Polymer coatings for stents. Can we judge a stent by its cover?
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Biocompatible Materials↗
Biomedical subjects
T A Fischell
Publications and source records attributed to T A Fischell.
The beta-particle-emitting radioisotope stent (isostent): animal studies and planned clinical trials.
Radiation delivered by intravascular stent is an appealing approach to prevent neointimal hyperplasia, since it nonselectively kills dividing cells. In particular, beta-particle-emitting radioisotope stents may prove to be an ideal means of local irradiation in that 95% of the dose is delivered within 4 mm of the stent edge and the dose drops off rapidly to < 1/1,000 of the original dose at 5 months postimplantation. In the in vitro smooth muscle cell model, one can observe a zone of growth inhibition around radioactive stent wires that averages about 6 mm at very-low-activity levels (0.006 microCi/cm of wire). In vivo studies in animal models, including porcine iliac and coronary arteries and rabbit iliac arteries, have shown the effectiveness of radioisotope stents in inhibiting neointimal proliferation. Proliferating endothelial cells appear to be relatively radioresistant. A computer model was employed to look at the radiation dose delivered as a function of distance from the stent. With very-low-activity stents, presumably, DNA of the smooth muscle cells is damaged as they migrate through the "electron fence" on the way to the neolumen, diminishing the population of myofibroblasts and reducing hyperplasia. Catheter-based radiation therapies may disable these cells before they migrate, although such an approach may not inhibit early recoil or late contraction. Based on the characteristics of beta emissions (i.e., rapid drop-off, minimal leaching), radioisotope stents containing phosphorus-32 appear to be safe. A randomized triple-blind clinical trial is planned to assess restenosis at 6 months in native coronary arteries treated with radioisotope stents.
Animals↗
Inhibition of neointimal proliferation with low-dose irradiation from a beta-particle-emitting stent.
BACKGROUND: Restenosis after successful percutaneous transluminal coronary angioplasty is the major factor limiting the long-term effectiveness of this procedure. Neointimal proliferation in response to arterial injury is an important contributor to restenosis. The use of radiation for the treatment of malignant and benign proliferative conditions has been well established. External beam irradiation and endovascular irradiation by use of an after-loading technique have been shown to inhibit neointimal proliferation in experimental models of restenosis. The objective of this study was to investigate whether low-dose irradiation from a beta-particle-emitting stent would inhibit neointimal proliferation after placement in porcine iliac arteries. METHODS AND RESULTS: Fourteen titanium-mesh stents were implanted in the iliac arteries of nine NIH miniature swine. There were seven beta-particle-emitting radioisotope stents (32P, activity level 0.14 microCi) and seven control stents (31P, nonradioactive). Treatment effect was assessed by angiography and histomorphological examination of the stented iliac segments 28 days after implantation. There was a significant reduction in neointimal area (1.76 +/- 0.37 mm2 versus 2.81 +/- 1.22 mm2, P = .05) and percent area stenosis (24.6 +/- 2.9% versus 36.0 +/- 10.7%, P = .02) within the beta-particle-emitting stents compared with the control stents. Neointimal thickness, which was assessed at each wire site, was also significantly less within the treatment stents (0.26 +/- 0.04 mm versus 0.38 +/- 0.10 mm, P = .012). Scanning electron microscopy was performed on sections from four stents. This demonstrated endothelialization of both the treatment and control stents. There was no excess inflammatory reaction or fibrosis in the media, adventitia, or perivascular space of vessels treated with the beta-particle-emitting stent compared with control vessels. At 28 days, there was no difference in smooth muscle cell proliferation as measured by the proliferating cell nuclear antigen index. CONCLUSIONS: A local, continuous source of low-dose endovascular irradiation via a beta-particle-emitting stent inhibits neointimal formation in porcine arteries. This low dose of local irradiation did not prevent endothelialization of the stents. This novel technique offers promise for the prevention of restenosis and warrants further investigation.
Animals↗
Pullback atherectomy (PAC) for the treatment of complex bifurcation coronary artery disease.
