Angioplasty Site Research Articles

Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries.

Tissue factor (TF) is a transmembrane glycoprotein that, after binding to factor VII/VIIa, initiates the extrinsic coagulation pathway, resulting in thrombin generation and its sequelae. Thrombin has been shown to induce TF mRNA in endothelium, monocytes, and smooth muscle cells, further perpetuating the thrombogenic cycle. This study was designed to determine the effect of specific inhibition of thrombin by recombinant hirudin (r-hirudin) on TF distribution after balloon angioplasty in the cholesterol-fed rabbit femoral artery and porcine coronary artery models. Thirty-five femoral arteries from 32 cholesterol-fed New Zealand White rabbits and 84 coronary arteries from 55 Yorkshire-Albino swine were studied by use of a recently developed in situ method of TF localization based on digoxigenin labeling of recombinant factor VIIa (Dig-VIIa), with correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1) or anti-human (sTF) antibodies. At sites of balloon angioplasty in rabbit femoral or pig coronary arteries (double or single injury), TF-antibody and Dig-VIIa staining were noted in association with endothelial cells, smooth muscle cells, and foam cells and within the fibrous tissue matrix primarily of the adventitia and neointima. Staining was significantly greater after balloon angioplasty than in vessels that had not undergone angioplasty but was similar after single and double balloon injury. Animals treated with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; pigs, 1 mg/kg bolus plus 0.7 mg x kg(-1) x d(-1) infusion for 14 days with implantable pump) had diminished TF-antibody and Dig-VIIa staining 28 days after balloon angioplasty compared with controls (bolus heparin only). This effect was more prominent on the neointima and was more striking in the porcine than the rabbit model. TF expression, persistent 1 month after balloon angioplasty in rabbit femoral arteries and porcine coronary arteries, is attenuated by specific thrombin inhibition with hirudin. These results suggest that thrombin inhibition, in addition to its effect on acute thrombus formation and its effect on luminal narrowing by plaque in experimental animals, may result in a prolonged reduction in thrombogenicity of the restenotic plaque through this effect on TF expression.

LOWER-EXTREMITY ARTERIAL ENDOVASCULAR STENTING

Intraluminal arterial stenting for the management of arterial occlusive disease of the lower extremities has evolved over the years. Most stents are used to correct inadequacies of PTA or to correct a PTA complication. These include (1) restenosis within 90 days of PTA, (2) chronic iliac occlusion, (3) acute occlusions during PTA, (4) a significant residual gradient following PTA, (5) dissections longer than the angioplasty site, and (6) a 30% or greater residual stenosis after PTA. Both the Palmaz stent and the Wallstent have performed well in the iliac artery system. Their use in the femoropopliteal system has not been as successful and should be reserved for selected cases. Long-term anticoagulation is generally required for femoropopliteal stent patency. Placement in the lower superficial femoral or popliteal artery is best avoided. Re-angioplasty or additional stenting may be used to prolong patency, although with the risk of a second intervention. Progression of arteriosclerosis is a factor to consider when choosing an endoluminal treatment versus standard bypass.

Retrograde balloon angioplasty of brachiocephalic or common carotid artery stenoses at the time of carotid endarterectomy

This study was performed to demonstrate the value and durability of intraoperative retrograde angioplasty for stenotic lesions of the aortic arch branches at the time of carotid endarterectomy for the treatment of tandem proximal and bifurcation carotid lesions. Retrospective analysis of the clinical data. Forty-four patients were included in this study when they presented with symptomatic extracranial vascular disease due to stenosis of both a proximal aortic arch branch and carotid bifurcation disease. Tandem disease was detected in the vascular laboratory and confirmed by angiography. Each patient was subjected to conventional carotid endarterectomy, and at the time of operation, the proximal lesion was subjected to transluminal angioplasty through the endarterectomy arteriotomy (brachiocephalic 24; left common carotid 15; right common carotid artery five). Patients were then followed up clinically and by non-invasive tests at 6-monthly intervals. Forty-three successful dilatations were achieved. The single initial technical failure was due to heavy calcification of a brachiocephalic artery. In the follow-up period restenosis was noted in four patients. All restenosis occurred within 24 months. No restenosis at the angioplasty site was noted on subsequent follow-up of the remaining 39 patients. No perioperative stroke or death was encountered. A surprisingly high mortality rate was noted on follow-up in this group of patients, suggesting the presence of more aggressive and advanced diffuse vascular disease. Retrograde intraoperative angioplasty of the proximal component of a tandem extracranial lesion has in this series proven to be a safe and durable therapeutic option. This technique has an acceptable restenosis rate in a subset of patients who have been demonstrated to have a shortened life expectancy and a high mortality rate in the follow-up period.

