Joseph F. Mitchel

Decreased platelet deposition and smooth muscle cell proliferation after intramural heparin delivery with hydrogel-coated balloons.

In vitro and in vivo studies have demonstrated both anticoagulant and antiproliferative effects of heparin. The purpose of this study was to assess the effect of local intramural delivery of heparin, using heparin-coated hydrogel balloons, on platelet deposition and early smooth muscle cell proliferation after in vivo balloon angioplasty. Methods and ResultsThe effects of local heparin delivery were assessed during balloon angioplasty of porcine peripheral arteries. All balloon dilatations were performed with oversized hydrogel balloons coated with a known quantity of heparin. Balloon dilatations in contralateral vessels with uncoated hydrogel balloons served as study controls. The pharmacokinetics of heparin delivery were assessed using 3H-heparin to quantitate heparin wash-off from the balloon surface, heparin delivery to the arterial wall, and intramural persistence of drug. Platelet deposition at 1 hour after balloon injury was quantified using 111In-labeled platelets. Smooth muscle cell proliferation was assessed 6 to 7 days after angioplasty with immunohistochemical staining for proliferating cell nuclear antigen. 3H-heparin wash-off from the hydrogel balloon surface occurred rapidly, with approximately 95% of the heparin coating disappearing within 10 seconds in the intact circulation. Approximately 2% of heparin on the balloon surface was delivered intramurally at the time of angioplasty. Intramural heparin dissipated rapidly, although small amounts of intramural heparin could still be detected for at least 48 hours. In comparison to control vessels, there was less 111In-platelet deposition (P = .002) and less medial smooth muscle cell proliferation (P = .03) in heparin-treated vessels. ConclusionsLocal intraluminal delivery of heparin at the time of balloon angioplasty with heparin-coated hydrogel balloons results in intramural deposition of drug that persists for at least 48 hours. This in vivo technique significantly decreases platelet deposition and early smooth muscle cell proliferation after angioplasty injury.

Localized intramural drug delivery during balloon angioplasty using hydrogel-coated balloons and pressure-augmented diffusion

OBJECTIVES This study was designed to assess the feasibility of using hydrogel-coated balloons to deliver biologically active agents to the blood vessel wall. BACKGROUND The local intramural delivery of therapeutic agents during balloon angioplasty has been proposed as an adjunctive technique for preventing early intracoronary thrombosis and late restenosis. METHODS To assess the efficacy of delivery and depth of penetration in vitro, local delivery of horseradish peroxidase was performed in 40 porcine peripheral arteries, and delivery of fluoresceinated heparin was performed in 20 porcine peripheral arteries and 7 human atheromatous arteries. To determine the persistence of these agents in the vessel wall in vivo, horseradish peroxidase was delivered to 18 porcine peripheral arteries that were harvested at intervals of 45 min to 48 h. Fluoresceinated heparin was delivered to 22 porcine peripheral arteries, 14 with the use of a protective sleeve, harvested at intervals of 30 s to 24 h. RESULTS In vitro agent delivery was successful in all specimens. The depth of penetration of horseradish peroxidase was directly related to both balloon pressure (p < 0.04) and duration of inflation (p < 0.01). In vivo peroxidase staining was evident at 45 and 90 min but not thereafter. With the use of a protective sleeve, heparin was present in all arteries harvested at 30 s, with marked dissipation at 1 and 24 h. Without a sleeve, no fluorescein staining was detected in any artery. With both agents, delivery occurred consistently over broad regions of the vessel wall that were free of architectural disruption. CONCLUSIONS Hydrogel-coated balloons can deliver biologically active agents to the vessel wall without gross tissue disruption and may provide an atraumatic method for the local delivery of therapeutic agents during balloon angioplasty.

Results of primary percutaneous transluminal coronary angioplasty plus abciximab with or without stenting for acute myocardial infarction complicated by cardiogenic shock

This study examines the effects of abciximab as adjunctive therapy in primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI) complicated by cardiogenic shock. Abciximab improves the outcome of primary PTCA for AMI, but its efficacy in cardiogenic shock remains unknown. Case report forms were completed in-hospital and follow-up was obtained by telephone, outpatient visit, and review of hospital readmission records. A total of 113 patients with cardiogenic shock from AMI were included. All underwent emergency PTCA during which abciximab was administered to 54 patients (48%). The 2 groups of patients who received and did not receive abciximab were similar at baseline. Coronary stents were implanted slightly more often in the abciximab group (59% vs 42%; p = 0.1). A significantly improved final TIMI flow, less no-reflow, and a decrease in vessel residual diameter stenosis occurred in the abciximab group. At 30-day follow-up, the composite event rate of death, myocardial reinfarction, and target vessel revascularization was better in the abciximab group (31% vs 63%; p = 0.002). The combination of abciximab and stents was synergistic and resulted in improvement of all components of the composite end point beyond that seen with each therapy alone. Thus, abciximab therapy improves the 30-day outcome of primary PTCA in cardiogenic shock, especially when combined with coronary stenting.