We report initial successful results using a novel retrograde cutting (pullback) atherectomy catheter (PAC) to treat complex bifurcation coronary artery disease, in 2 patients. In one case a bifurcation lesion involving the left anterior descending and a large diagonal branch was treated without the need for two-wire or kissing-balloon technique. In the second case a high-grade eccentric lesion of the right coronary artery at the site of a right ventricular marginal branch was treated successfully. This report describes the first clinical application of pullback atherectomy in human coronary circulation, and suggests that this device may play a useful role in the treatment of complex bifurcation coronary artery disease.
Angioplasty, Balloon, Coronary↗
Association of acidic fibroblast growth factor and untreated low grade rejection with cardiac allograft vasculopathy.
Acidic fibroblast growth factor (aFGF) is a potent growth factor for vascular smooth muscle cells and may mediate vasculopathy in cardiac allografts subjected to chronic immunological injury. Therefore, we examined cardiac expression of aFGF, the number of rejection episodes, and other potential risk factors in 32 heart transplant patients who underwent intravascular ultrasound (IVUS) for detection of cardiac allograft vasculopathy (CAV). As defined by IVUS, CAV was present in 21 patients and absent in 11 patients (follow-up time: 52 +/- 21 vs. 51 +/- 12 months, respectively, P = NS). The level of aFGF in myocardial biopsies obtained at the time of IVUS was measured by semiquantitative reverse transcriptase polymerase chain reaction and expressed as the aFGF:GAPDH ratio. Higher level of aFGF were associated with CAV (mean aFGF:GAPDH ratio was 1.45 +/- 0.99 in patients with vs. 0.18 +/- 0.12 in patients without CAV [P < 0.001]). A strong association was found between high levels of cardiac aFGF and CAV, as 18 of 19 patients (95%) with high levels of aFGF (aFGF:GAPDH > 1) but only 3 of 13 patients with low levels of aFGF had CAV (P < 0.001). The relative risk of high level of aFGF for CAV was 4.1. Untreated low grade rejection (ISHLT I), but not treated high grade rejection (ISHLT > 2), was also associated with CAV (average number of untreated low grade rejection episodes was 3.5 +/- 1.8 in patients with vs. 2.1 +/- 1.0 in patients without CAV [P = 0.04]). Among other risk factors examined (age, sex, serum cholesterol, blood pressure, CMV infection, dose of immunosuppressants, and ischemic time), only triglycerides were higher in patients with than those without CAV (P = 0.003). We conclude that increased cardiac production of aFGF is significantly associated with CAV, which suggests that aFGF may serve as an important mediator in CAV. Untreated low grade rejection also poses an increased risk for CAV.
Adult↗
External beam irradiation inhibits neointimal hyperplasia following balloon angioplasty.
Restenosis is a serious problem limiting the long-term efficacy of percutaneous transluminal coronary angioplasty. Neointimal smooth muscle proliferation is the major process underlying restenosis. The objective of this study was to investigate the effects of external irradiation on neointimal hyperplasia following balloon angioplasty. We examined the ability of external X-ray irradiation to inhibit intimal hyperplasia following balloon angioplasty in a non-atherosclerotic rabbit model. Baseline quantitative angiography (day 0) was performed in all rabbits and balloon angioplasty was performed in the right (control) and the left iliac arteries. Five days after balloon angioplasty, the left iliac in each rabbit was irradiated with either 600 cGy (n = 5) or 1200 cGy (n = 5). Twenty-eight days following angioplasty final angiography was performed. All rabbits were sacrificed, and the iliac arteries were fixed for morphometric measurements. Comparison of baseline and final angiographic measurements revealed a significant decrease in average and minimum lumen dimensions for both control and irradiated segments (600 and 1200 cGy) [average: P (baseline vs. final) 0.008 (control), 0.001 (600 cGy); 0.05 (control), 0.007 (1200 cGy)]. Morphometric analysis showed no difference in neointimal cross-sectional area between control (0.29 +/- 0.05 mm2) and 600 cGy irradiated segments (0.32 +/- 0.07 mm2) (P = 0.82). However, there was a statistically significant reduction in neointimal hyperplasia in the 1200 cGy irradiated segments (0.09 +/- 0.02 mm2) compared to control (0.23 +/- 0.06 mm2, P = 0.02). There was no significant difference in medial cross-sectional area between control and irradiated segments (600 and 1200 cGy). We conclude that in this model, external beam X-ray irradiation (1200 cGy) was successful in reducing neointimal proliferation after balloon angioplasty. Whether or not this approach can be used successfully to inhibit restenosis in the clinical setting requires further investigation.
