Frank Litvack

Laser ablation of human atherosclerotic plaque without adjacent tissue injury

Seventy samples of human cadaver atherosclerotic aorta were irradiated in vitro using a 308 nm xenon chloride excimer laser. Energy per pulse, pulse duration and frequency were varied. For comparison, 60 segments were also irradiated with an argon ion and an Nd:YAG (neodymium:yttrium aluminum garnet) laser operated in the continuous mode. Tissue was fixed in formalin, sectioned and examined microscopically. The Nd:YAG and argon ion-irradiated tissue exhibited a central crater with irregular edges and concentric zones of thermal and blast injury. In contrast, the excimer laser-irradiated tissue had narrow deep incisions with minimal or no thermal injury. These preliminary experiments indicate that the excimer laser vaporizes tissue in a manner different from that of the continuous wave Nd:YAG or argon ion laser. The sharp incision margins and minimal damage to adjacent normal tissue suggest that the excimer laser is more desirable for general surgical and intravascular uses than are the conventionally used medical lasers.

Localized arterial wall drug delivery from a polymer-coated removable metallic stent. Kinetics, distribution, and bioactivity of forskolin.

BackgroundCoronary stenting is associated with two major complications: subacute thrombosis and neointimal proliferation resulting in restenosis. Our hypothesis is that the biocom-patibility of metallic stents can be improved by coating with a polymer membrane that delivers agents that favorably modify the local arterial microenvironment. This study evaluates the kinetics, distribution, and bioactivity of the model drug for-skolin delivered to the local arterial wall by a polyurethane-coated removable metallic stent. Methods and ResultsStents were used in rabbit carotid arteries (n=20) for as long as 24 hours. The quantity of forskolin bound to the stent decreased exponentially with a half-life of 5.8 hours. Blood concentrations peaked at 140±39 pg/μL at 4 hours. The adjacent arterial media contained 60±39 ng/mg, which was 380- and 460-fold greater than the contralateral carotid media and the systemic blood, respectively (P<.0001). Media forskolin concentrations declined exponentially over time with a tissue half-life of 5.0 hours. Drug distributed throughout the vessel wall with decreasing gradients in the radial and axial dimensions consistent with a diffusion process. Removal of the stent was associated with a 100-fold decline in media forskolin concentration within 2 hours. Forskolin release was associated with a sustained 92% increase in carotid blood flow and a 60% decrease in local arterial resistance compared with coated control stents (P<.005). In another set of rabbits (n=14) using a carotid crush injury, flow-reduction model, forskolin prolonged the time to flow variation and occlusion by 12-fold compared with the use of bare metal stents and 5-fold compared with the use of polyurethane-coated stents (P<.0001). ConclusionsA polymer-coated metallic stent can deliver forskolin to the local arterial wall in high concentrations relative to the blood or other tissues. High local drug concentrations are dependent on maintaining stent-to-tissue gradients. The delivered drug is biologically active, demonstrating vasodilating and antiplatelet properties.

Immediate results and late outcomes after stent implantation in saphenous vein graft lesions: The multicenter U.S. Palmaz-Schatz stent experience

OBJECTIVES This study reports the multicenter registry experience evaluating the safety and efficacy of the Palmaz-Schatz stent in the treatment of saphenous vein graft disease. BACKGROUND Saphenous vein graft angioplasty is associated with frequent periprocedural complications and a high frequency of restenosis. Stent implantation has been shown to reduce restenosis, with improved long-term outcomes in the treatment of native coronary artery disease. Preliminary experience with stent placement in the treatment of saphenous vein graft lesions has been favorable. METHODS Twenty U.S. investigator sites enrolled a total of 589 symptomatic patients (624 lesions) for treatment of focal vein graft stenoses between January 1990 and April 1992. Follow-up angiography was performed at 6 months, and the clinical course of all study patients was prospectively collected at regular intervals for up to 12 months. RESULTS Stent delivery was successful in 98.8% of cases, and the procedural success rate was 97.1%. The lesion diameter stenosis decreased from 82 +/- 12% (mean +/- SD) before to 6.6 +/- 10.2% after treatment. Major in-hospital complications occurred in 17 patients (2.9%); stent thrombosis was found in 8 (1.4%); and major vascular or bleeding complications were noted in 83 (14.3%). Six-month angiographic follow-up revealed an overall restenosis rate (> or = 50% diameter stenosis) of 29.7%. Multivariate logistic regression analysis indicated that 1) restenotic lesions, 2) smaller reference vessel size, 3) history of diabetes mellitus, and 4) higher percent poststent diameter stenosis were independent predictors of restenosis. The 12-month actuarial event-free survival was 76.3%. CONCLUSIONS Stent implantation in patients with focal saphenous vein graft lesions can be achieved with a high rate of procedural success, acceptable major complications, reduced angiographic restenosis and favorable late clinical outcome compared with historical balloon angioplasty control series. The rigorous anticoagulation regimen after stent placement results in more frequent vascular and other bleeding complications. Future randomized studies comparing standard balloon angioplasty with stent implantation are warranted to properly assess the full impact of stent placement in the treatment of saphenous vein graft lesions.

