regression modeled neointimal thickness versus injury assessed by an ordinal injury score proportional to the depth of injury for each species. This analysis confirmed the differences across multiple injury levels. The slope of the regression line for dogs was small, suggesting that no relation may exist between injury and neointimal thickness in this species. The pig may be a more appropriate model for the study of the genesis of stenosing neointima.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of angiotensin converting enzyme inhibition on neointimal proliferation in a porcine coronary injury model.

To assess the effectiveness of angiotensin converting enzyme inhibition in a proliferative porcine coronary restenosis model, 35 animals received orally administered trandolapril (10 mg) or captopril (200 mg) or no drug (control group) for 6 days before and 28 days after injury by oversized metallic coils in one or more coronary arteries. Twenty arterial lesions in the trandolapril group, 17 in the captopril group, and 18 in the control group were evaluated. There was no significant difference in neointimal thickness or percentage luminal area stenosis for the groups as a whole. However, in quantitative comparisons in which vessel injury score was used as a covariate, the fractional increase in mean neointimal thickness per unit of injury was significantly less for the trandolapril group (p = 0.019) but not for the captopril group when compared with control animals. In this model, neointimal proliferation from arterial injury was inhibited by angiotensin converting enzyme inhibition with trandolapril but only modestly. Such an effect may not be clinically significant.

Coronary restenosis: prospects for solution and new perspectives from a porcine model.

Coronary restenosis, a major unresolved problem for percutaneous coronary revascularization procedures, has thus far been resistant to all therapeutic strategies. In part, ineffective treatment or prevention of coronary restenosis may be due to reliance on a conceptualization of the restenosis process that incompletely reflects the pathophysiologic factors associated with neointimal formation after arterial injury. In a porcine coronary restenosis model, three stages of neointimal growth after arterial injury have been identified: an early thrombotic stage, with platelets, fibrin, and erythrocytes; a cellular recruitment stage, with endothelialization and an infiltration by lymphocytes and monocytes; and a proliferative stage, in which smooth muscle cells migrate into and proliferate within the fibrin-rich degenerating thrombus. Evaluation of basic mechanisms responsible for neointimal formation has been possible with this model. In particular, a direct relationship exists between the depth of arterial injury and subsequent neointimal thickness. This relationship can be used for investigating the efficacy of new therapies. Treatment strategies for restenosis should be directed toward interference with the cellular or humoral events that lead to neointimal formation, with the specific goal of decreasing the neointimal volume. These strategies may include delivery of drugs to the site of arterial injury to limit the amount of early mural thrombus or decreasing subsequent cellular recruitment and proliferation as well as synthesis of extracellular matrix.

Percutaneous polymeric stents in porcine coronary arteries. Initial experience with polyethylene terephthalate stents.

BACKGROUND: To test the feasibility of percutaneous deployment of intracoronary polymeric stents, a prototype polyethylene terephthalate (PET) stent and a catheter-based delivery system were developed. METHODS AND RESULTS: Polymeric stents were deployed in the coronary arteries of 11 Yucatan swine: six stents were placed in the left anterior descending coronary artery, four stents were placed in the circumflex artery, and one stent was placed in the right coronary artery. Stent deployment was achieved by withdrawal of an outer delivery sheath, thus allowing the PET stent to self-expand to a preformed configuration. Two animals died during surgery, one during stent placement and the other several hours after implantation due to intracoronary thrombus formation. Two animals were electively sacrificed within 24 hours of stent implant to examine the adequacy of stent deployment within the coronary vessel. The remaining seven animals survived until the termination of the study 4-6 weeks later. Light microscopic examination of the stented vessels showed an extensive neointimal proliferative response with vessel occlusion in all animals who survived initial stent placement. There were two distinct types of histological responses to the PET stent--a chronic foreign body inflammatory response around the stent tines and a neointimal proliferative response in the center of the occluded vessel lumen. The histological response seen in the central area of the vessel was morphologically similar to that seen in patients with restenosis after successful percutaneous transluminal coronary angioplasty, whereas the morphological response seen at the periphery of the stent tine was similar to that exhibited by a chronic foreign body reaction and was not typical of that seen in a restenosis lesion. A ventricular aneurysm also developed in the area of myocardium that was previously supplied by the occluded vessel. CONCLUSIONS: This study demonstrates that percutaneous deployment of polymeric stents in the coronary arteries is technically feasible. The use of PET polymer was associated with an intense proliferative neointimal response that resulted in complete vessel occlusion. Histological examination of the stented segments of the vessel revealed no evidence that dissection of the vessel wall had occurred at the time of initial stent deployment. Although the PET polymer was of similar quality to that used in the manufacture of balloon angioplasty catheters, a toxic chemical or contaminant effect cannot be completely excluded as the stimulus to intimal proliferation. This finding may have relevance to the selection of materials for use as intravascular devices.