Radiation Vascular Therapy: A Novel Approach to Preventing Restenosis

In animal studies, beta and gamma radiation delivered via catheter-based systems to sites of angioplasty after arterial injury has decreased the neointimal proliferation that is a part of the restenotic process. Extending radiotherapy to the clinical setting, results of the double-blind, placebo-controlled, randomized Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) study showed dramatic reductions in the rate of restenosis after coronary stenting when catheter-based gamma radiotherapy (with iridium-192) was used. In the Beta Energy Restenosis Trial (BERT), angiographic, intravascular ultrasound, and clinical outcomes were better than expected with beta brachytherapy. Strontium-90/yttrium-90 seeds were delivered via a unique catheter system in 35 patients who underwent coronary angioplasty. Future trials are being planned to confirm these promising results.

Intramural injection of biodegradable microspheres as a local drug-delivery system to inhibit neointimal thickening in a rabbit model of balloon angioplasty.

Restenosis remains the major limitation of coronary angioplasty. The objective of this study was to develop microspheres able to be delivered at the angioplasty site for long-term drug release and to test their effects in a model of balloon angioplasty. Polylactic-co-glycolide acid microspheres (5-10 microm in diameter) were prepared by using an oil-in-water emulsion-solvent evaporation method. In vitro experiments with hydrocortisone-loaded microspheres revealed a hydrocortisone release for 4 weeks. We studied the in vivo effect of injection of microspheres into the arterial wall of New Zealand White rabbits by using a perforated balloon. Deep penetration of microspheres in the arterial wall was documented immediately after angioplasty. Intimal hyperplasia was assessed in iliac arteries 4 weeks after angioplasty. The morphometric analysis was performed in four groups of animals; the first group was subjected only to conventional angioplasty (control, n = 10), whereas the other three groups after conventional angioplasty were received perforated balloon angioplasty with saline (n = 10), microspheres (n = 10), or hydrocortisone-loaded microspheres (n = 7). Intramural injection of saline did not induce greater intimal hyperplasia compared with control (0.17 +/- 0.03 vs. 0.18 +/- 0.03 mm2, respectively). Microspheres injection was associated with a trend toward a greater degree of intimal hyperplasia that did not reach statistical significance. Hydrocortisone-loaded microspheres were associated with a significant reduction in intimal hyperplasia compared with unloaded microspheres (0.16 +/- 0.02 vs. 0.26 +/- 0.03 mm2, respectively). The polylactic-co-glycolide acid microspheres are well tolerated, easily injected into the arterial wall, and the increase of intimal hyperplasia is easily inhibited by release of hydrocortisone for 4 weeks after initial injury.

Upregulation of angiotensin-converting enzyme during the healing process after injury at the site of percutaneous transluminal coronary angioplasty in humans.