Angioplasty, Balloon↗
Balloon angioplasty results in increased segmental coronary distensibility: a likely mechanism of percutaneous transluminal coronary angioplasty.
OBJECTIVES: The purpose of this study was to evaluate the hypothesis that the increase in lumen area induced by percutaneous transluminal coronary angioplasty is secondary to a change in lesion (segmental) distensibility. BACKGROUND: Despite the widespread use of coronary angioplasty, the precise mechanism (or mechanisms) of lumen area improvement remains poorly understood. METHODS: Quantitative coronary angiography was used to measure the minimal (contrast agent filled) balloon diameters at 1 to 5 atm, inclusive, during the first and final balloon inflations in 24 lesions successfully treated with coronary angioplasty. To rule out possible confounding effects due to changes in balloon material distensibility during repeated inflations, five control balloons were studied ex vivo. In parallel, intravascular ultrasound imaging was utilized to compare the segmental distensibility (change in lumen area during the cardiac cycle) of eight disease-free and seven mildly diseased coronary segments and seven segments after successful balloon angioplasty. RESULTS: Minimal balloon diameters increased significantly between the first and final inflations (46%, 33%, 26%, 14% and 10% at 1, 2, 3, 4 and 5 atm, respectively, all p < 0.0001), demonstrating an increase in arterial distensibility after successful coronary angioplasty. No significant changes in balloon diameters were observed during sequential initial inflations at 1 and 2 atm (n = 5). Minimal increases in balloon diameters were observed during repeated balloon inflations in the ex vivo studies (4.9 +/- 1% [mean +/- SEM]). A distensibility index, derived from the intravascular ultrasound data, was not different between the balloon-dilated and the normal segments but was significantly lower in mildly diseased sites (14.7 +/- 2.2 vs. 12.9 +/- 1.2 vs. 6.9 +/- 1.9, respectively, p < 0.05) despite a smaller plaque area (7.3 +/- 1 vs. 11.3 +/- 1 mm2, proximal/nondilated vs. dilated segments, respectively, p < 0.05). CONCLUSIONS: Coronary distensibility is significantly impaired in atherosclerotically diseased coronary segments and increases significantly after balloon angioplasty. This increase in segmental coronary compliance after coronary angioplasty may create a larger lumen area by allowing the vessel to distend in response to normal intraarterial pressure.
Adult↗
Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.
BACKGROUND: Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of L-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis. METHODS AND RESULTS: Acetylcholine (10(-6), 10(-5), 10(-4) mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of L-arginine (10 mg.kg-1.min-1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n = 14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of L-arginine (10(-4) mol/L, -6.8% versus -2.8%; P < .01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with L-arginine (at a dose of 10(-4) mol/L, + 121% versus 176%; before versus after L-arginine, P < .002). CONCLUSIONS: The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. L-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by L-arginine is more likely in vessels with normal wall morphology.
Acetylcholine↗
Low-dose, beta-particle emission from 'stent' wire results in complete, localized inhibition of smooth muscle cell proliferation.