Effect of external beam irradiation on neointimal hyperplasia after experimental coronary artery injury.

Human coronary artery restenosis after percutaneous revascularization is a response to mechanical injury. Smooth muscle cell proliferation is a major component of restenosis, resulting in obstructive neointimal hyperplasia. Because ionizing radiation inhibits cellular proliferation, this study tested in a porcine coronary injury model the hypothesis that the hyperplastic response to coronary artery injury would be attenuated by X-irradiation. Deep arterial injury was produced in 37 porcine left anterior descending coronary artery segments with overexpanded, percutaneously delivered tantalum wire coils. Three groups of pigs were irradiated with 300-kV X-rays after coil injury: Group I (n = 10), 400 cGy at 1 day; Group II (n = 10), 400 cGy at 1 day and 400 cGy at 4 days and Group III (n = 9), 800 cGy at 1 day. Eight pigs in the control group underwent identical injury but received no radiation. Treatment efficacy was histologically assessed by measuring neointimal thickness and percent area stenosis. Mean neointimal thickness in all irradiated groups was significantly higher than in the control groups and thickness was proportional to X-ray dose. X-irradiation delivered at these doses and times did not inhibit proliferative neointima. Rather, it accentuated the neointimal response to acute arterial injury and may have potentiated that injury.

Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model.

Restenosis is a reparative response to arterial injury occurring with percutaneous coronary revascularization. However, the quantitative characteristics of the relation between vessel injury and the magnitude of restenotic response remain unknown. This study was thus performed to determine the relation between severity of vessel wall injury and the thickness of resulting neointimal proliferation in a porcine model of coronary restenosis. Twenty-six porcine coronary artery segments in 24 pigs were subjected to deep arterial injury with use of overexpanded, percutaneously delivered tantalum wire coils. The vessels were studied microscopically 4 weeks after coil implantation to measure the relation between the extent of injury and the resulting neointimal thickness. For each wire site, a histopathologic score proportional to injury depth and the neointimal thicknesses at that site were determined. Mean injury scores were compared with both mean neointimal thickness and planimetry-derived area percent lumen stenosis. The severity of vessel injury strongly correlated with neointimal thickness and percent diameter stenosis (p less than 0.001). Neointimal proliferation resulting from a given wire was related to injury severity in adjacent wires, suggesting an interaction among effects at injured sites. If the results in this model apply to human coronary arteries, restenosis may depend on the degree of vessel injury sustained during angioplasty.

Restenosis after balloon angioplasty. A practical proliferative model in porcine coronary arteries.

A model of proliferative human restenosis was developed in domestic pigs by using deep injury to the coronary arterial media. Metal wire coils were delivered percutaneously to the coronary arteries of 11 pigs with an oversized, high-pressure (14 atm) balloon and were left in place for times ranging from 28 to 70 days. During placement, the balloon expanded the coils and delivered them securely within the arterial lumen. Light microscopic examination of the vessels confirmed fracture of the internal elastic lamina by the coil. An extensive proliferative response occurred in 10 of the 11 pigs and was associated with a luminal area narrowing of at least 50% in all but one pig. The histopathologic features of the proliferative response were identical to those observed in human cases of restenosis after angioplasty. Immunohistochemical studies confirmed the prominence of smooth muscle cells in the proliferative tissue. A similar response was obtained in two of five porcine coronary arteries in which balloon inflation only was performed, without coil implant. This model is practical and inexpensive and closely mimics the proliferative portion of human restenosis both grossly and microscopically. Thus, it may be useful for understanding human restenosis and for testing therapies aimed at preventing restenosis after balloon angioplasty or other coronary interventional procedures.