Slow pathway catheter ablation of atrioventricular nodal re-entrant tachycardia guided by electroanatomical mapping: a randomized comparison to the conventional approach.

BACKGROUND: Electroanatomical mapping may be expected to improve safety, efficiency and efficacy of selective slow pathway ablation for atrioventricular nodal re-entrant tachycardia (AVNRT). The goal of this prospective randomized study was to compare the efficiency of conventional fluoroscopic and electroanatomical mapping in guiding catheter ablation of AVNRT. METHODS AND RESULTS: Following induction of typical AVNRT, 20 consecutive patients were randomized to either conventional fluoroscopic or electroanatomical (CARTO) mapping to guide slow pathway ablation using a 4mm electrode. Endpoints for ablation were non-inducibility and no more than a single AV nodal echo on aggressive retesting. Acute procedural success was 100% in both groups, with no complications. Although there were no differences in time taken for pre- and post-ablation electrophysiological evaluations, in the electroanatomical group the ablation portion of the procedure showed a substantial reduction in duration (12.6+/-6.8 vs 35.9+/-18.3 min; P< 0.001) and fluoroscopic exposure (0.7+/-0.5 vs 9.6+/-5.0 min; P< 0.001) compared with the fluoroscopic group, reflected in reduced total procedure time (83.6+/-23.6 vs 114+/-19.3 min; P=0.008) and total fluoroscopic exposure (4.2+/-1.4 vs 15.9+/-6.4 min; P< 0.001). Electroanatomical mapping was associated with a lower number (2.7+/-1.6 vs 5+/-2.8; P=0.018), duration (165.3+/-181.6 vs 341+/-177.7s; P=0.013), and total energy delivery (24.3+/-3.1 vs 28.7+/-4.5 watts; P=0.042) of RF applications. There were no acute or long-term (8.9+/-2.2 month) complications or arrhythmia recurrence in either group. CONCLUSIONS: While both conventional and non-fluoroscopic electroanatomical mapping are associated with excellent results in guiding ablation of typical AVNRT, the latter offers significantly shorter procedure and fluoroscopy times, improving the efficiency of the procedure and reducing X-ray exposure.

High-dose external beam irradiation inhibits neointima formation in stented pig coronary arteries.

PURPOSE: To evaluate high-dose external beam irradiation (EBRT) in a pig coronary stent preparation because low and intermediate-dose EBRT failed to show inhibition of neointima formation in stented animal models. METHODS AND MATERIALS: Thirty-five stents were implanted in the coronary arteries of 17 pigs. Seven pigs were exposed to a single dose of 21 Gy EBRT immediately after stenting. Ten stented, nonirradiated pigs served as controls. After 4 weeks, the study arteries and myocardium were examined by light and scanning electron microscopy. RESULTS: Compared with controls, 21 Gy EBRT resulted in a larger lumen area (7.57 +/- 1.67 mm2 vs. 4.00 +/- 1.63 mm2, p <0.001), a smaller neointima area (0.47 +/- 0.43 mm2 vs. 3.36 +/- 2.26 mm2, p <0.001) and a smaller maximal intimal thickness (0.16 +/- 0.09 mm vs. 0.68 +/- 0.31 mm, p <0.001). Unresorbed intramural hemorrhages and adherent mural thrombi were present in the irradiated vessels, which also showed incomplete re-endothelialization. The irradiated hearts demonstrated diffuse interstitial and perivascular inflammation and fibrosis. CONCLUSIONS: EBRT at 21 Gy to the entire heart significantly inhibited neointima formation in stented pig coronary arteries but also resulted in incomplete re-endothelialization, myocardial inflammation, and fibrosis. Improvements in localization and delivery techniques are required to allow clinical implementation of this technique.

Intracoronary beta-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries.