INHIBITION OF PLATELET DEPOSITION AND LYSIS OF INTRACORONARY THROMBUS DURING BALLOON ANGIOPLASTY USING UROKINASE-COATED HYDROGEL BALLOONS

BACKGROUND Conventional balloon angioplasty of intracoronary thrombus is associated with a high incidence of abrupt closure, distal embolization, and no-reflow phenomenon. The purpose of this study was to assess a new technique for treating intracoronary thrombus consisting of the local delivery of urokinase directly to the angioplasty site with urokinase-coated hydrogel balloons. METHODS AND RESULTS We assessed local urokinase delivery using hydrogel balloons in four protocols. First, we evaluated the pharmacokinetics of urokinase delivery in vitro using 125I-labeled urokinase to measure drug loading onto hydrogel balloons, drug retention by the hydrogel polymer during blood exposure, and drug transfer from the balloon surface to the arterial wall during balloon dilatation. Second, we measured 125I-urokinase washoff from the hydrogel balloon in the intact circulation and intramural drug delivery during in vivo balloon angioplasty in 10 anesthetized New Zealand rabbits. Third, we assessed the effect of local urokinase delivery on 111In-labeled platelet deposition after balloon angioplasty in vivo in 13 porcine carotid or iliac arteries dilated with urokinase-coated balloons and compared them with contralateral control arteries dilated with saline-coated balloons. Finally, we determined the clinical efficacy of urokinase-coated balloons in 15 patients with intracoronary thrombus, including 7 who demonstrated abrupt thrombotic closure after conventional angioplasty. Between 241 and 1509 U urokinase could be loaded onto hydrogel balloons ranging in size from 2 to 8 mm. In vitro and in vivo studies demonstrated that hydrogel balloons absorbed significantly more urokinase and demonstrated less drug wash-off than nonhydrogel balloons (P < .01). Similarly, both in vitro and in vivo studies demonstrated urokinase transfer from the hydrogel to the arterial wall during balloon angioplasty, with greater intramural drug deposition with larger balloons (P < .01). Local urokinase delivery after in vivo porcine angioplasty decreased 111In-labeled platelet deposition by 47% compared with contralateral control vessels (P = .03). Use of urokinase-coated balloons in patients with intracoronary thrombus resulted in thrombus dissolution and reversal of abrupt closure in all cases, without evidence of distal embolization. CONCLUSIONS With the use of hydrogel-coated balloons, urokinase can be delivered locally to an angioplasty site. This technique decreases platelet deposition after in vivo balloon angioplasty and is efficacious in treating intracoronary thrombus in patients, including those with abrupt thrombotic closure.

Identification of Coronary Thrombus With a IIb/IIIa Platelet Inhibitor Radiopharmaceutical, Technetium-99m DMP-444 A Canine Model

BACKGROUND A diagnostic test that could distinguish between stable and unstable coronary atherosclerotic plaques would be useful. We tested the ability of a new glycoprotein IIb/IIIa platelet inhibitor DMP-444, labeled with technetium (Tc)-99 m, to identify platelet-rich thrombus by nuclear imaging in a canine model. METHODS AND RESULTS Combinations of a flow-limiting stenosis and 0 to 15 minutes of endothelial electrical stimulation at a site in the left anterior descending coronary artery were used to induce varying amounts of thrombus formation. In 10 animals with markedly positive nuclear images after the injection of Tc-99m DMP-444, the presence of platelet-rich thrombus was confirmed postmortem by gross appearance, high nuclear counts, and abundant platelets on electron microscopy. The 10 animals with negative images had lower counts, smaller thrombus weights (P<0.05 for each), and fewer platelets by electron microscopy. CONCLUSIONS Activated platelets participating in acute thrombus formation can be accurately detected by nuclear imaging using Tc-99 m DMP-444.

