Experimental Angioplasty Research Articles

Experimental studies on prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis Paniculata Nees and Fish Oil

In order to search for effective drugs to reduce restenosis incidence after coronary angioplasty, we studied the effects of a Chinese herb, extract of Andrographis Paniculata Nees (APN), and Fish Oil (FO) on atherosclerotic stenosis and restenosis after experimental angioplasty. Preliminary results showed that APN can significantly alleviate atherosclerotic iliac artery stenosis induced by both deendothelialization and high cholesterol diet (control group, stenosis incidence 100%, stenotic severe degree 60.53 +/- 31.03%, of which 30% arteries (6) are total occlusion; FO group: stenotic incidence and severe degree are 77% and 53.00 +/- 21.17%, respectively, and in APN group they are 70% and 25.39 +/- 10.52%, respectively, P < 0.01), and follow-up angiography 4 weeks after angioplasty showed that dilated iliac arteries in control group all had severe restenosis, but in APN group no or only mild restenosis occurs, and in FO group restenosis is as severe as stenotic degree prior to angioplasty. These preliminary results suggest that APN and FO can significantly alleviate stenosis induced by deendothelialization and high cholesterol diet and restenosis after angioplasty, while the former has a more marked effect. The above findings lead the authors to conclude that APN may play an important role in preventing restenosis after coronary angioplasty, but FO may be useful in reducing the extent of of restenosis after coronary angioplasty.

Inhibition of smooth muscle cell proliferation and experimental angioplasty restenosis by beta-cyclodextrin tetradecasulfate.

Heparin inhibits smooth muscle cell proliferation in vitro, a property that makes it potentially useful in preventing restenosis after angioplasty. Its utility in this setting is limited by the inability to use high doses (secondary to anticoagulant effects) and the need for subcutaneous administration. We tested the ability of beta-cyclodextrin tetradecasulfate (CDT), a nonanticoagulant synthetic heparin mimic, to inhibit smooth muscle cell proliferation in vitro and tested its efficacy when orally administered for the prevention of angioplasty restenosis in a rabbit atherosclerosis model. Vascular smooth muscle cells were cultured from rabbit aortas by the explant technique. Passaged cells were plated at low density in microtiter plates in the presence or absence of varying concentrations of heparin or CDT in culture medium containing 10% fetal calf serum. Using both 3H-thymidine incorporation and total protein assays, both heparin and CDT caused a similar dose-dependent inhibition of proliferation. We next tested the effect of orally administered CDT in the prevention of restenosis in focal femoral artery arteriosclerotic lesions created in hypercholesterolemic New Zealand White rabbits by air-dessication endothelial injury and subsequent peripheral angioplasty. Animals were followed up for 1 month and were fed normal chow supplemented by tap water with or without CDT. In animals receiving the highest concentration of CDT (2 mg/mL drinking water), the percentage of arterial cross-sectional area with intimal hyperplasia decreased from 50.5 +/- 1.7% (control) to 26.9 +/- 2.2% (p < 0.001), with the intimal/medial ratio being decreased from 1.4 +/- 0.4 to 0.5 +/- 0.2 (p = 0.056).(ABSTRACT TRUNCATED AT 250 WORDS)

SIN-1 reduces platelet adhesion and platelet thrombus formation in a porcine model of balloon angioplasty.

Nitric oxide inhibits platelet adhesion and platelet aggregation in vivo. In this study, we investigated the effects of the nitric oxide donor SIN-1 on platelet adhesion and platelet-thrombus formation following experimental angioplasty. Bilateral carotid angioplasty was performed in 20 anesthetized pigs. Animals received either SIN-1 (3-morpholino-sydnonimine; 10 micrograms/kg/min; n = 8) or placebo (n = 8) before and during angioplasty. An additional control group of pigs received trimetaphan (n = 4), which induced hemodynamic changes similar to those that followed treatment with SIN-1. Platelet deposition was quantified by the injection of autologous 111In-labeled platelets. SIN-1 reduced platelet deposition after deep arterial injury compared with placebo (mean +/- SEM, 10.870 +/- 2.415 versus 40.326 +/- 9.889 platelets x 10(6)/cm2, p < 0.05). SIN-1 reduced platelet adhesion after superficial injury compared with both placebo and trimetaphan (2.231 +/- 0.333 versus 5.278 +/- 0.606 versus 5.022 +/- 1.136 platelets x 10(6)/cm2, respectively; p < 0.005). Scanning electron microscopy confirmed that platelets were deposited in the form of an adherent monolayer following superficial endothelial denudation and were reduced in number following treatment with SIN-1. The effects of SIN-1 on platelet function were associated with a significant increase in platelet cyclic GMP concentration from baseline (3.15 +/- 0.88 versus 1.58 +/- 0.73 pmol/10(9) platelets, p < 0.005). SIN-1 reduces platelet adhesion and platelet-thrombus formation following experimental angioplasty. The antiadhesive effects of SIN-1 are independent of changes in systemic hemodynamics. These results imply that the administration of a nitric oxide donor may prove effective in modifying the pathophysiological response to angioplasty injury.