BACKGROUND: Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by medial and/or intimal smooth muscle cell (SMC) proliferation. The objective of this study was investigate the ability of local emission of beta-particles from a 32P-impregnated titanium "stent" wire source to inhibit vascular SMC and endothelial cell proliferation in cell culture and to determine the dose-response characteristics of this inhibition. METHODS AND RESULTS: A series of experiments were performed using 0.20-mm-diameter titanium wires that were impregnated with varying low concentrations of 32P (activity range, 0.002 to 0.06 microCi/cm wire, n = 47) or 31P (nonradioactive control, n = 28) in cultures of rat and human aortic SMCs and in cultured bovine aortic endothelial cells. The zone of complete cell growth inhibition (in millimeters from stent wire) was measured using light microscopy in the cultures exposed to the radioactive (32P) or control (31P) wires at 6 and 12 days after plating. In both rat and human SMC cultures there was a distinct 5.5- to 10.6-mm zone of complete SMC inhibition at wire activity levels > or = 0.006 microCi/cm. In contrast, there was no zone of inhibition surrounding the control (31P impregnated) wires (P < .001 versus 32P wires at all wire activities > or = 0.006 microCi/cm for human and rat SMCs). Proliferating bovine endothelial cells were more radioresistant than SMCs, with no zone of inhibition observed at wire activity levels up to 0.019 microCi/cm (P < .001 versus SMCs at 0.006 microCi/cm and 0.019 microCi/cm). CONCLUSIONS: We conclude that very low doses of beta-particle emission from a 32P-impregnated stent wire (activity levels as low as 0.006 microCi/cm of wire) completely inhibit the growth and migration of both rat and human SMCs within a range of 5.5 to 10.6 mm from the wire. Endothelial cells appear to be much more radioresistant than SMCs. These data suggest that an intra-arterial stent impregnated with a low concentration of 32P may have a salutary effect on the restenosis process. Whether this approach can be used successfully and safely to inhibit restenosis in vivo and in the clinical setting is under investigation.
Animals↗
Fish oil improves endothelium-dependent coronary vasodilation in heart transplant recipients.
OBJECTIVES: The purpose of this study was to determine whether dietary fish oil supplementation enhances endothelium-mediated vasodilator responses in human heart transplant recipients, a group known to have coronary artery disease and endothelial dysfunction. BACKGROUND: Omega-3 fatty acid supplementation has been shown to enhance endothelium-dependent coronary vasodilation in animal models of atherosclerosis. METHODS: Endothelium-dependent vasodilator responses to intracoronary acetylcholine infusion and endothelium-independent responses to nitroglycerin were evaluated in heart transplant recipients who received a high dose of dietary supplementation with omega-3 fatty acids for 3 weeks (5 g of eicosapentaenoic acid plus docosahexaenoic acid/day, n = 7) and compared with responses in a group of matched heart transplant recipients who did not receive fish oil (control patients, n = 7). Acetylcholine was selectively infused into the midportion of the left anterior descending or left circumflex coronary artery, with the noninfused left coronary artery serving as a control vessel. Serial coronary angiograms were performed after infusion with increasing doses of acetylcholine (infused concentrations 10(-6) to 10(-3) mol/liter) and after intracoronary nitroglycerin administration. RESULTS: The patients treated with fish oil showed a normal vasodilator response to acetylcholine with 14 +/- 2.5% and 15 +/- 7% vasodilation (vs. baseline diameter) at infused acetylcholine concentrations of 10(-5) and 10(-4) mol/liter, respectively. In contrast, the control patients demonstrated vasoconstrictor responses (-1 +/- 1% and -9 +/- 4%) to acetylcholine at these same doses (p < 0.05 and < 0.005, respectively, for treated vs. control patients). There were no differences in the response to nitroglycerin between the control and treated patients. CONCLUSIONS: Dietary supplementation with fish oil significantly alters endothelium-dependent coronary vasodilation in heart transplant recipients without alteration of the responses to endothelium-independent vasodilation. Whether this enhancement of endothelial function can beneficially alter the natural history of heart transplant atherosclerosis warrants further study.
Acetylcholine↗
Immediate and one-year safety of intracoronary ultrasonic imaging. Evaluation with serial quantitative angiography.