BACKGROUND: Long-term biological effects of ionizing radiation on coronary arteries remain poorly defined. We examined late arterial responses 6 months after balloon angioplasty and beta-radiation in normal pig coronary arteries. METHODS AND RESULTS: Coronary arteries of 25 adult pigs were randomized to receive 20 Gy (n=8) or 30 Gy (n=9) of (186)Re beta-radiation or sham radiation (n=8) immediately after balloon angioplasty. Aspirin was given daily during follow-up. The study vessels were analyzed histopathologically at 6 months. beta-Radiation decreased lumen area (20 Gy, 1.55+/-0.99 mm(2); 30 Gy, 1.03+/-0.82 mm(2); and 0 Gy, 2.05+/-0.80 mm(2); P<0.05) but not overall vessel area. The neointimal area was significantly larger within the injured segment with beta-radiation (20 Gy, 1.92+/-1.23 mm(2); 30 Gy, 1.51+/-0.97 mm(2); and 0 Gy, 0.89+/-0.31 mm(2); 0 Gy versus 20 Gy, P<0.05), and a significant increase of edge stenosis was observed with beta-radiation. Irradiated vessels also had larger thrombus areas within the neointima (30 Gy, 0.24+/-0.61 mm(2); 20 Gy, 0.98+/-1.57 mm2; and 0 Gy, 0.00+/-0.01 mm(2); P<0.05) and larger adventitial areas (20 Gy, 2.25+/-0.75 mm(2); 30 Gy, 2.38+/-0.98 mm(2); and 0 Gy, 1.23+/-0.29 mm(2); 0 Gy versus 20 or 30 Gy, P<0.05) that showed substantial collagen accumulation. CONCLUSIONS: Intracoronary beta-radiation did not inhibit neointima formation in balloon-injured normal pig coronary arteries 6 months after the interventional procedure. Unresorbed thrombus contributed to, but was not the sole component of, augmented neointima formation. Irradiated vessels demonstrated more adventitial thickening and fibrosis. These observations may have relevance for long-term clinical outcomes after intracoronary beta-radiation.

Antithrombotic effects of ionic and non-ionic contrast media in nonhuman primates.

Thromboembolic complications have been attributed to the use of radiographic contrast media (CM) during interventional procedures for arterial revascularization. However, due to the low frequency of adverse events, comparisons between different CM have been difficult to perform, although it has been suggested that ionic (vs. non-ionic) CM may be associated with fewer thrombotic events. The present study was undertaken using well-characterized baboon thrombosis models in order to compare different CM under physiologically relevant and controlled conditions of blood flow, exposure time, and CM concentration. Three CM were studied: ioxaglate, iohexol, and iodixanol. CM were locally infused into the proximal segment of femoral arteriovenous shunts. Palmaz-Schatz stents (4 mm i.d.) and expanded tubular segments (9 mm i.d.), which exhibited venous-type flow recirculation and stasis, were deployed into the shunts distally. Saline was infused in identical control studies. Blood flow was maintained at 100 ml/min. Thrombosis was measured over a blood exposure period of 2 hours by gamma camera imaging of 111In-platelets and by gamma counting of deposited 125I-fibrin. CM concentrations within the flowfield were predicted using computational fluid dynamics. At infusion rates of 0.1 and 0.3 ml/min, the low-osmolar ionic CM ioxaglate reduced both platelet and fibrin deposition on the stents by 75-80% (p <0.005), while both iohexol and iodixanol reduced platelet deposition by 30-50% (p <0.05). In the regions of low shear flow, ioxaglate (0.3 ml/min) also reduced platelet deposition significantly (by 52% vs. control results; p <0.05). Thus the three agents evaluated--ioxaglate, iohexol, and iodixanol--all produced anticoagulant and antiplatelet effects and were inherently antithrombotic in vivo. The most striking effects were seen with the low osmolarity, ionic contrast agent ioxaglate.

Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease.

Fibroblast growth factor-2 (FGF-2) is a heparin-binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF-2 (rFGF-2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF-2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF-2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration-time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 micrograms/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF-2 infusion, consistent with slower clearance of heparin/rFGF-2 complexes. Infusion of rFGF-2 was associated with changes in acute hemodynamics. While a clear PK/PD dose-response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF-2 doses was observed.

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study.

OBJECTIVES: Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND: FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS: Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS: Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS: Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.

Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary.

The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.

Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation.