Local Drug Delivery via a Coronary Stent With Programmable Release Pharmacokinetics

Background—Fixed drug release kinetics and vessel wall partitioning may limit the effectiveness of drug-eluting stents. We report preliminary experience using a new coronary stent with programmable pharmacokinetics. Methods and Results—A newly designed metallic stent contains honeycombed strut elements with inlaid stacked layers of drug and polymer. In vitro studies evaluated recipes for loading paclitaxel to establish the parameters for controlling drug release. Manipulation of the layers of biodegradable polymer and drug allowed varying of the initial 24-hour burst release of paclitaxel from 69% to 8.6% (P <0.0001). Late release of drug could be adjusted dependently or independently of early burst release. A biphasic release profile was created by the addition of blank layers of polymer within the stack. In the 30-day porcine coronary model (n=17 pigs), there was a 70% reduction in late loss (0.3±0.5 versus 1.0±0.5 mm, P =0.04), a 28% increase in luminal volume (132±12 versus 103±21 mm3, P =0.02), and a 50% decrease in histological neointimal area (2.0±0.5 versus 4.0±1.6 mm2;P <0.001) compared with bare metal controls. Temporal and regional variations in vascular healing were seen histologically. Conclusions—Layered polymer/drug inlay stent technology permits flexible and controllable pharmacokinetic profiles. Programmable, complex chemotherapy using this approach may be feasible for the treatment of cardiovascular disease.

Early ambulation after 5 French diagnostic cardiac catheterization: Results of a multicenter trial☆

Because earlier ambulation and discharge after cardiac catheterization may result in the increased utilization of outpatient facilities, a prospective five center clinical pilot trial assessing the safety and outcome of early ambulation after routine left heart catheterization was performed in 287 patients. Catheterization routines at each clinical center were unchanged throughout the study. After the diagnostic catheterization using 5 French (F), preformed, large lumen catheters and arterial puncture compression (mean 15 min, range 5 to 52), 260 patients were ambulated by a physician at a mean time of 2.6 h (range 1.8 to 3.1) after catheterization. Follow-up examination or a phone call 24 to 72 h later was performed to assess late results. The mean age of the patients was 58 years (range 25 to 91); 166 (58%) were men. Left ventricular ejection fraction was 54 +/- 15%. One hundred twenty-seven patients (44%) received intravenous heparin (1,500 to 5,000 U as an intravenous bolus) and 136 (47%) received aspirin. Major complications included transient ischemic attack (one patient) and ventricular tachycardia requiring cardioversion during ventriculography (two patients). A small hematoma (less than 5.0 cm) after ambulation occurred early (from compression to standing) in 14 patients (5%; 9 received heparin, 8 were taking aspirin) and later (after standing to 72 h) in 9 patients (3%; 2 receiving heparin, 2 taking aspirin). Five patients with a hematoma had studies with a 6F sheath. No patient required surgical intervention for early or late hematoma. Only three patients (1%) needed a 7F or 8F catheter because of suboptimal 5F coronary angiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous excimer laser coronary angioplasty of lesions not ideal for balloon angioplasty.