A canine iliac artery occlusion model.

This report describes an occlusive canine iliac artery model for use in experimental angioplasty procedures. Lesions were induced by overdistending and breaking the internal elastic lamina of the artery and implanting a 2-cm long occlusive collagen plug. The collagen plug diameter was varied to fit the iliac artery and caused immediate bilateral iliac occlusions. Histology of the lesions at 9 and 14 days (n = 2) showed that the lumen was filled with a mixture of fresh thrombus and collagen pad material (more collagen than thrombus) with focal disruptions of the internal elastic lamina. At 36 days (n = 2) the lumen was obliterated with a mixture of organizing thrombus and collagen pad material (more organizing thrombus than collagen). At 60 (n = 4) and 80 (n = 8) days the collagen pad had been completely replaced with organizing thrombus consisting of collagen fibers and hemosiderin-laden macrophages with persistent focal disruptions of the internal elastic lamina. These initial data demonstrate the ability to create fibrotic arterial occlusions in as short a time as 60 days and to provide a practical model to study methods for treating localized peripheral vascular occlusive disease.

The effect of antiplatelet therapy on platelet accumulation after experimental angioplasty in the rabbit iliac model

Antiplatelet therapy is routinely used in balloon angioplasty. Yet recent clinical trials have not shown these agents to reduce the incidence of restenosis. As this might be due to inadequate antiplatelet effect, this study was designed to evaluate the effectiveness of antiplatelet therapy in reducing platelet accumulation immediately after angioplasty. Sixty-six atherosclerotic rabbits underwent angioplasty of a focal (50–99%) iliac stenosis after pretreatment with an antiplatelet drug. The animals were randomly given aspirin (10 mg/kg orally) ( n = 10), aspirin (10 mg/kg intravenously) ( n = 7), aspirin (10 mg/kg per os) plus dipyridamole (25 mg orally) ( n = 8), a thromboxane synthetase inhibitor (GS13080, 1 mg/kg/h intravenously) ( n = 9) or heparin (500 U/kg intravenously) ( n = 9). Platelet accumulation, determined by 51Cr-labeled platelet counts 30 min after angioplasty disclosed a significant reduction from control (44.1 ± 51.2 platelets/cm × 10 6) with intravenous aspirin (3.3 ± 1.9; p < 0.007) and the thromboxane synthetase inhibitor CGS13080 (15.1 ± 16.6, p < 0.04). Aspirin plus dipyridamole reduced platelet accumulation as well (10.4 ± 9.8, p = 0.076), while oral aspirin (109.5 ± 240) and heparin (34.7 ± 35.5) were ineffective. The results of this study demonstrate that pretreatment with antiplatelet agents can reduce platelet accumulation significantly after experimental angioplasty. However, the wide variability in effectiveness particularly with oral aspirin may have important clinical implications. Further investigation into more effective antiplatelet therapy may help to reduce the incidence of abrupt vessel closure and restenosis.

Real-time assessment of experimental arterial angioplasty with transvenous intravascular ultrasound

Optimal evaluation of experimental angioplasty procedures would allow real-time simultaneous assessment during the procedure without direct manipulation of treated arterial segments. To assess the feasibility and utility of transvenousreal-time intravascular ultrasound imaging during experimental angioplasty, 11 consecutive atherosclerotic iliac artery segments in rabbits were imaged before, during and after thermal or conventional perfusion balloon angioplasty. A 20-MHz intravascular ultrasound catheter was positioned in the adjacent vein, and images were correlated with data from quantitative angiography and histologic studies.Images suitable for analysis were obtained at all 11 sites. Arterial distension and recoil were observed during balloon inflation and deflation. Measurements of lumen diameter and cross-sectional area by intravascular ultrasound and angiography were closely correlated (r2= 0.90, SEE = 0.2 mm, and r2= 0.90, SEE = 0.8 mm2, respectively). Intimal dissections were identified in six segments by intravascular ultrasound and all were concordant with histologic findings.Thus, real-time transvenous ultrasound avoids manipulation of the treated artery, and is a feasible modality for dynamic quantitative and qualitative assessment of arterial interventions.