BACKGROUND: Intracoronary ultrasound (ICUS) has the ability to quantitatively evaluate vessel wall morphology and is well suited for serial studies of coronary artery disease regression and progression. However, the potential risk for catheter-induced endothelial damage and accelerated atherosclerosis in instrumented vessels is a concern. The acute effects as well as the 1-year safety of ICUS regarding its impact on the atherosclerotic process were assessed. METHODS AND RESULTS: The acute studies include 240 intracoronary studies performed in 170 cardiac transplant recipients. Patients were systematically heparinized. Only vessels > or = 2 mm in diameter were visualized. Coronary arteries of 38 patients were measured by quantitative coronary angiography in matched angiograms at an interval of 1 year after the initial ICUS examination was performed to assess long-term effects. The angiographic measurements in the previously instrumented and noninstrumented vessels were compared. Forty-nine vessels that had been imaged (IM) in these 38 patients with a 5F ICUS catheter were compared with 61 vessels not previously imaged (NIM) in the same patients. Absolute and percentage change in angiographically measured mean vessel diameters in the ICUS imaged and nonimaged segments were compared. Despite pretreatment with nitroglycerin, 20 patients (8.3%) had angiographically evident coronary spasm. In all cases, this was reversed by giving nitroglycerin. One year after the original imaging study, no difference was noted between imaged and nonimaged vessels in change in absolute vessel diameter (IM, -0.11 +/- 0.28 mm vs NIM, -0.07 +/- 0.22 mm; P = .49) or in percentage change in diameter (IM, -5 +/- 11% vs NIM, -3 +/- 7%; P = .32). CONCLUSIONS: Intracoronary ultrasound in cardiac transplant recipients was associated with no clinical morbidity and a low incidence of vessel spasm in large and medium-size coronary arteries. It does not accelerate progression of angiographically quantifiable coronary artery disease. This study suggests that ICUS can be safely used even in coronary arteries not undergoing interventions.
Cardiac Catheterization↗
Clinical demonstration that catheter-delivered ultrasound energy reverses arterial vasoconstriction.
OBJECTIVES: This study was designed to describe the clinical effects of ultrasound energy on guide-wire-induced arterial vasoconstriction. BACKGROUND: We have previously shown that ultrasound energy (20 kHz) delivered by a wire probe produces dose-dependent, endothelium-independent smooth muscle relaxation capable of reversing both receptor-mediated and voltage-dependent vasoconstriction in vitro. METHODS: A high intensity, low frequency ultrasound catheter system was used to recanalize total occlusions in the superficial femoral arteries of two patients. After recanalization, the proximal residual stenoses were each less than 15%. However, distal arterial vasospasm was found angiographically in a popliteal artery of one patient and in an anterior tibial artery of another. Subsequently, the ultrasound catheter probe was advanced to the sites of arterial vasospasm (diffuse in one, focal in one). RESULTS: After 30 and 90 s, respectively, of exposure to ultrasound energy with a frequency of 19.5 kHz, peak tip amplitude of 111 microns and power output at the transducer of 25 W, the vasospasm resolved in each arterial segment. CONCLUSIONS: Our findings are the first reported clinical cases documenting that catheter-delivered low frequency, high intensity ultrasound induces arterial vasodilation at the site of vasoconstriction. These biologic effects appear to be relatively unique for an angioplasty device and may have potential clinical importance.
Aged↗
Nitroglycerin-induced coronary vasodilation in cardiac transplant recipients. Evaluation with in vivo intracoronary ultrasound.
BACKGROUND: Coronary artery vasomotion is altered after cardiac transplantation. The impact of accelerated transplant coronary atherosclerosis and myocardial rejection on vasomotion is not well understood. Intravascular ultrasound is a new imaging method with the ability to study real-time changes in coronary artery dimensions. METHODS AND RESULTS: Epicardial coronary artery response to nitroglycerin was studied in 32 cardiac transplant recipients (age, 47 +/- 11 years) 3 weeks to 10 years after transplantation with intracoronary ultrasound. Cross-sectional luminal area and diameter were measured at a fixed position in the left anterior descending artery immediately before and every 30 seconds for 5 minutes after 0.4 mg of sublingual nitroglycerin. Cross-sectional area increased from a baseline of 13.1 +/- 3.9 mm2 to 15.8 +/- 3.9 mm2 at maximal vasodilation; luminal diameter increased from 4.0 +/- 0.6 mm to 4.5 +/- 0.6 mm. This increase reached statistical significance (p less than 0.001) at 1.5 minutes after administration of nitroglycerin; mean maximum increase occurred at 4.5 minutes (24% for cross-sectional area and 11% for luminal diameter). Patients with biopsy-proven mild or moderate concurrent rejection had a significantly blunted vasodilatory response versus the nonrejection group (9% versus 27% for cross-sectional area, p less than 0.04), although a vasodilatory effect was still present. Nitroglycerin response was well preserved in patients up to 10 years after transplantation; however, there was a trend toward a decreased response in patients studied immediately after transplantation (21% versus 29%, p = 0.37). Coronary intimal thickness, as measured by ultrasound, had no impact on the vasodilatory response (R = 0.23, p = 0.34). CONCLUSIONS: Vasodilatory response to nitroglycerin in cardiac transplant recipients is attenuated during episodes of cardiac rejection. This response is preserved in long-term survivors and is independent of the degree of intimal thickening. Intravascular ultrasound provides a new method to document real-time epicardial coronary vasomotion.
