RESUMO
BACKGROUND: The data on the long-term safety and efficacy of intracoronary beta-radiation in animal models are limited. METHODS AND RESULTS: A total of 30 coronary arteries in 15 swine were subjected to balloon or stent injury followed by beta-radiation from a centered 32P source (2000 cGy to 1 mm beyond lumen surface) or a sham radiation procedure. The animals received aspirin for 6 months and ticlopidine for 30 days. Five of the 10 animals subjected to radiation died (at 5 days, 7 days, 3 months [n = 2], and 4 months) as a result of layered, occlusive thrombus at the intervention site (3 stent and 2 balloon injury sites). No deaths occurred in the control group. In the surviving animals, balloon-injured and irradiated vessels showed a trend toward larger lumens than controls (2.15 +/- 0.17 versus 1.80 +/- 0.08 mm2, P=0.06) and larger external elastic lamina areas (3.32 +/- 0.21 versus 2.62 +/- 0.10 mm2, P=0.003). In the stent-injured vessels from surviving animals, lumen, neointimal, and external elastic lamina areas were 3.58 +/- 0.33, 3.16 +/- 0.35, and 8.12 +/- 0.42 mm2 for irradiated vessel segments; these values were not different from those in controls (3.21 +/- 0.15, 2.84 +/- 0.27, and 7.76 +/- 0.28 mm2, respectively). Histologically, healing was complete in most survivors, although intramural fibrin and hemorrhage were occasionally seen. CONCLUSION: In the long-term (6 month) porcine model of restenosis, the inhibition by intracoronary beta-radiotherapy of the neointimal formation that is known to be present at 1 month is not sustained. This lack of effect on neointimal formation after balloon and stent arterial injury is accompanied by subacute and late thrombosis that leads to cardiac death on a background of continuous aspirin but relatively brief ticlopidine treatment.
Assuntos
Angioplastia com Balão/efeitos adversos , Partículas beta/efeitos adversos , Reestenose Coronária/radioterapia , Vasos Coronários/efeitos da radiação , Stents/efeitos adversos , Animais , Braquiterapia/efeitos adversos , Reestenose Coronária/complicações , Reestenose Coronária/patologia , Trombose Coronária/etiologia , Trombose Coronária/patologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Masculino , Taxa de Sobrevida , Porco Miniatura , Tempo , Ultrassonografia de Intervenção , Grau de Desobstrução Vascular/efeitos da radiaçãoRESUMO
Beta radiation has been clearly shown, in a specific dose range, to be highly effective in the inhibition of the restenotic process after balloon or stent injury in animal experiments, as well as in randomized, placebo-controlled human trials. The major advantage of beta radiation, in comparison with gamma radiation, is a significantly lower radiation exposure to the personnel and patient, and easier adaptability to existing cardiac catheterization laboratories. Rapidly accumulating evidence indicates that the two major problems, late thrombosis and edge stenosis, may be minimized with prolonged antiplatelet therapy (6 months or more) and broader radiation coverage of the intervention site. Although there may be better, safer, and easier options to reduce restenosis in the years to come, intravascular radiotherapy is the first breakthrough modality that has been shown to significantly reduce restenosis after percutaneous vascular interventions.
Assuntos
Partículas beta/uso terapêutico , Braquiterapia/métodos , Doença das Coronárias/prevenção & controle , Angioplastia/efeitos adversos , Angioplastia/métodos , Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/métodos , Animais , Feminino , Humanos , Masculino , Prognóstico , Doses de Radiação , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária , Resultado do TratamentoRESUMO
PURPOSE: A dose-response study was performed in swine to investigate the vascular effects of 32P over a broad range of doses in order to define the therapeutic window of intracoronary radiotherapy (ICR) with 32P. METHODS AND MATERIALS: A total of 131 porcine arteries were subjected to balloon injury or stenting followed by 0-36 Gy of ICR from a centered 32P source wire to 1 mm beyond lumen surface or a sham ICR procedure. Animals were euthanized at 4 weeks, and vessels were harvested for histomorphometry. RESULTS: In the balloon-injured arteries, doses of 7 and 9 Gy did not impact restenosis. At doses of 14-36 Gy, neointima was markedly reduced, with mild dilatation at the highest dose, 36 Gy. In the stent-injured arteries, the lowest dose of 9 Gy failed to reduce neointimal growth, while 14-26 Gy showed the most favorable response. CONCLUSIONS: ICR with 32P features a broad therapeutic window. Doses of 14-26 Gy to 1 mm beyond lumen surface provided an optimal combination of efficacy and safety. Doses of 7 and 9 Gy were generally ineffective, suggesting a minimum threshold for ICR with 32P to effectively inhibit restenosis.