OBJECTIVES: We evaluated the effect of orally administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes after angioplasty or stent implantation in pig coronary arteries. BACKGROUND: Tranilast, which has antikeloid and antiallergic properties and therefore may modulate the fibrotic and inflammatory tissue responses to angioplasty and stenting, has been shown to inhibit angiographic restenosis in small clinical trials. However, its effect on histomorphometric changes in coronary arteries after angioplasty and stenting is unknown. METHODS: Following initial pharmacokinetic studies in two pigs to determine desirable plasma levels of orally administered tranilast, 36 crossbred juvenile pigs were randomized to placebo or tranilast before undergoing balloon angioplasty in both the left anterior descending and left circumflex plus stent implantation in the right coronary artery. Oral tranilast was administered at 3 g/day starting 3 days before coronary injury and continued for 28 days until euthanasia. Injured vessels were harvested and sections analyzed by computer-assisted microscopic planimetry. RESULTS: In balloon-injured vessels, tranilast was associated with a 37% reduction in neointimal area normalized to fracture length (0.47 +/- 0.01 vs. 0.74 +/- 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized to vessel size (0.43 +/- 0.02 vs. 0.56 +/- 0.03; p = 0.003). In stented arteries, neointimal area normalized to injury score was 32% lower in the tranilast-treated group compared to control (1.94 +/- 0.17 vs. 2.86 +/- 0.29; p = 0.01). CONCLUSIONS: In pig coronary arteries, tranilast was associated with a reduction in neointima formation and adventitial reaction after balloon injury. In stented vessels, tranilast was associated with a reduction in neointima formation normalized to injury score.

Reduced thrombus formation by hyaluronic acid coating of endovascular devices.

Biocompatible stent coatings may alleviate problems of increased (sub)acute thrombosis after stent implantation. Hyaluronic acid (HA), a ubiquitous, nonsulfated glycosaminoglycan, inhibits platelet adhesion and aggregation and prolongs bleeding when administered systemically. However, the effects of immobilized HA for reducing stent platelet deposition in vivo are unknown. We therefore quantified the antithrombotic effects of coating stainless steel stents and tubes with HA using an established baboon thrombosis model under physiologically relevant blood flow conditions. HA-coated and uncoated (control) stents (3.5 mm in diameter, n=32) and stainless steel tubes (4.0 mm in diameter, n=18) were deployed into exteriorized arteriovenous shunts of conscious, nonanticoagulated baboons. Accumulation of (111)In-radiolabeled platelets was quantified by continuous gamma-camera imaging during a 2-hour blood exposure period. HA coating resulted in a significant reduction in platelet deposition in long (4 cm) tubes (0.24+/-0.15 x 10(9) versus 6.12+/-0.49 x 10(9) platelets; P<0.03), short (2 cm) stainless steel tubes (0.18+/-0.06 x 10(9) versus 3.03+/-0.56 x 10(9) platelets; P<0.008), and stents (0.82+/-0.20 x 10(9) versus 1.83+/-0. 23 x 10(9) platelets; P<0.02) compared with uncoated control devices. Thus, HA coating reduces platelet thrombus formation on stainless steel stents and tubes in primate thrombosis models. These results indicate that immobilized HA may represent an attractive strategy for improving the thromboresistance of endovascular devices.

The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries.

BACKGROUND: Endovascular irradiation (EI) inhibits balloon-induced neointima formation in animals and is now in clinical trials for restenosis prevention. However, little is known of the effect of EI on vessel thrombogenicity due to delayed arterial healing. We investigated EI effects on platelet recruitment in pig coronary arteries. METHODS AND RESULTS: EI was performed using (90)Sr/Y at 0 Gray (Gy), 15Gy, or 30Gy at 2 mm after balloon overstretch injury. At 1 day, 1 week, and 1 month, platelet recruitment and thrombus formation were assessed using autologous (111)In-oxine-platelet labeling and light and scanning electron microscopy. In balloon-injured nonirradiated vessels, there was complete reendothelialization at 1 month, and platelet recruitment was similar to normal uninjured arteries. In irradiated vessels, scanning electron microscopy showed incomplete reendothelialization at 1 month, and these areas demonstrated attachment of activated platelets. Light microscopy of irradiated coronaries showed adherent partially organized thrombi and incomplete resolution of intramural hemorrhages. There was a significant increase in platelet recruitment at 1 month in arteries receiving EI at 15Gy (5.1+/-2. 8x10(6), P=0.02) or 30Gy (12.5+/-9.9x10(6), P=0.005) compared with nonirradiated controls (2.7+/-1.5x10(6)); 30Gy was also higher than 15Gy (P=0.05). Platelet recruitment was also increased for 30Gy compared with control at 1 day. CONCLUSIONS: Endovascular irradiation at 15Gy or 30Gy after balloon angioplasty results in incomplete endothelial recovery, impaired resolution of intramural hemorrhage, and a dose-dependent increase in platelet recruitment at 1 month.