BackgroundExcimer laser coronary angioplasty is a new, investigational technique for treating coronary artery stenoses. Initial reports have demonstrated acute efficacy and relative safety of this procedure, but have not addressed the effect of lesion type on acute success and complication rates. Methods and ResultsIn the first 100 patients undergoing percutaneous excimer laser coronary angioplasty at our institution, acute laser success was obtained in 84% and procedural success was obtained in 94%. There were six acute closures during laser angioplasty and one myocardial infarction. Two patients required emergency coronary bypass surgery. Sixty-five percent of patients had lesions not ideal for balloon angioplasty because of lesion morphology (tubular, diffuse, or chronic total occlusion) or ostial location. There were 10 tubular stenoses, 29 diffuse lesions, 18 chronic total occlusions, and eight ostial lesions, including five aorto-ostial lesions. In this nonideal subgroup, the acute success rate with laser was 86% (72% of chronic total occlusions and 91% of non-totally occluded lesions), and the procedural success rate was 94%. There were three acute occlusions during laser angioplasty but no myocardial infarctions, emergency bypass surgeries, or deaths. One coronary artery perforation occurred without clinical sequelae. Laser angioplasty was successful in four of six lesions (67%) in which balloon angioplasty had failed. Laser success was obtained in 10 of 11 (91%) moderately or heavily calcified stenoses. Eight eccentric lesions and two lesions on bends were successfully treated without dissection or perforation. No side branch occlusions occurred in the 15 patients in whom one or more major branches originated within the lesion treated. Adjunctive balloon angioplasty was performed in 47% of cases, usually to obtain a larger final luminal diameter. Need for adjunctive balloon angioplasty decreased to 36% after a larger (2.0 mm) laser catheter became available. Twenty-eight percent of the 105 lesions treated were American College of Cardiology/American Heart Association classification type A, 47% were type B, and 25% were type C. Laser and procedural successes were obtained in 83% and 97% of type A, 88% and 96% of type B, and 85% and 88% of type C lesions, respectively. ConclusionsIn our initial experience, excimer laser angioplasty was found to be acutely effective and safe therapy for lesions identified as not ideal for balloon angioplasty. This technique may provide a useful adjunct or alternative to balloon angioplasty in selected patients.

Influence of gender on in-hospital clinical and angiographic outcomes and on one-year follow-up in the New Approaches to Coronary Intervention (NACI) registry.

Higher complication rates and lower success rates for treatment of women compared with men have been reported in prior studies of coronary angioplasty and in most early reports of outcome with new coronary interventional devices. In multivariate analysis this has been attributed largely to older age and other unfavorable clinical characteristics. These results are reflected in the current guidelines for coronary angioplasty. Women in prior studies have also had different distributions of vessel and lesion characteristics, but the influence of these differences on the outcome of new-device interventions have not been adequately evaluated. This article evaluates the influence of gender on clinical and angiographic characteristics, interventional procedure and complications, angiographic success, and clinical outcomes at hospital discharge and 1-year follow-up, as observed in the New Approaches to Coronary Intervention (NACI) registry. The NACI registry methodology has been reported in detail elsewhere in this supplement. This study focuses on the 90% of patients-975 women and 1,880 men-who had planned procedures with a single new device and also had angiographic core laboratory readings. Women compared with men were older, had more recent onset of coronary ischemic pain that was more severe and unstable, and had more frequent histories of other adverse clinical conditions. The distributions of several but not all angiographic characteristics before intervention were considered more favorable to angioplasty outcome in women. Differences were observed in device use and procedure staging. Angiographically determined average gain in lumen diameter after new-device intervention, with or without balloon angioplasty, was significantly less in women (1.38 mm) than in men (1.53 mm; p < 0.001); this 0.15 mm difference is consistent with the 0.16-mm smaller reference vessel lumen diameter of women. However, final percent diameter stenoses and TIMI flow and lesion compliance characteristics were similar. Among procedural complications, only treatment for hypotension, blood transfusion, and vascular repair occurred more often in women. More women than men were clinically unstable (2.1% vs 1.1%) or went directly to emergent coronary artery bypass graft surgery (CABG; 1.2% vs 0.6%) on leaving the interventional laboratory. However, in-hospital death (1.4% vs 1.1%), Q-wave myocardial infarction (MI) (0.9% vs 1.1%), and emergent CABG (1.5% vs 1.0%, for women and men, respectively) were not significantly different. Nonemergent CABG was more frequent in women (1.8% vs 0.9%; p < 0.05) and length of hospital stay after device intervention was longer (4.4 days vs 3.8 days in men; p < 0.01). In both univariate and multivariate analyses gender did not emerge as a significant variable in relation to the combined endpoint, death, Q-wave MI, or emergent CABG at hospital discharge. At 1-year follow-up more women than men reported improvement in angina (70% vs 62%) and fewer women than men had had repeat revascularization (32% vs 36%). Similar proportions were alive and free of angina, Q-wave MI and repeat revascularization (46% of women vs 45% of men). Although several procedure-related complications were more frequent in women than men after coronary interventions with new devices, no important disadvantages were observed for women in the rates of major clinical events at hospital discharge and at 1-year clinical follow-up. Additional studies are needed to evaluate the complex interplay of clinical, vessel, and lesion characteristics on success and complications of specific interventional techniques and to determine whether gender, per se, is a risk factor and whether gender specific interventional strategies may be beneficial.

Coronary perforation after excimer laser coronary angioplasty: the Excimer Laser Coronary Angioplasty Registry experience.