Vascular Endoscopy for Intravascular Surgery —An Experimental Study—

A combination of endoscope and high-pressure saline irrigation system was tested in the occlusion of experimental aneurysms, and angioplasty and fibrinolysis of vascular occlusive lesions in canine femoral arteries. Endoscopy provided detailed information about the aneurysmal orifice and lumen and aided balloon placement and detachment. Endoscopy visualized the dynamic changes accompanying thrombolysis and the fine intimal injury due to angioplasty invisible on angiography. Vascular endoscopy is valuable for pre-, intra-, and postoperative evaluation of intravascular interventions.

Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty: Hanke H, Strohschneider T, Oberhoff M, Betz E, Karsch KR. Circ Res 1990;67:651–9

Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty: Hanke H, Strohschneider T, Oberhoff M, Betz E, Karsch KR. Circ Res 1990;67:651–9

Use of the perforated balloon catheter to infuse marker substances into diseased coronary artery walls after experimental postmortem angioplasty

A perforated balloon catheter was used in human coronary arteries after postmortem angioplasty had been performed. The catheter used has a standard angioplasty balloon with a pattern of laser-produced holes, 25 μm in size, which generate streams of fluid under pressure. Studies of the routes by which marker substances enter diseased arterial tissue when infused by the perforated balloon after experimental angioplasty are described. A colored marker dye entered the new crevices and dissection planes created by the angioplasty, but did not extend > 2 cm either proximal or distal to the perfused segment.Horseradish peroxidase entered tissue not only from the lumen and adventitia as occurs with its infusion into normal tissue with the perforated balloon, but also extended from new crevices and dissection planes created by the angioplasty. Platelet aggregation, coagulation and cell proliferation, the likely causes of restenosis after angioplasty, originate in the sites of greatest tissue disruption and blood stasis. These postmortem studies suggest that active drugs are delivered to the arterial wall in a manner likely to be effective in preventing these events.

Angiotensin converting enzyme inhibition reduces restenosis in experimental angioplasty

Angiotensin converting enzyme inhibition reduces restenosis in experimental angioplasty

Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty.

Smooth muscle cell (SMC) proliferation is known to be an important factor for the development of restenosis after percutaneous transluminal coronary angioplasty. To determine the time course of intimal and medial SMC proliferation and morphological changes after experimental angioplasty, an intimal atheroma was produced with repeated weak electrical stimulations in the right carotid artery of 45 male New Zealand White rabbits. Angioplasty was subsequently performed in 35 rabbits, and the proliferative responses were analyzed with histomorphological and immunohistological criteria at 3, 7, 14, 21, 28, and 42 days after intervention. A hemodynamic relevant stenosis after angioplasty was found in eight (23%) of 35 dilated arteries. In five rabbits the stenosis was due to a mural thrombus, and in three animals restenosis was caused by intimal SMC proliferation. In all dilated arteries the intimal wall thickness increased from 13 +/- 5 intimal cell layers (after electrical stimulation) to 33 +/- 14 cell layers during 28 days after angioplasty (p less than 0.05). Later than 4 weeks after angioplasty, no additional increase of intimal thickening occurred. Application of bromodeoxyuridine 18 and 12 hours before excision of the vessels allowed determination of the percent of cells undergoing DNA synthesis in the intima and media using monoclonal antibody against bromodeoxyuridine. SMCs were identified by alpha-actin staining. Immunohistological quantification of intimal SMC proliferation showed a maximum of cells undergoing DNA synthesis within the first 7 days after angioplasty (p less than 0.01). In contrast, medial proliferation of SMCs was delayed and showed a small but significant increase 21 days after dilatation (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental argon laser thermal angioplasty as an adjunct to balloon angioplasty in peripheral arteriosclerotic disease