Assuntos
Angioplastia Coronária com Balão , Reestenose Coronária/prevenção & controle , Vasos Coronários/lesões , Radioisótopos de Fósforo/uso terapêutico , Stents , Animais , Braquiterapia , Reestenose Coronária/radioterapia , Relação Dose-Resposta à Radiação , Feminino , Masculino , SuínosRESUMO
BACKGROUND: Intracoronary gamma- and beta-radiation have reduced restenosis in animal models. In the clinical setting, the effectiveness of beta-emitters has not been studied in a broad spectrum of patients, particularly those receiving stents. METHODS AND RESULTS: A prospective, randomized, sham-controlled study of intracoronary radiotherapy with the beta-emitting (32)P source wire, using a centering catheter and automated source delivery unit, was conducted. A total of 105 patients with de novo (70%) or restenotic (30%) lesions who were treated by stenting (61%) or balloon angioplasty (39%) received 0 (control), 16, 20, or 24 Gy to a depth of 1 mm in the artery wall. Angiography at 6 months showed a target site late loss index of 11+/-36% in radiotherapy patients versus 55+/-30% in controls (P:<0.0001). A low late loss index was seen in stented and balloon-treated patients and was similar across the 16, 20, and 24 Gy radiotherapy groups. Restenosis (>/=50%) rates were significantly lower in radiotherapy patients at the target site (8% versus 39%; P:=0.012) and at target site plus adjacent segments (22% versus 50%; P:=0.018). Target lesion revascularization was needed in 5 radiotherapy patients (6%) and 6 controls (24%; P:<0.05). Stenosis adjacent to the target site and late thrombotic events reduced the overall clinical benefit of radiotherapy. CONCLUSIONS: beta-radiotherapy with a centered (32)P source is safe and highly effective in inhibiting restenosis at the target site after stent or balloon angioplasty. However, minimizing edge narrowing and late thrombotic events must be accomplished to maximize the clinical benefit of this modality.
Assuntos
Doença das Coronárias/terapia , Radioisótopos de Fósforo/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Angioplastia Coronária com Balão/instrumentação , Aspirina/uso terapêutico , Automação , Partículas beta , Terapia Combinada , Angiografia Coronária , Doença das Coronárias/prevenção & controle , Doença das Coronárias/radioterapia , Vasos Coronários/patologia , Vasos Coronários/efeitos da radiação , Relação Dose-Resposta à Radiação , Sistemas de Liberação de Medicamentos , Humanos , Radioisótopos de Fósforo/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Stents , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To assess the clinical course of patients who have undergone coronary stent placement less than six weeks before noncardiac surgery. BACKGROUND: Surgical and percutaneous transluminal coronary angioplasty revascularization performed before high-risk noncardiac surgery is expected to reduce perioperative cardiac morbidity and mortality. Perioperative and postoperative complications in patients who have undergone coronary stenting before a noncardiac surgery have not been studied. METHODS: Forty patients who underwent coronary stent placement less than six weeks before noncardiac surgery requiring a general anesthesia were included in the study (1-39 days, average: 13 days). The records were screened for the occurrence of adverse clinical events, including myocardial infarction, stent thrombosis, peri- and postoperative bleeding and death. RESULTS: In 40 consecutive patients meeting the study criteria, there were seven myocardial infarctions (MIs), 11 major bleeding episodes and eight deaths. All deaths and MIs, as well as 8/11 bleeding episodes, occurred in patients subjected to surgery fewer than 14 days from stenting. Four patients expired after undergoing surgery one day after stenting. Based on electrocardiogram, enzymatic and angiographic evidence, stent thrombosis accounted for most of the fatal events. The time between stenting and surgery appeared to be the main determinant of outcome. CONCLUSIONS: Postponing elective noncardiac surgery for two to four weeks after coronary stenting should permit completion of the mandatory antiplatelet regimen, thereby reducing the risk of stent thrombosis and bleeding complications.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Doença das Coronárias/complicações , Doença das Coronárias/terapia , Cuidados Pré-Operatórios/métodos , Stents/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Angioplastia Coronária com Balão/instrumentação , Angioplastia Coronária com Balão/mortalidade , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/mortalidade , Desenho de Equipamento , Evolução Fatal , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Radiografia , Recidiva , Estudos Retrospectivos , Fatores de Risco , Stents/classificação , Trombose/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
More than 50 different pharmacological and mechanical interventions have been tested to date for prevention of vascular restenosis without success. Intracoronary radiotherapy is the first one showing promise of significantly attenuating neointimal proliferation, causing positive vascular remodelling and thus inhibiting restenosis. This promising modality has moved from animal experiments via safety and feasibility testing into the phase of clinical trials of efficacy in large numbers of patients. While ongoing research continues to search for new sources and delivery techniques, currently available technology is being optimized. The randomized clinical trials conducted to date have shown consistently a reduction of target site restenosis rates by 55-79%. Lower incidence of major adverse cardiac events after radiotherapy has also been demonstrated, primarily as a result of reduction in target site and target vessel revascularization rates. However, experimental and clinical research has identified two major complications of this approach: stenosis at the ends of the radiation zone ('edge effect' or 'candywrapper') as well as late thrombosis (beyond 30 days after intervention) of the angioplasty or stent site. If these two adverse effects can be minimized, intracoronary radiotherapy may prove to be a major breakthrough in percutaneous coronary interventions.