Balloon injury models in rat have shown enhanced expression of ACE in the developing neointima. However, neointimal lesions in human coronary arteries are complex due to atherosclerosis and different types of wall laceration. This study was designed to investigate whether ACE is present in the neointima of humans, including patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA). Thirty-seven sites with angioplasty injury, obtained at autopsy, were studied using immunocytochemical techniques. Sites with injury limited to a fibrous plaque and those with injury extending into the media (<2 months after PTCA) showed fibrocellular repair tissue composed mainly of smooth muscle cells that were distinctly positive for ACE. In cellular reactions at the site of injury limited to the atheromatous plaque (<2 months after PTCA), the expression of ACE appeared first in accumulated macrophages; once smooth muscle cells appeared in the repair tissue, they also expressed ACE. At a later stage (3 months after PTCA), the number of cells with ACE expression decreased markedly; from 7 months on, ACE was no longer expressed within the repair tissue. Basically, there were no differences with regard to ACE expression during the healing process after PTCA between segments with and those without angiographic evidence of restenosis. These results show that PTCA injury in humans results in upregulation of ACE at sites of active repair and, therefore, ACE could play an important role as one of the mediators of the healing process after PTCA.

Mural Delivery of Iloprost with Use of Hydrogel-coated Balloon Catheters Suppresses Local Platelet Aggregation

To develop reproducible and quantifiable methods for mural delivery of iloprost, a potent agent against platelet aggregation, with use of hydrogel-coated angioplasty balloons, and to determine the in vivo effect of direct iloprost delivery on platelet aggregation at the angioplasty site. Drug loading of tritiated iloprost from an immersion solution onto hydrogel-coated balloons was evaluated as a function of balloon size (3 mm x 2 cm, 6 mm x 2 cm, 8 mm x 3 cm; n = 4 each), drug concentration (0.0715 mg/mL, 0.1072 mg/mL, 0.1430 mg/mL; n = 3 each), and duration of immersion (40 seconds, 60 seconds, 120 seconds; n = 3 each). In another set of experiments, optimal drying methods were tested to minimize drug loss within a protective delivery sheath (n = 3 each). Ex vivo angioplasty was performed on excised swine arteries to estimate how much of the drug present on the balloon could be delivered to the wall (n = 3 iliac segments). Finally, in vivo angioplasty was performed in three Yorkshire pigs (n = 6 iloprost-treated and 6 control arteries) and indium-111-labeled platelet aggregation was measured at these sites, which were harvested 1 hour after the procedure. In the initial set of experiments, the authors found that the volume of drug loaded is determined by the wet-volume of the hydrogel coating, that the majority of volume loading occurs within the first 2 minutes, and that the volume uptake is independent of the drug concentration. The optimal drying method resulting in the least loss of iloprost within the sheath (only 4%) was prolonged drying (5 hours) under ambient conditions. Ex vivo angioplasty experiments showed that approximately 33% of the drug present on the balloon can be delivered to the wall. Finally, in vivo experiments showed that platelet aggregation is significantly suppressed at treated sites (by approximately 33% compared to control sites; P = .03) by minuscule mural doses of iloprost (roughly estimated at under 1 microg). Quantifiable and reproducible methods for loading iloprost onto hydrogel-coated angioplasty balloons were developed. The best of these methods was able to deliver enough iloprost into the wall to significantly reduce local platelet aggregation.

Local heparin delivery prior to coronary stent implantation: acute and six-month clinical and angiographic results.

Stents increase smooth muscle cell proliferation, which may also lead to in-stent restenosis. A local delivery strategy provides higher drug concentration at the angioplasty site and may limit the proliferative response following stenting. Local heparin delivery was attempted in 35 patients following balloon angioplasty using an "over-the-balloon" style catheter (infusion sleeve). The infusion sleeve was successfully tracked and heparin was delivered in 33 (94%) patients. Heparin (1,000 IU/ml) was delivered under low (45 psi, 2 ml, n = 4), intermediate (75 psi, 4 ml, n = 11), and high (100 psi, 4 ml, n = 18) proximal infusion pressures. Stent placement was successful in all cases. Acute and in-hospital complications were a severe arterial spasm after heparin delivery, a non Q-wave myocardial infarction, and two vascular complications. Ten dissections were observed after PTCA and prior to heparin delivery. Of these dissections, 7 remained unchanged, 2 worsened, and 1 improved with local delivery. When heparin was delivered in the absence of dissection, no new dissections were observed. Of the 33 patients who received heparin, 30 (91%) had no symptoms and a negative exercise test at clinical follow-up. QCA analysis of 6-month follow-up angiograms, performed in 32 of 33 (97%) patients, demonstrated an acute gain of 1.98 +/- 0.67 mm, a late loss of 0.94 +/- 0.78 mm, a net gain of 1.04 +/- 0.78 mm, and a loss index of 0.48 +/- 0.32. Restenosis (> or = 50% stenosis) was observed in 4 of 32 (12%) patients. Local delivery of heparin via the infusion sleeve following PTCA and prior to stent deployment is feasible with an acceptable safety profile and a low clinical and angiographic restenosis rate at 6 months.