Laser thermal recanalization has been used clinically as an adjunct to balloon angioplasty in the treatment of peripheral arteriosclerotic disease, with improved initial success rates in total peripheral occlusions and greater 1 yr vessel patency suggested, as compared to balloon angioplasty alone. However, the morphological effects of laser-assisted balloon angioplasty are unknown. Therefore, the goals of the present study were to evaluate 1) the angiographic and histologic effects of laser thermal recanalization followed by balloon angioplasty and 2) the hypothesis that balloon-catheter-induced neointimal fracture could be sealed by subsequent laser thermal angioplasty in an experimental rabbit iliac artery atherosclerotic model. In Group 1 (7 vessels), a 1.5 mm metal capped argon laser fiberoptic was introduced via femoral arteriotomy and 10 W of thermal power was applied to the iliac artery stenosis for 5 sec while maintaining constant back-and-forth motion. Thereafter, balloon angioplasty was performed in the same vessel segment with a 2.5 mm balloon catheter inflated 3 times at 5 atm for 30 sec each. Mean angiographic luminal diameter increased from 1.1 mm to 2.0 mm after both procedures, and mean final post balloon dissection grade was 0.6 on a scale of 0, 1+, and 2+. Perforation occurred once with the laser probe and once with the balloon catheter. Histologic examination of these vessels was characterized by irregular thermal erosions with minimal reactive thrombosis. In Group 2 (10 vessels), the sequence was reversed, with laser thermal angioplasty following balloon dilation. Mean angiographic luminal diameter improved from 1.2 mm to 1.8 mm after both procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombotic Effects of Recombinant Hirudin in Experimental Angioplasty and Intravascular Thrombolysis

The effect of recombinant desulphatohirudin CGP 39393 (rH) on arterial thrombus formation and especially on thrombotic reocclusion after experimental angioplasty as well as after thrombolysis was investigated in rabbits. In the femoral artery thrombi were induced after endothelial damage of the vessel wall by a balloon catheter and following stasis. After removing the thrombus by angioplasty or after lysing it by streptokinase reocclusion of the artery was observed within a relatively short period of time. Subcutaneous injection of rH reduced the incidence of both primary thrombus formation and reocclusion in dependence on the dose administered. After a dose of rH of 2 mg/kg s.c. arterial thrombus formation was completely prevented and after administering 4 mg/kg s.c. thrombotic reocclusion did also not occur. Comparative studies with heparin showed that similar antithrombotic effects were only achieved at doses of 12 mg heparin/kg s.c. The results obtained suggest a clear potential of rH for prevention of thrombotic reocclusion in clinical states.

低エネルギーレーザーとヘマトポルフィリン誘導体を用いた血管形成術の臨床応用への検討

低エネルギーレーザーとヘマトポルフィリン誘導体を用いた血管形成術の臨床応用への検討

Platelet accumulation in experimental angioplasty: time course and relation to vascular injury.

Since platelet accumulation may be an important determinant of restenosis after angioplasty, the time course of 51Cr-labeled platelet accumulation after experimental angioplasty was evaluated in a deendothelialized, hypercholesterolemic rabbit preparation of atherosclerosis. Marked platelet accumulation (39.5 +/- 8.7 X 10(6) platelets/1 cm vessel length) was observed at 30 min and remained active until 4 hr after angioplasty. Total accumulation over 24 hr was 56.4 +/- 4.7 X 10(6) platelets/1 cm length. Histologic dissection was directly related to the degree of platelet accumulation, with 64 +/- 15 X 10(6) platelets/1 cm in the group with marked dissection and 8.7 +/- 3.7 X 10(6) platelets/1 cm in the group with minimal dissection (p less than .05). Increasing angiographic dissection also resulted in a trend toward increased platelet accumulation, and angiographic change in luminal diameter showed a significant correlation with platelet accumulation. It is concluded that marked platelet accumulation occurs early after transluminal angioplasty and is related to the extent of dissection. Restenosis may result from a complex interaction of platelet accumulation, vascular damage, and blood flow.

Laser irradiation and balloon dilatation in experimental transluminal angioplasty.

Percutaneous transluminal balloon angioplasty (PTA) is being currently used in patients with coronary artery disease. Laser irradiation (LI) has been effective in vaporizing atherosclerotic plaques. The purpose of this work was twofold: to compare PTA and LI techniques in the recanalization of experimental obstructive arterial lesions, and to evaluate the possibility of reducing the failures and local complications and increasing the success rate of PTA by the combined use of LI. Atherosclerotic iliac stenoses were induced in 27 rabbits; lesions were evaluated angiographically before and after intervention and were studied histologically and by electron microscopy. Argon-ion LI delivered through microlens-tip optic fibers reduced the stenotic area from 64.2 +/- 21.8% to 40.3 +/- 10.7% (n = 10, P less than .01) and PTA from 60.7 +/- 15.9% to 30.4 +/- 7.7% (n = 9, P less than .01). However, percentage reduction was higher in PTA-treated stenoses (48.4 +/- 10.1% vs 34.5 +/- 13.5%, P less than .0125). In eight more rabbits, low power LI (4.55 +/- 1.25 J) was delivered after PTA in dilated segments. Post-PTA LI further decreased stenoses (from 31.2 +/- 7.8% to 29.1 +/- 8.1%, P less than .0125); laser-irradiated segments showed diffuse carbonization of the disrupted intimal layer. The normalized transtenotic pressure gradient decreased significantly in all groups: LI reduced the gradient from .40 +/- .25 to .17 +/- .07 (P = .005); PTA from .37 +/- .14 to .11 +/- .04 (P = .001); LI after PTA from .40 +/- .16 to .12 +/- .06 (P = .001). Thus, LI is effective (less than PTA) in relieving experimental atherosclerotic stenoses and seems useful when combined with PTA.

