Daniel B. Fram

Coronary Angioplasty Induces a Systemic Inflammatory Response

C-reactive protein (CRP) levels increased more than sixfold above baseline when measured 48 hours after elective percutaneous transluminal coronary angioplasty (PTCA) in patients without underlying inflammatory conditions and did not change significantly in controls undergoing coronary angiography. Only 3 of the 42 PTCA patients had clinical restenosis and underwent target vessel revascularization during the 6-month follow-up, but 2 of the 3 had very high CRP levels 48 hours after the procedure.

Feasibility of Radiofrequency Powered, Thermal Balloon Ablation of Atrioventricular Bypass Tracts Via the Coronary Sinus: In Vivo Canine Studies

Radiofeequency catheter ablation of left sided accessory pathways is technically demanding and usually requires left heart catheterization. The feasibility of creating lesions from within the coronary sinus of sufficient size to ablate accessory pathways in humans using a thermal balloon catheter was studied in 20 dogs. In group 1 (n == 14), 17 thermal inflations were performed in 12 dogs at either 70°, 80°, or 90°C each for 30 or 60 seconds (in 2 dogs two non‐thermal control inflations were performed). Animals were sacrificed 6.3 ± 1.6 days later. In group 2 (n = 6), seven thermal inflations were performed at 90°C each for 180, 300, or 360 seconds. Group 2 animals received antiplatelet and anticoagulant therapy for 1 week and were sacrificed at 13 ± 10.7 days. In both groups, hemodynamic, angiographic, and electrocardiographic studies were performed at baseline, 1 hour after inflation, and prior to sacrifice. All dogs remained clinically stable throughout the procedure and no complications were attributed to the effect of thermal inflation. Thermal lesions measured 14.4 ± 4.4 mm in length and extended from the coronary sinus intima to a mean depth of 2.9 ± 1.2 mm (range 1.4‐6.5 mm). Group 2 lesions were significantly deeper than group 1 lesions (P = 0.03). Of the 24 thermal lesions created, atrial necrosis was present in 23 and ventricular necrosis in 11. In all lesions there was some degree of either atrial necrosis, ventricular necrosis, or both. A variable degree of coronary sinus thrombus was present in 18 dogs without clinical sequelae. It is concluded that radiofrequency balloon heating via the coronary sinus can create thermal lesions in the atrioventricular sulcus of dogs that may be of sufficient size to ablate accessory left‐sided pathways in humans. (PACE 1995; 18: 1518‐1530)

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.

Short- and medium-term outcome differences in women and men after primary percutaneous transluminal mechanical revascularization for acute myocardial infarction.

Women presenting with acute myocardial infarction (AMI) have a higher mortality with conventional medical and thrombolytic therapy when compared with men. The outcome after primary percutaneous transluminal mechanical revascularization has not yet been fully investigated. This study was performed to compare the characteristics and the short- and medium-term outcomes of women and men with AMI treated with primary percutaneous revascularization. A total of 182 consecutive patients (62 women and 120 men) were included. Baseline clinical characteristics were similar except that women were older than men, presented more often in cardiogenic shock, and had smaller reference vessel diameters. Stents and abciximab were used equally, but abciximab was stopped more often in women before completion of the 12-hour infusion because of higher bleeding rates. Acute procedural success rates were similar (92% and 97%) but mortality was much higher in women, both at 30-day follow-up (100% vs 0.9%; p <0.05) and during a mean follow-up of 6.9 +/- 4.1 months (15% vs 4.4%; p <0.05). Women also experienced more unfavorable cardiovascular events (recurrent unstable angina or AMI, target vessel revascularization) than men. However, after control for baseline clinical differences in a multivariate analysis, gender was not an independent predictor of survival, whereas age, cardiogenic shock, and completion of a 12-hour abciximab infusion were.

Abciximab in primary coronary angioplasty for acute myocardial infarction improves short- and medium-term outcomes

OBJECTIVES The purpose of this study was to compare the outcome of primary percutaneous transluminal coronary angioplasty for acute myocardial infarction (MI) when performed with or without the platelet glycoprotein IIb/IIIa antibody, abciximab. BACKGROUND Abciximab improves the outcome of angioplasty but the effect of abciximab in primary angioplasty has not been investigated. METHODS Data were collected from a computerized database. Follow-up was by telephone or review of outpatient or hospital readmission records. RESULTS A total of 182 consecutive patients were included; 103 received abciximab and 79 did not. The procedural success rate was 95% in the two groups. At 30-day follow-up, the composite event rate of unstable angina, reinfarction, target vessel revascularization and death from all causes was 13.5% in the group of patients who did not receive abciximab, 4% (p < 0.05) in the abciximab group and 2.4% (p < 0.05) in the subgroup of patients (n = 87) who completed the 12-h abciximab infusion. At the end of follow-up (mean 7+/-4 months), the composite event rate was 32.4%, 17% (p < 0.05) and 13.1% (p < 0.01) in these three categories respectively. Abciximab bolus followed by a 12-h infusion was an independent predictor of event-free survival, in a Cox proportional hazards model (relative risk 0.49; 95% confidence interval 0.24 to 0.99; p < 0.05). CONCLUSIONS Abciximab given at the time of primary angioplasty may improve the short- and medium-term outcome of patients with acute MI, especially when a 12-h infusion is completed.

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.

Intracardiac ultrasound determination of left ventricular volumes: In vitro and in vivo validation☆

OBJECTIVES This study was designed to assess the feasibility of calculating left ventricular volumes using intracardiac ultrasound. BACKGROUND Previous studies have validated transthoracic echocardiographic determinations of left ventricular volumes and have indicated the superiority of Simpson rule reconstruction algorithms. The feasibility of imaging the left ventricle with intracardiac ultrasound has also been demonstrated. METHODS The determination of left ventricular volumes with Simpson rule reconstruction of intracardiac ultrasound images was evaluated in two phases. In vitro validation was performed in 29 animal hearts preserved in either a nondistended or distended state. Latex cast volumes were the reference standard. In vivo studies used 14 pigs, and compared intracardiac ultrasound volumes and ejection fraction with single-plane contrast angiographic values. A 12.5-MHz device was used to record short-axis images at 0.5-cm intervals. These were used to reconstruct the ventricle as a stack of cylindric elements using all imaged levels as well as sections recorded every 1 and 2 cm and at a single midventricular level. RESULTS In the in vitro hearts, when all recorded sections were used, there was excellent agreement between intracardiac ultrasound and latex cast volumes (intracardiac ultrasound volume = 0.89 latex cast volume + 2.22, r = 0.95; intracardiac ultrasound volume = 0.97 latex cast volume + 0.91, r = 0.99) for nondistended and distended hearts, respectively. In vivo, there was again close correspondence between ultrasound and angiographic volumes (intracardiac ultrasound volume = 1.04 angiographic volume - 3.6, r = 0.91). The relation between intracardiac ultrasound and angiographic ejection fraction was fair (intracardiac ultrasound ejection fraction = 1.00 angiographic ejection fraction + 6.85, r = 0.69). Excellent correlations for the volumes were maintained as the number of cross sections was reduced to those recorded every 1 and 2 cm (r = 0.87 to 0.99). With a single midventricular site more variable but generally good correlations were obtained (r = 0.77 to 0.99). CONCLUSIONS The application of Simpson rule reconstruction to short-axis images of the left ventricle obtained with intracardiac ultrasound provides accurate determination of left ventricular volumes in animal hearts. This technique may prove useful in the analysis of left ventricular structure and function.

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.