Haemostatic and rheological factors as predictors of restenosis following percutaneous transluminal angioplasty

To determine whether pre-angioplasty levels of haemostatic and rheological factors predicted restenosis of the dilated arterial segment following percutaneous transluminal angioplasty. Prospective study, Two regional hospital centres for angioplasty in Edinburgh and Glasgow, Scotland, UK. Haemostatic and rheological factors were measured in 102 subjects with atherosclerotic disease of the lower limbs, immediately prior to percutaneous transluminal angioplasty. Subjects were followed up after 2-3 years for restenosis of the original angioplasty site using duplex scanning. Baseline clinical characteristics were similar between subjects who restenosed (n = 27) and those with no restenosis (n = 39), except that occluded lesions were more likely to restenose than stenoses (p < or = 0.05). There was no significant difference in age- and sex-adjusted mean levels of whole blood viscosity, plasma viscosity, haematocrit, von Willebrand factor, fibrin D-dimer or plasminogen activator inhibitor-1 activity between the stenosed and no restenosis groups (p > 0.1), but mean plasma fibrinogen was lower in the restenosed group (3.31 g/l vs. 3.75 g/l; p < or = 0.05). These results persisted after multivariate adjustment for smoking habit and type of lesion dilated. This study provides no evidence that raised, pre-angioplasty levels of haemostatic and rheological factors predict restenosis following percutaneous transluminal angioplasty of the arteries of the lower limbs.

Balloon angioplasty of intracranial arteries for stroke prevention.

Stroke from surgically inaccessible intracranial atherostenosis remains a formidable clinical challenge. While antithrombotic or antiplatelet therapy may prevent distal embolism, there is no effective program for plaque stabilization preventing progression of atherosclerotic stenosis. In patients with isolated circulations (single vertebral with absent posterior communicating arteries, single carotid with contralateral internal carotid artery occlusion, or single carotid with an absent anterior communicating artery), occlusion of the stenotic vessel may produce a low flow-mediated stroke. Fifteen patients with atherosclerotic intracranial stenoses were treated by balloon angioplasty after medical therapy with warfarin failed. Treated territories included the distal internal carotid, proximal middle cerebral, distal vertebral, and basilar arteries. Dilation was successful in all vessels, with residual stenoses averaging less than 30%. Two complications included one paramedian pontine stroke and a single vessel rupture that proved fatal. There was no recurrence of transient ischemic attacks and no restenosis at the angioplasty site over a follow-up period of more than 24 months. In this small series, balloon angioplasty of intracranial vessels provided a therapeutic option for secondary stroke prevention in highly selected patients. Further studies will be necessary to establish the efficacy and safety of endovascular treatment in larger series.