Deep arterial injury during experimental angioplasty: Relation to a positive indium-111-labeled platelet scintigram, quantitative platelet deposition and mural thrombosis

Although it is not clear why coronary occlusion and restenosis occur after successful coronary angioplasty, factors related to the procedure may influence early and late results. The possible adverse effects of a medial tear documented histologically and produced during balloon angioplasty of the common carotid arteries were studied in 30 fully heparinized (100 U/kg body weight) normal pigs. Scanning electron microscopy showed endothelial denudation and extensive platelet deposition in all dilated arterial segments. Visible macroscopic mural thrombus was present within an hour of the procedure in 29 (91%) of the 32 arteries that had a medial tear documented by histologic study; the tear produced an indium-111-labeled platelet deposition of 116.4 +/- 26.5 X 10(6)/cm2 (mean +/- SE) and total thrombotic occlusion in 2 arteries (4%). None of the 24 arteries without a medial tear had a thrombus, and the mean platelet deposition in that group was 7.0 +/- 0.5 X 10(6)/cm2 (p less than 0.0008). In 12 pigs scanned with a gamma camera, visible thrombus was associated with platelet deposition in excess of 20 X 10(6)/cm2 in 12 arteries, 9 of which had a positive indium-111-labeled platelet scintigram. Thus, arterial angioplasty causes deep arterial injury, which appears to be a major cause of mural thrombosis, heavy platelet deposition, a positive indium-111-labeled platelet scintigram and acute arterial occlusion. A positive indium-111-labeled platelet scintigram was always associated with macroscopic thrombus of at least 20 > 10(6) platelets/cm2 and underlying deep arterial injury.

Expansion, deformation and bursting characteristics of frequently used balloon dilatation catheters. In vivo studies on canine vessels (2)

In an experimental angioplasty study in dogs, we evaluated the characteristics of dilatation and deformation, as well as the pressure requirements, bursting points, and types of bursting of four different balloon dilatation catheters. The balloons, which were selected 0%, 30%, and 80-100% larger than the arterial lumen, measured 4, 6, and 8 mm in diameter and were inflated with an automated pump which simultaneously recorded balloon pressure and volume. Changes to the vessel wall were assessed radiographically and by histology. In vivo, balloon dilatation catheters demonstrated a markedly different behaviour than in vitro. Significantly higher pressures were tolerated due to the support of the arterial sleeve. Non-compliant oversized balloons caused more damage to the arterial wall than compliant ones. Oversized balloons attained their required diameters only with high inflation pressures of 10 to 12 atm or after rupture of the artery.

The relation between arterial and balloon rupture in experimental angioplasty.

Canine carotid, iliac, and femoral arteries underwent transluminal angioplasty with increasing balloon pressure from 4.5 to 12.5 atm. Balloons were selected according to vessel diameter: equal to (zero), 50% larger, and 100% larger than the vessel. The aim of this study was to assess possible disruption of the artery by a bursting balloon. With zero or 50% overdilation, arterial rupture did not occur despite balloon rupture. With 100% overdilation, arterial rupture always preceded balloon rupture. Rupture of all layers of the vessel was caused by severe overdistension, followed by secondary rupture of the balloon because it had lost its external support.

Percutaneous perfusion of occluded coronary arteries with blood from the femoral artery: a dog study.

The idea of perfusing the distal coronary artery with arterial blood during balloon dilatation was implemented in early experimental coronary angioplasty but then abandoned. We pursued this concept in an animal model using a specially designed roller pump. The pump delivers blood from a femoral artery catheter through the central lumen of a balloon catheter occluding a coronary artery. Perfusion of large proximally occluded coronary arteries for at least 60 min was possible in 8 of 11 heparinized dogs. Hemolysis occurring in the pump system due to the small catheter lumen proved a minor problem. For a limited period of time, occluded coronary arteries can be adequately perfused with arterial blood by this percutaneous system that is readily applicable in any catheterization laboratory. Its use is conceivable not only for temporary treatment of acute complications during angioplasty but also for prolonged balloon dilatations of spastic or thrombosed coronary arteries.