Adult↗
Effects of luminal eccentricity on spontaneous coronary vasoconstriction after successful percutaneous transluminal coronary angioplasty.
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Angioplasty, Balloon, Coronary↗
New technologies for the treatment of obstructive arterial disease.
The well-known limitations of balloon angioplasty include unpredictable abrupt closure, chronic total occlusion, diffuse disease, and restenosis, among other factors. These limitations have prompted the development of new technologic approaches to angioplasty including laser applications for plaque ablation, mechanical device applications for plaque removal/debridement, and stent devices for structural maintenance of vascular lumen patency. Devices which directly apply laser energy for ablation of plaque material include a balloon-centered laser angioplasty system, excimer laser ablation catheter systems, and a fluorescence-guided spectral feedback laser system. Experience with these devices indicates that plaque can be successfully ablated by using laser energy. Vessel perforation and dissection are complications reported with these devices and the effects of laser angioplasty on restenosis remain unclear. Indirect application of laser energy has been tested by using a "hot tip" catheter and a laser balloon angioplasty system. Although the hot tip device has received FDA approval for use in peripheral arteries, it appears to have very limited applications in the coronary arteries. Laser balloon angioplasty appears to be beneficial in the setting of threatened acute closure; the device continues to be evaluated for potential beneficial impact on restenosis. Mechanical atherectomy catheters are designed to remove atherosclerotic plaque from the arterial system and include the AtheroCath, the Transluminal Extraction Catheter (TEC), and the Pullback Atherectomy Catheter (PAC). The Rotablator is an atheroablation device which debrides the obstructing plaque material with distal embolization of the particulate debris. Successful removal/debridement of atherosclerotic plaque has been demonstrated with the AtheroCath, Rotablator, and the TEC device. Pre-clinical studies demonstrate successful removal of plaque material with the PAC device. Despite the theoretic advantage of removing plaque material when performing angioplasty with these devices, there has been little or no reduction in restenosis rates based on a significant experience with the AtheroCath and the Rotablator. Intravascular stent devices including one self-expanding device design and two balloon-expandable device designs have been employed successfully in the elective setting to treat recurrent restenosis lesions. Two of the devices have been successfully tested in the setting of threatened acute closure. Early follow-up studies suggest some improvement in restenosis rates in certain clinical settings following intravascular stenting. Acute and subacute thrombosis remain substantial problems for stent devices and very aggressive anticoagulation regimens are necessary to minimize the adverse events. In summary, a number of a new technologic approaches for treatment of atherosclerotic lesions have been developed and are undergoing significant clinical evaluation.(ABSTRACT TRUNCATED AT 400 WORDS)
Angioplasty, Laser↗
Coronary occlusion following diagnostic angiography: salvage by intracoronary stenting.
Catheter-induced coronary artery dissection and occlusion is a rare but serious complication of diagnostic cardiac angiography. This report describes the successful management of this complication with an intracoronary stent after prolonged balloon inflations and intracoronary thrombolytic therapy were unsuccessful.
Aged↗
Roles of thrombin and platelet membrane glycoprotein IIb/IIIa in platelet-subendothelial deposition after angioplasty in an ex vivo whole artery model.