Quantitative evaluation of local drug delivery using the InfusaSleeve catheter

Background Restenosis is the most common long-term complication after angioplasty. Local delivery of pharmacologic agents at the site of angioplasty holds promise as a means of achieving higher concentrations of drug in the arterial wall than can be obtained by systemic infusion. In this study, a novel local drug delivery catheter system, the InfusaSleeve™ catheter, was evaluated in a porcine coronary balloon injury model. The purpose of the study was to evaluate the efficacy of solute transfer to the arterial wall and the influence of varying supporting angioplasty balloon pressure. Methods and Results: Ten pigs (total of 22 arterial segments) underwent overstretch balloon injury (artery/balloon ratio 1:1.29) with a standard angioplasty balloon. In 7 animals (16 arterial segments) horseradish peroxidase (HRP; 10 mg/ml) was administered locally after injury, by tracking the local infusion catheter as a sheath over the angioplasty balloon to the intended site of arterial drug delivery. Supporting angioplasty balloons were inflated to one of the three different pressures. In 3 pigs HRP (10 mg/ml) was administered intravenously. No significant arterial injury caused by the local delivery device was evident on histological examination (disruption of the internal lamina elastica, arterial media, or thrombosis). Radial concentrations of the HRP reaction product in the first 150 μm of the arterial wall were quantified against known standards by measurement of light transmission through tissue sections. Mean HRP concentrations were not significantly different from those obtained by intravenous infusion using a supporting pressure of 1 atm or a supporting pressure of 3 atm of the underlying angioplasty balloon. However, a supporting pressure of 6 atm resulted in a 6-fold greater mean HRP concentration in the arterial wall than that which could be achieved by systemic administration of an equal volume of tracer (P < 0.001). Conclusion Thus solute can be delivered throughout the coronary media by the InfusaSleeve, with the magnitude of wall uptake related to support pressure. Local delivery at 6 atm support pressure produced substantially greater uptake than did systemic delivery. Cathet. Cardiovasc. Diagn. 42:102–108, 1997. © 1997 Wiley-Liss, Inc.

Quantitative evaluation of local drug delivery using the InfusaSleeve catheter.

Restenosis is the most common long-term complication after angioplasty. Local delivery of pharmacologic agents at the site of angioplasty holds promise as a means of achieving higher concentrations of drug in the arterial wall than can be obtained by systemic infusion. In this study, a novel local drug delivery catheter system, the InfusaSleeve catheter, was evaluated in a porcine coronary balloon injury model. The purpose of the study was to evaluate the efficacy of solute transfer to the arterial wall and the influence of varying supporting angioplasty balloon pressure. Ten pigs (total of 22 arterial segments) underwent overstretch balloon injury (artery/balloon ratio 1:1.29) with a standard angioplasty balloon. In 7 animals (16 arterial segments) horseradish peroxidase (HRP; 10 mg/ml) was administered locally after injury, by tracking the local infusion catheter as a sheath over the angioplasty balloon to the intended site of arterial drug delivery. Supporting angioplasty balloons were inflated to one of the three different pressures. In 3 pigs HRP (10 mg/ml) was administered intravenously. No significant arterial injury caused by the local delivery device was evident on histological examination (disruption of the internal lamina elastica, arterial media, or thrombosis). Radial concentrations of the HRP reaction product in the first 150 microns of the arterial wall were quantified against known standards by measurement of light transmission through tissue sections. Mean HRP concentrations were not significantly different from those obtained by intravenous infusion using a supporting pressure of 1 atm or a supporting pressure of 3 atm of the underlying angioplasty balloon. However, a supporting pressure of 6 atm resulted in a 6-fold greater mean HRP concentration in the arterial wall than that which could be achieved by systemic administration of an equal volume of tracer (P < 0.001). Thus solute can be delivered throughout the coronary media by the InfusaSleeve, with the magnitude of wall uptake related to support pressure. Local delivery at 6 atm support pressure produced substantially greater uptake than did systemic delivery.