Effect of systemic sclerosis on left ventricular long-axis motion and left ventricular mass assessed by magnetic resonance.

The aim of this study was to assess the effect of scleroderma on left ventricular mass and subendocardial function using cardiovascular magnetic resonance (CMR) to determine parameters reflecting early dysfunction from fibrosis. Fifteen patients with a history of scleroderma had left ventricular mass measured with standard techniques and regional subendocardial contractile function assessed using myocardial velocity mapping in the basal short-axis plane with long-axis sensitized velocity mapping. Peak myocardial velocities in systole and diastole were measured to reflect systolic and diastolic function. The variance in the regional myocardial velocity, was determined as a parameter of function heterogeneity around the ventricle. The results were compared with 19 healthy volunteers without a history of cardiovascular disease. In 10 patients, pulmonary transfer factor was measured using a single-breath helium dilution technique. The duration of scleroderma correlated with left ventricular mass (r = 0.7, p < 0.05), the coefficient of variation of velocity (r = 0.63, p < 0.05), and inversely with the mean left ventricular diastolic long-axis velocity (r = -0.63, p < 0.05). There was also a correlation between left ventricular diastolic long-axis velocity and the pulmonary transfer factor (r = 0. 7, p < 0.05). Trends suggested differences between control subjects and scleroderma patients for mean systolic (64 vs. 49 mm/sec, p = 0.09) and diastolic (90 vs. 72 mm/sec, p = 0.07) velocities, as well as velocity variance (26 vs. 33, p = 0.09). In conclusion, there is a relationship between duration of scleroderma and both left ventricular mass and diastolic function, which may result from increased myocardial fibrosis. Trends suggest absolute differences in functional values with control subjects that reflect impaired diastolic and systolic function, with greater regional heterogeneity that is consistent with nonuniform collagen deposition, but a larger sample size is required to confirm this. CMR should be explored further as a technique for monitoring myocardial involvement in scleroderma noninvasively.

Short- and long-term histopathologic evaluation of stenting using a self-expanding nitinol stent in pig carotid and iliac arteries.

Stenting is increasingly being used to treat carotid artery disease. However, complications including distal embolization, stent thrombosis, stent collapse from external compression, the need for high-pressure inflation with increased neointimal response, or balloon rupture during stent expansion and stent loss are all potential problems and of concern. To address each of these specific concerns, a new stent was designed, which is self-expandable, made of nitinol, with temperature-dependent superelastic properties, and with high vessel wall surface coverage. Since this device has a number of novel characteristics, we aimed to assess the short- and long-term histopathologic response in pig carotid and iliac arteries. Single stents were deployed in pig carotid and iliac arteries after overstretch balloon injury. Angiograms were performed pre- and poststenting and prior to sacrifice. Intravascular ultrasound was used before implantation to determine vessel size. Vessels were examined histologically at 1 month (n = 6) and 6 months (n = 6) for morphometric analysis, hemorrhage and thrombus, endothelialization, and inflammatory and fibrotic responses. There was a 100% angiographic success rate at implantation. In one case, it was determined histologically that a single stent was implanted in a dissection plane of a pig's left iliac artery and was occluded by organized thrombus, with the true lumen being patent. At 6-month follow-up, this was the only evidence of a single stent occlusion, with flow adjacent to the stent in the true lumen. In the other vessels, the stents showed good vessel wall-stent apposition and the lumens were patent with a concentric and thin neointima. Inflammatory cells were rare and there were no mural thrombi. Coverage of the vessel wall by endothelial-like cells was complete at 1 month. The novel nitinol EndoStent appears to have favorable biocompatibility with minimal thrombus deposition or inflammatory response, and its use is feasible for clinical application in carotid and iliac arteries.