Duration of Abnormal SPECT Myocardial Perfusion Imaging Following Resolution of Acute Ischemia: An Angioplasty Model

OBJECTIVES This study was designed to determine how long nuclear myocardial perfusion imaging (MPI) remains abnormal following transient myocardial ischemia. BACKGROUND Acute rest MPI identifies myocardial ischemia with a high sensitivity when the radionuclide is injected during chest pain. However, the sensitivity of this technique is uncertain when the radionuclide is injected following the resolution of symptoms. METHODS Forty patients undergoing successful coronary angioplasty were randomized into four equal groups. Tc-99m sestamibi was injected intravenously during the last balloon inflation (acute MPI) in 30 patients and then reinjected 1, 2, or 3 h later (delayed MPI). In a fourth group, the radiopharmaceutical was injected at 15 min following balloon deflation (delayed MPI). A final injection was performed at 24 to 48 h (late MPI) in 37 patients (93%). RESULTS A perfusion defect was detected in all 30 acute MPI studies; in 7/10 patients (70%) injected at 15 min; in 11/30 patients (37%) injected at 1, 2, or 3 h; and in 7/37 patients (19%) injected at 24 to 48 h. Perfusion scores were 13.0 +/- 9.2 on acute MPI, 5.1 +/- 2.8 at 15 min (p < 0.001 vs. acute MPI); 2.6 +/- 3.0 at 1, 2, and 3 h (p < 0.001 vs. acute MPI); and 1.3 +/- 2.4 at 24 to 48 h (p < 0.001 vs. acute MPI; p < 0.03 vs. delayed MPI). CONCLUSIONS Myocardial perfusion imaging may remain abnormal for several hours following transient myocardial ischemia even when normal flow is restored in the epicardial coronary artery.

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.

Local delivery of c‐myb antisense oligonucleotides during balloon angioplasty

Intraluminal delivery of antisense oligonucleotides to c-myb was assessed following balloon angioplasty in swine peripheral arteries. Successful delivery and intramural persistence of oligonucleotide for over 24 h were demonstrated following angioplasty with hydrogel balloons coated with 32P-labeled antisense. Delivery of fluorescein-labeled antisense demonstrated further localization within the arterial media and intracellularly. Preliminary in vitro studies demonstrated the feasibility of inhibition of porcine lymphocyte proliferation using the murine antisense to c-myb. Twelve iliac or carotid arteries underwent angioplasty with antisense-coated balloons, while the contralateral vessels underwent angioplasty with the same-sized balloons coated with the complementary sense strand. Six to seven days later, dilated arterial segments were surgically isolated. In 10 of 12 vessel pairs, antisense-treated vessels demonstrated less cellular proliferation than did contralateral sense-treated vessels, as assessed by quantitative immunohistochemical staining of proliferating cell nuclear antigen, and smooth muscle cell proliferation was reduced 18% in antisense-treated vessels compared to the contralateral sense-treated vessels (PCNA-positive nuclear area: 7.7 +/- 4.9% vs. 9.3 +/- 5.2%, P < 0.04)-intraluminal delivery of antisense oligonucleotides to c-myb is feasible with a catheter-based system and may reduce smooth muscle cell proliferation following arterial injury.

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 urokinase delivery with the Channel balloon: Device safety, pharmacokinetics of intracoronary drug delivery, and efficacy of thrombolysis

The Channel balloon is a new local drug-delivery catheter that has the dual capability of high-pressure lesion dilation and low-pressure drug infusion. The purpose of this study was to assess the safety and efficacy of this device in the local delivery of urokinase in the porcine model. Three in vivo protocols were performed in 57 anesthetized swine to assess the safety of Channel balloon use in the coronary vasculature, the pharmacokinetics of local urokinase delivery, and the ability of the catheter to lyse intraluminal thrombus. First, safety studies were performed in 18 coronary vessels in 13 pigs to compare angiographic and histologic changes following use of the Channel balloon with conventional balloon angioplasty. Second, intramural deposition of 123I-labeled urokinase was measured in 24 coronary arteries in 20 pigs to assess the efficiency and technical determinants of urokinase delivery and the time course of intramural drug retention. Finally, an in vivo thrombus model was used in 24 pigs to compare the thrombolytic capacity of local urokinase delivery with the Channel balloon in comparison with conventional urokinase infusion techniques. All balloon inflations and drug infusions with the Channel balloon were well tolerated in all animals without adverse angiographic, hemodynamic, or electrical sequelae. Comparative histologic studies with the Channel balloon demonstrated no additional vessel trauma beyond that seen with conventional balloon angioplasty. Between 0.09 and 0.35% of infused urokinase was intramurally deposited, with intracoronary persistence for at least 5 h. Drug infusion pressure did not significantly affect drug deposition, although larger amounts of urokinase were deposited with larger balloon:artery ratios and higher urokinase concentrations. In comparison to conventional systemic and guiding catheter infusions, local delivery of urokinase with the Channel balloon resulted in higher levels of clot dissolution. These studies have demonstrated safe intracoronary use of the Channel balloon in the porcine model. Local infusion of urokinase with this device results in significant intramural drug deposition that persists for at least 5 h. In comparison with conventional thrombolytic techniques, local urokinase delivery with the Channel balloon may result in enhanced intravascular thrombolysis.