Histologic Consequences of Endoluminal Coronary Artery Hydrogel Polymer Paving

Abstract Coronary artery balloon catheter angioplasty for the treatment of obstructive atherosclerosis has an unacceptably high restenosis rate of about 40% within 6 months. Local delivery of pharmaceuticals and nucleotide-based compounds is under investigation as one means to decrease recurrence. Labeled molecules, when delivered to arterial angioplasty sites in aqueous solution using porous balloon catheters, are quickly lost from the tissue. Alternative strategies include drug encapsulation in microparticles, and implantation of drug-containing polymers. We tested the feasibility of a catheter-based system to deposit a 70-μm thick layer of polyethylene glycol-lactate based hydrogel (polymerized by cross-linked end-terminal acrylate groups) onto the luminal surface of coronary arteries in pigs after balloon angioplasty, and examined the histologic consequences at one hour and seven days using light, scanning electron, and transmission electron microscopy. At one hour the gel layer was readily visualized by all three microscopic techniques and appeared well adhered to and in intimate contact with the blood vessel surface (Figs. 1-2).

Balloon angioplasty by vascular surgeons

Endovascular treatment of arterial disease of the lower extremity is performed by radiologists, cardiologists, and some vascular surgeons. This retrospective review was performed to measure complications and success rates in patients with extensive occlusive disease treated by vascular surgeons. Balloon angioplasties were performed on 336 vascular segments as a part of 239 lower extremity revascularization procedures in 200 patients between April 1990, and May 1996. Immediate technical success was determined by completion angiography, measurement of pressure gradients, or ankle brachial indices (ABI) within 30 days. Late technical success was determined by duplex imaging or ABI. Late clinical success was defined as relief of presenting symptoms. Indications for intervention included claudication (51%), limb threat (45%), and failing grafts (4%). Sixty-one percent of the endovascular procedures were performed open, and 39% were percutaneously performed. Stents were utilized at 17% of the angioplasty sites. Procedures involved angioplasty of multiple arterial sites in 117 cases (55%), angioplasty combined with open surgical bypass (endarterectomy or thrombectomy) in 65 cases (19%), and a combination of surgery with a second angioplasty in 43 (13%). Complications occurred in 9 cases (3%). There were 2 deaths within 30 days (0.5%). Immediate technical success was 93% (140 of 151) for all aortoiliac segments, 88% (75 of 85) for femoral segments, 92% (54 of 59) for popliteal, and 84% (21 of 25) for tibials. The late technical success was 81% (118 of 145) for aortoiliac segments, 67% (55 of 82) for femoral, 73% (41 of 56) for the popliteals, and 75% (18 of 24) for the tibial segments. These data demonstrate that balloon angioplasty can be performed effectively by vascular surgeons with a low complication rate in a population of patients where limb salvage was a significant indication for the procedure, and treatment often required the correction of multilevel disease.

Localized delivery of heparin to angioplasty sites with iontophoresis.

Drug delivery by iontophoresis involves the application of an electric field to move selectively charged drug molecules across biological membranes. The purpose of this study was to assess the efficacy of intravascular iontophoresis in the local delivery of heparin to balloon angioplasty sites by using a recently designed iontophoretic catheter. In vivo heparin iontophoresis was assessed in 33 rats and 21 pigs in four protocols designed to measure the technical determinants of intramural drug deposition, the pharmacokinetics and localization of coronary delivery, and the effect of this technique on platelet deposition following balloon injury. First, iontophoresis of 3H-heparin into the aorta of 33 rats was performed to determine the effects of iontophoretic current, iontophoretic membrane balloon initiation pressure, iontophoresis time, and heparin concentration on intramural drug deposition. Second, iontophoresis of 3H-heparin was performed in 16 porcine coronary arteries to quantitate immediate drug delivery and subsequent wash-out over 24 h. Third, iontophoresis of fluorescent heparin was performed in 8 porcine coronary arteries to define intramural localization of locally delivered drug. Fourth, 111In-labeled platelet deposition was measured 1 h following balloon angioplasty and local iontophoretic heparin delivery in 16 porcine carotid and iliac vessels. Contralateral control vessels that were dilated with the same size balloon and treated with iontophoresis of saline served as controls. Rat aortic studies demonstrated that iontophoresis resulted in 13 times more intramural heparin deposition than passive delivery (passive: 0.3 +/- 0.4 microgram, iontophoresis: 4.6 +/- 1.6 micrograms, P < 0.0004). Iontophoretic membrane balloon inflation pressure had no significant effect on intramural drug deposition, but longer iontophoresis times and higher heparin concentrations resulted in higher levels of intramural heparin (P < 0.05). Porcine coronary studies demonstrated successful intramural deposition of heparin in all arteries without adverse electrical or hemodynamic sequelae, with persistence of the drug for at least 24 h. Localization studies demonstrated immediate deposition of fluorescent heparin in the intima and internal elastic lamina, with subsequent rapid diffusion of the drug into the media. Porcine platelet studies demonstrated that heparin iontophoresis decreased platelet deposition following balloon injury by approximately 66% compared with saline-treated control vessels (heparin-treated: 1.46 +/- 2.51 x 10(8), control: 4.27 +/- 7.02 x 10(8), P = 0.001). This study has demonstrated that local intramural heparin delivery is feasible with an intravascular iontophoretic catheter. Following intracoronary heparin iontophoresis in the porcine model, intramural drug is detected for at least 24 h. Local delivery of heparin with this technique significantly decreases early platelet deposition following balloon injury in peripheral porcine arteries.