OBJECTIVES This study assessed the frequency of perforation with excimer coronary angioplasty. BACKGROUND Coronary artery perforation after conventional percutaneous transluminal coronary angioplasty is extremely rare. Because laser coronary angioplasty involves actual tissue ablation, it has an increased potential for perforation. METHODS All patients in the Excimer Laser Coronary Angioplasty Registry were included in this prospective study. Those who had a perforation related to the procedure were compared with those who did not have this complication. RESULTS Of 2,759 consecutive patients in the Excimer Laser Coronary Angioplasty Registry, 36 (1.3%) had perforation. In these patients, the left anterior descending coronary artery was the most frequently treated vessel (53%). There were no differences in fiber sizes between patients with and those without perforation. Among the patients with perforation, 36.1% required coronary artery bypass surgery, 16.7% experienced an infarction and 5.6% had a fatal outcome. Among the patients without perforation, the rates were 3.1%, 3.8% and 0.6%, respectively. However, 41.7% of the patients with documented coronary artery perforation did not need coronary artery bypass surgery or experience myocardial infarction or death. No angiographic characteristics distinguished lesions with from those without perforation. The frequency of coronary artery perforation declined over time with increasing operator experience, from 1.6% in the first 1,888 patients to only 0.4% in the last 1,000 patients (p = 0.002). CONCLUSIONS With increasing operator experience, the rate of perforation with excimer laser coronary angioplasty has decreased. When perforation occurs, subsequent event rates increase.

Subacute Thrombosis and Vascular Injury Resulting From Slotted-Tube Nitinol and Stainless Steel Stents in a Rabbit Carotid Artery Model

BACKGROUND Our objectives were to quantify the thrombogenicity and extent of vascular injury created by slotted-tube geometry stainless steel and nitinol coronary stents in a rabbit carotid artery model. METHODS AND RESULTS Stents were implanted in rabbit right carotid arteries without antiplatelet therapy. Stainless steel stents were implanted for 4 days while nitinol stents were placed for 4 and 14 days (n = 8, 8, and 6, respectively). Stent thrombosis was assessed by thrombus weight, grading thrombus encroachment of the lumen, and by blood flow in the stented and contralateral arteries. Stainless steel stents at 4 days contained more thrombus than 4- and 14-day nitinol stents (20.0 +/- 5.9 versus 2.5 +/- 0.6 and 2.7 +/- 0.3 mg, respectively; P < .000001). Stainless steel stents were more often occluded by thrombus (6 of 8) or contained more subocclusive thrombus (2 of 8) than nitinol stents (0 of 14, P < .002). Resting blood flow was reduced in arteries with stainless steel stents compared with 4- and 14-day nitinol stents (1.5 +/- 2.8 versus 24.0 +/- 2.0 and 25.5 +/- 1.9 mL/min, respectively, P < .000001). Stainless steel stents were less uniformly expanded, had deeper strut penetration into the vascular wall, and were associated with more extensive medial smooth muscle cell necrosis. There were strong correlations (r = .77 to .95) between variables of thrombosis extent (thrombus weight and grade) and histologically determined vascular injury (strut penetration and medial necrosis). CONCLUSIONS Slotted-tube stainless steel stents were more thrombogenic and created more extensive vascular injury than nitinol stents in a rabbit carotid artery model. The mechanisms underlying these differences probably are related to metallurgic and design geometry properties of the two stent types.

Chimeric DNA-RNA Hammerhead Ribozyme to Proliferating Cell Nuclear Antigen Reduces Stent-Induced Stenosis in a Porcine Coronary Model

BACKGROUND Stent-induced coronary restenosis is a major clinical and public health problem. Proliferating cell nuclear antigen (PCNA) is an important regulator of cell division, and blocking of its expression after angioplasty may limit intimal proliferation. METHODS AND RESULTS We cloned the porcine PCNA gene and constructed a chimeric hammerhead ribozyme to a segment of the gene with human homology. In vitro studies with both cultured porcine and human vascular smooth muscle cells demonstrated uptake of ribozyme within the nucleus and significant inhibition of cellular proliferation. The ribozyme was then delivered locally into pig coronaries in a stent model. At 30 days, histomorphometric analysis showed neointimal thickness of 0.51+/-0.20 mm in the ribozyme group versus 0.71+/-0.27 and 0.66+/-0.25 mm in stent controls and scrambled ribozyme control, respectively (P=0.002, P=0.03). Quantitative angiographic analysis showed late loss of 1.4+/-0.5 mm for ribozyme versus 1.9+/-0.4 and 2.0+/-0.4 mm for the controls (P=0.05 and P=0. 02). CONCLUSIONS Chimeric hammerhead ribozyme to PCNA inhibits smooth muscle cell proliferation in vitro and reduces both histomorphometric and angiographic restenosis in the porcine coronary stent model when delivered locally.