BACKGROUND: Platelet deposition at the site of injury caused by balloon angioplasty is associated with acute closure and restenosis. METHODS AND RESULTS: In a new ex vivo whole artery angioplasty model, we examined the roles of thrombin inhibition with D-Phe-Pro-ArgCH2Cl (PPACK) and inhibition of the platelet membrane fibrinogen receptor glycoprotein IIb/IIIa (GPIIb/IIIa) with monoclonal antibody 7E3 on platelet deposition at the site of balloon injury. Fresh rabbit aortas were mounted in a perfusion chamber. One half of the mounted arterial segment was dilated with a standard angioplasty balloon catheter and the uninjured half served as the control segment. The vessels were perfused with human blood at physiological pressure and shear rates of 180-250 second-1 for 30 minutes. Platelet deposition was measured using 111In-labeled platelets and scanning electron microscopy. With heparin (2 units/ml) anticoagulation, 8.2 +/- 2.2 x 10(6) platelets/cm2 were deposited at the site of balloon injury compared with 0.7 +/- 0.2 x 10(6) platelets/cm2 on uninjured segments (p less than 0.02, n = 7). PPACK was tested at a concentration (10 microM) that totally inhibited platelet aggregation in response to thrombin. 7E3 was tested at a concentration (10 micrograms/ml) that totally inhibited platelet aggregation. Platelet deposition at the site of balloon injury was reduced 47% by PPACK and 70% by 7E3 compared with heparin. CONCLUSIONS: At shear rates seen in nonstenotic coronary arteries, PPACK and 7E3 are more effective than heparin in reducing platelet deposition at the site of balloon injury. The significant inhibition of platelet deposition by PPACK demonstrates the importance of heparin-resistant thrombin in platelet thrombus formation. The 7E3 results suggest that approximately 70% of platelet deposition at the site of balloon injury is GPIIb/IIIa dependent and that the remaining 30% results from non-GPIIb/IIIa-mediated platelet-subendothelial adhesion. Finally, the ex vivo whole artery system is a useful model for studying platelet-vessel wall interactions under physiologically defined parameters.
Amino Acid Chloromethyl Ketones↗
Ultrasonic energy. Effects on vascular function and integrity.
BACKGROUND: Ultrasonic energy transmitted via flexible wire probes provides a new means of ablating atherosclerotic plaque. We studied the effects of ultrasonic energy (20 kHz) delivered via a ball-tipped wire probe on arterial vasomotor behavior in rabbit thoracic aortas in a perfused whole-vessel model. METHODS AND RESULTS: After precontraction with phenylephrine (10(-5) M) or KCl (60 mM), the effects of ultrasonic energy (0.7-5.5 W x 60 seconds, 42-330 J) on arterial vasomotor behavior were measured using long-axis ultrasonic vessel imaging of the proximal (ultrasonic probe-treated) and distal (untreated) control segments. The efficacy of plaque ablation at these same probe-tip power outputs was evaluated in atherosclerotic, human cadaver iliofemoral arteries. Ultrasonic energy caused dose (energy)-dependent relaxation in rabbit aortas after precontraction with phenylephrine in arteries with endothelium (n = 8) and without endothelium (n = 8) (p less than 0.001 versus ultrasound treated at power outputs of 2.9 and 5.5 W). There was no difference in the relaxation dose responses between endothelialized and endothelially denuded segments (p = NS). Ultrasonic energy also caused significant relaxation (67 +/- 8%) after voltage-dependent precontraction with 60 mM KCl. Temperature measurements revealed less than 1 degrees C warming of the vessel wall during as long as 2 minutes of treatment at a power output of 5.5 W. Pathological examination showed no smooth muscle injury at (moderate) power outputs that caused arterial relaxation. At probe-tip power outputs of 2.9-5.5 W, ultrasonic energy recanalized two of two totally occluded cadaveric iliofemoral vessel segments. The ultrasonic ablation catheter was also demonstrated to cause arterial relaxation in a recanalized canine femoral artery in vivo. CONCLUSIONS: Ultrasonic energy delivered via a flexible-wire probe produces dose-dependent, endothelium-independent smooth muscle relaxation capable of reversing both receptor-mediated and voltage-dependent vasoconstriction in vitro. At moderate power outputs, this relaxation response does not appear to be due to thermal effects or irreversible smooth muscle cell injury. This vasorelaxant effect of ultrasonic energy is also apparent in vivo, at doses that effectively ablate atherosclerotic plaque, and may improve the safety of arterial recanalization using ultrasonic energy.
Animals↗