The progression of thrombus in an ex-vivo shunt model evaluated by intravascular ultrasound radiofrequency analysis.

We tested the ability of ultrasound radiofrequency (RF) signal analysis to characterize thrombus accumulation in a Dacron graft incorporated into the exteriorized arteriovenous shunt in 3 baboons with constant blood flow for 60 min. Thrombus formation was quantified by sequential measurements of 111Indium-labeled platelet deposition. RF signals were acquired every 15 min at 2 sites in the graft, using a 2.9 Fr intravascular ultrasound catheter-based transducer (30 MHz) and digitized at 250 MHz in 8-bit resolution. Regions of interest were placed within a 0.5-mm perimeter adjacent to the graft wall. Integrated backscatter increased significantly (p < 0.001) with increasing platelet deposition. However, mean-to-standard deviation ratio of the RF envelope showed no significant change and the distribution pattern of the RF probability function remained constant and consistent with a Rayleigh scattering process. These results provide a basis for using RF analysis to monitor the time-course of thrombus formation.

Phosphorylcholine-coated metallic stents in rabbit iliac and porcine coronary arteries.

The arterial wall reaction to phosphorylcholine-coated metal stents was examined in rabbits and pigs. Compared to non-coated stents, no significant difference was found by angiography and histology. We conclude that although phosphorylcholine-coating does not provoke arterial neointima formation or decrease luminal diameter compared to stainless steel stents, the coating does not seem to reduce restenosis.

Coronary stents: a safe and effective intervention for treating coronary artery disease

Percutaneous Transluminal Coronary Angioplasty (PTCA) is a less invasive form of coronary revascularisation than Coronary Artery Bypass Grafting (CABG). The major limitation of PTCA is renarrowing of the dilated lesion (restenosis), which may occur in up to one-third of cases. Stents are the only new devices proven to lower the restenosis rate. To evaluate the efficacy and safety of coronary stent implantation, we reviewed the charts of the first 121 patients (133 stents) undergoing coronary stenting using the J & J Stent at Emory University Hospital. Age of the patients studied (yrs; mean ñ SD) was 60.5 ñ 10.5. 77 percent were male, 46 percent were hypertensive and 27 percent were diabetic. 82 percent had class 3 or 4 angina. Prior surgical revascularisation was performed in 66 percent, previous PTCA in 55 percent and previous PTCA to stented vessel in 19.5 percent. Multivessel disease was present in 74 percent. The mean ejection fraction was 52 ñ 11.8 percent. The target lession was located in- a saphenous vein graft in 60.3 percent. The mean baseline diameter stenosis was 80.2 ñ 11.2 percent and this was reduced to 8.8 ñ 8.2 percent after stenting. The stent/s were successfully deployed in 98.6 percent of cases. In hospital clinical success was defined as procedural success in the absence of in-hospital death (0.8 percent), Q-wave myocardinal infarct (MI) (1.7 percent), repeat PTCA (3.3 percent), or emergent CABG (2.5 percent). At a mean follow up of 2.5 years the incidence of death was 11 percent, subsequent MI (15.2 percent), CABG (26.6 percent) and repeat PTCA (39.6 percent). Restenosis was defined as more than 50 percent residual diameter stenosis of the previously dilated coronary segment on follow up angiography. Follow up angiography was performed in 34 of the 121 stented patients because of recurrence of symptoms or a positive stress test. 16 patients had restenosis (15 percent of 121 patients). Coronary stents can be successfully implanted with low hospital morbidity and mortality. Stents markedly reduce the diameter stenosis of the coronary lesion during PTCA. The incidence of restenosis after stenting is low.(AU)

Reduction in stent and vascular graft thrombosis and enhancement of thrombolysis by recombinant Lys-plasminogen in nonhuman primates.