Local delivery of heparin to balloon angioplasty sites with a new angiotherapy catheter: pharmacokinetics and effect on platelet deposition in the porcine model.

The purpose of this study was to assess the efficacy of local heparin delivery to balloon angioplasty sites in an in vivo porcine model by using a newly designed angiotherapy catheter that allows for prolonged drug infusion while maintaining distal arterial perfusion. Protocols were designed to assess the safety of intracoronary drug delivery, the effect of infusion time and drug concentration on intramural heparin deposition, the distribution of heparin within the arterial wall, the histologic effects of local heparin delivery, the wash-out of intramurally deposited heparin, and the effect of heparin delivery on early platelet deposition following balloon injury in peripheral and coronary vessels. Local intracoronary delivery of heparin was well tolerated in all animals. Between 0.04 and 0.08% of infused heparin was intramurally deposited at the time of drug delivery, with longer infusion durations and higher concentrations of heparin resulting in greater intramural deposition. Autoradiography demonstrated homogenous distribution of heparin throughout the intima, media, and adventitia, with localization in the nuclei, cytoplasm, and extracellular space. Histologic analysis demonstrated no additional vessel trauma from local drug delivery beyond that seen with conventional angioplasty. Wash-out studies demonstrated a biexponential disappearance of intramurally deposited drug, with rapid release of heparin over the first 60 min and persistence of small amounts of drug for at least 7 d. Locally delivered heparin significantly attenuated the deposition of platelets in peripheral vessels, although a similar decrease in platelet deposition in the coronary arteries was not statistically significant. Local delivery of heparin directly to coronary angioplasty sites is possible with the use of a new angiotherapy catheter. Wash-out of heparin from the arterial wall is initially rapid, although drug is detectable for up to 1 wk following delivery. In porcine peripheral arteries, use of this technique significantly decreases early platelet deposition following balloon injury.

Intravascular Ultrasound Assessment of the Prevalence and Causes of Angiographic “Haziness” Following High-Pressure Coronary Stenting

Haziness at sites of balloon angioplasty is believed to represent plaque fractures or platelet deposition. The etiology of haziness adjacent to coronary stents remains uncertain. This study examines the prevalence and etiology of “peri-stent” haziness following high-pressure deployment. Consecutive patients undergoing coronary stenting and intravascular ultrasound imaging were included. Haziness was defined as nonhomogeneous contrast density and/or indistinct vessel borders by consensus of 2 observers. Patients were excluded if angiography revealed an obvious cause of haziness (thrombus, dissection). Matched control segments without haziness were selected for comparison. The most diseased site within the reference segment was identified by ultrasound. Lumen and plaque areas, percent plaque area, and plaque echo density were assessed. Haziness was identified within 31 segments in 30 patients (15% of 201 angiograms examined). At hazy sites, ultrasound revealed a large percent plaque area in 15, dissections in 14, and near-normal findings in 2 segments. In the absence of dissection, percent plaque area and lumen area step-down from the stent to the diseased reference were greater than controls (percent plaque area 64 ± 12% vs 56 ± 10%, p = 0.04 and lumen step-down 35 ± 20% vs 13 ± 25%, p = 0.006). With dissections, percent plaque area and lumen step-down were not different from controls (p = 0.13 and 0.30, respectively), but underlying plaques were more frequently echolucent (64% vs 23%, p = 0.02). Thus, in this study, peri-stent haziness was evident in 15% of patients after high-pressure coronary stent deployment. Etiologies identified by intravascular ultrasound included unrecognized reference plaque and angiographically occult dissections.