BACKGROUND: To enhance thrombolytic responses without increasing hemorrhagic risks, the antithrombotic effects of recombinant Lys-plasminogen (r-LysPgn), a prothrombolytic plasminogen intermediate, were examined in baboon models of thrombus formation and dissolution. METHODS AND RESULTS: The dose-response effects of r-LysPgn, alone or in combination with subthreshold dosing of tissue plasminogen activator (TPA), were measured with respect to the accumulation of (111)In-labeled platelets and (125)I-fibrin in thrombus forming on endovascular metallic stents or thrombogenic segments of vascular graft interposed in exteriorized long-term arteriovenous (AV) femoral shunts. Thrombolytic losses have also been determined for preformed, stable, (111)In-platelet- and (125)I-fibrin-labeled graft thrombus and corresponding propagated thrombotic tails, together with changes in blood tests of thrombosis, thrombolysis, and hemostasis. Bolus intravenous r-LysPgn in escalating doses (2, 4, or 8 mg/kg) increased circulating plasminogen levels in a dose-dependent manner, was removed by log-linear clearance with a T50 of 120 minutes, and reciprocally decreased the accumulating thrombus on metallic stents and segments of vascular graft (P<.001 in all cases for 8-mg/kg doses). r-LysPgn also impaired platelet aggregatory responses to physiological agonists in vitro but not ex vivo. Prethrombosis administration of low-dose r-LysPgn (2 mg/kg) greatly enhanced the lysis of radiolabeled nonoccluding thrombus by a subthreshold dose of TPA (0.1 mg/kg) compared with TPA-only controls (P=.03). CONCLUSIONS: Elective bolus injections of r-LysPgn before stent deployment decrease the amount of thrombus formed without compromising hemostasis by facilitating endogenous TPA thrombolysis. r-LysPgn may provide effective and safe antithrombotic therapy for interventional vascular procedures.

Endoluminal local delivery of PCNA/cdc2 antisense oligonucleotides by porous balloon catheter does not affect neointima formation or vessel size in the pig coronary artery model of postangioplasty restenosis.

Localized delivery of antisense oligonucleotides directed against cell cycle regulatory proteins has been proposed as a means to prevent restenosis after angioplasty. To test whether single endoluminal delivery of a combination of proliferating cell nuclear antigen (PCNA) and cell-division cycle 2 kinase (cdc2) antisense might affect restenosis, we delivered 2 ml of lipid-complexed PCNA/cdc2 antisense oligomers (1.35 mg) to the coronary arteries of pigs after balloon overstretch angioplasty (AS group) and performed planimetric histomorphometry on arterial sections of the tissue, harvested at 4 wk. Compared with controls receiving 3'-5' reversed sequence oligomers (REV group), there were no differences in absolute intimal area (AS 1.36 +/- 0.08 mm2, REV 1.23 +/- 0.10 mm2, P = NS), intimal area normalized to extent of injury (AS 0.67 +/- 0.03, REV 0.77 +/- 0.10, P = NS), or vessel perimeter (AS 7.72 +/- 0.19 mm, REV 7.36 +/- 0.22 mm, P = NS). We conclude that single endoluminal delivery of antisense against key cell cycle regulatory proteins does not affect neointima formation or vessel size in this model of restenosis.

Pharmacokinetics and tissue localization of antisense oligonucleotides in balloon-injured pig coronary arteries after local delivery with an iontophoretic balloon catheter.

When delivered locally to the arterial wall by passive fluid transfer systems such as perforated balloons, water-soluble compounds in aqueous solution are not readily taken up by tissue, show low levels of cellular localization, and are quickly lost by wash-out. One approach to improve delivery is addition of an "active" component to the catheter system to change the nature of the drug-to-tissue interaction. Using an iontophoretic balloon catheter to deliver antisense oligonucleotide (ODN) to pig coronary arteries after balloon angioplasty, we determined the quantity and localization of ODN in the tissue. By radiolabeling, 7.3 +/- 2.4 micrograms ODN was present at 30 min, 1.5 +/- 0.6 at 2 h, 0.52 +/- 0.35 at 24 h, and 0.26 +/- 0.11 at 7 d. By fluorescent labeling, circumferential medial uptake and adventitial delivery at the site of medial injury was observed, with primarily cellular localization. The iontophoretic catheter thus appears to be a useful device for ODN delivery to arterial tissue.