Localized delivery of heparin to angioplasty sites with iontophoresis

Localized delivery of heparin to angioplasty sites with iontophoresis

A randomized animal study evaluating the efficacies of locally delivered heparin and urokinase for reducing in-stent restenosis.

In-stent restenosis is primarily due to neointimal hyperplasia. Results from recent nonrandomized studies suggest that local delivery of heparin or urokinase to the site of angioplasty or stenting results in a lower rate of restenosis. To determine whether local delivery of heparin or urokinase reduces in-stent restenosis. Thirty-three pigs were assigned randomly to one of three groups: controls (n = 9) administered local saline infusion, the heparin group (n = 15) administered local heparin (6000 u/10 min), and the urokinase group (n = 9) administered local urokinase (250000 u/10 min), via a local delivery catheter (Dispatch) at the site of subsequent stent implantation. Prior to local delivery, all of the animals were subjected to balloon injury (balloon:artery diameter ratio approximately or = 1.3) to facilitate intramural drug impregnation. After local therapy, one Palmaz-Schatz stent (mean stent: artery diameter ratio approximately or = 1.25) was implanted within the left anterior descending coronary artery. The degree of neointimal hyperplasia was evaluated 4 weeks later by angiography (as the maximal percentage diameter stenosis) and histology (as the maximal neointimal area stenosis). We found no difference in percentage diameter stenosis (46 +/- 18% control, 42 +/- 27% heparin group, and 37 +/- 20% urokinase group, P = 0.7) and corrected neointimal area (1.06 +/- 0.42 mm2 control, 0.94 +/- 0.29 mm2 heparin, and 0.88 +/- 0.26 mm2 urokinase group, P = 0.7) among groups at follow-up. The activated clotting time rose slightly for heparin-treated animals, suggesting that systemic delivery had occurred, whereas fibrinogen levels did not change in urokinase-treated animals. Local deliveries of heparin and urokinase via the Dispatch catheter, at the chosen dosages, do not reduce in-stent neointimal hyperplasia in this porcine model.

Thrombosis and restenosis after peripheral angioplasty: Does acute 111indium-platelet accumulation predict angioplasty outcome?

Use of platelet deposition to predict failure following angioplasty. Prospective study of angioplasty patients in a 9 months surveillance period. Thirty-eight successful angioplasty patients. Autologous 111indium-labelled platelets were re-injected immediately after angioplasty. Gamma camera and probe measures of radioactivity were obtained daily for 2-4 days and compared to a reference site to obtain a radioactivity ratio. Patient follow up was with duplex and arteriography from day 0 to 9 months or at angioplasty failure. Thirty-one patients remained asymptomatic; two developed acute occlusion and five developed restenosis. Platelet accumulation (increased mean radioactivity ratio) occurred at all angioplasty sites and was significantly higher after acute occlusion (camera: 2.93 and probe: 1.93) compared to asymptomatic patients (camera: 1.25 and probe: 1.15) and restenotic patients (camera: 1.31 and probe: 1.23). Radioactivity ratio was not different in patients who later developed restenosis. 111Indium platelet radioactivity effectively detected acute angioplasty reocclusions, but was unable to predict subsequent angioplasty restenosis.