Assuntos
Angiografia Coronária , Oclusão de Enxerto Vascular/prevenção & controle , Animais , Ensaios Clínicos como Assunto , HumanosRESUMO
PURPOSE: To develop and evaluate an intravascular radiation delivery catheter that incorporates a centering mechanism and that allows side branch and distal artery perfusion. METHODS AND MATERIALS: The Galileo Centering Catheter (Guidant Vascular Interventions, Houston, TX) incorporates a rapid exchange tip design. A unique spiral balloon allows centering and facilitates perfusion to the distal artery and side branches. The catheter contains a dedicated dead-end lumen for source wire delivery to the lesion site. The treatment area is precisely defined by radiopaque markers. RESULTS: In three clinical trials to date, radiation (or placebo) was delivered successfully to 300 of 312 patients (96%). With balloon inflation, TIMI grade 2 or 3 flow was achieved in side branches in 82% and in the distal artery in 77% of patients. Despite treatment (dwell) times ranging from 87 to 948 s (mean = 250 s), only 8% of patients required fractionation of treatment. CONCLUSION: The Galileo Centering Catheter is a safe and highly effective method for delivering intracoronary radiation therapy. Its unique design provides centering of the source while allowing side branch and distal coronary perfusion during treatment. This catheter would facilitate intracoronary radiation therapy and allow uniform and reproducible dose delivery to the target in the artery wall.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Braquiterapia/instrumentação , Doença das Coronárias/radioterapia , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/terapia , Humanos , Radiografia , Dosagem Radioterapêutica , RecidivaRESUMO
BACKGROUND: The purpose of this study was to determine coronary flow reserve in cardiac allograft recipients early (0 to 3 years) and late (3 to 7 years) after heart transplantation. METHODS AND RESULTS: With the use of a Doppler tipped guide wire, coronary flow reserve (ratio of hyperemic to baseline coronary flow velocity) was measured in 82 patients before and after intracoronary adenosine. Forty-five patients were early (< or =3 years) after transplantation, 24 were late, and 13 were control patients with single-vessel coronary artery disease. Coronary flow reserve in the early transplantation patients was similar to that in the control group (2.9+/-0.2 vs 3.0 +/-0.6, p=not significant) but was reduced in the late transplantation group (2.2+/-0.5 vs 3.0+/-0.6, p < 0.001). There were differences in coronary flow reserve between the early and late transplantation patient groups (3.0+/-0.6 vs 2.2+/-0.5, p < 0.001 ) despite equally elevated mean arterial pressure, mean heart rate, mean pulmonary capillary wedge pressure, and mean left ventricular mass in the two groups. Coronary flow reserve in patients with angiographic allograft arteriopathy (n=19) was reduced when compared with coronary flow reserve of patients with normal vessels (n=50) (1.9+/-0.3 vs 3.1+/-0.6, p < 0.001). CONCLUSIONS: There is progressive deterioration of coronary flow reserve over time after transplantation. Dysfunction of the coronary microcirculation rather than determinants of myocardial oxygen consumption contributes to this reduction.
Assuntos
Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária , Transplante de Coração , Adenosina , Adolescente , Adulto , Idoso , Cateterismo Cardíaco , Fármacos Cardiovasculares , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
The major limitations of the Palmaz-Schatz stent stem from the design of its stent delivery system (SDS). The SDS is bulky and has poor trackability in lesions with proximal tortuosity and/or vessel calcification. The use of bare-mounted Palmaz-Schatz stents on low profile balloons represents an alternate approach for lesions that are not accessible for stenting with the SDS. Thus we evaluated the indications, procedural success rate, and in-hospital complications of patients undergoing bare stenting at a single center between 1 October 1995 through 30 September 1996. A total of 363 coronary interventions were performed during this period, including coronary stenting in 194 vessels. In 18 of these 194 vessels, bare-mounted Palmaz-Schatz stents were used. The indications for bare stenting were: inability to deliver the Palmaz-Schatz stent on SDS for suboptimal angioplasty results or acute/threatened abrupt closure; use of half stents; stenting in vessels < 3.0 mm; intermediate disease in the proximal segment that would have precluded optimal visualization of stent placement; and use of guides 7 French or smaller. Bare stenting was successful in 15 of the 18 patients (vessels) in whom it was attempted. There were no deaths, myocardial infarctions, stent thrombosis, repeat interventions, or significant bleeding in patients with successful bare stent delivery. The stents were successfully retrieved in the three patients in whom the stent could not be advanced into the target coronary segment. One of these patients had a propagated spiral dissection prior to attempts at bare stenting and required emergent bypass surgery. The remaining two patients with failed deployment had suboptimal angioplasty results but had an uncomplicated hospital course. Thus bare stenting represents an alternate percutaneous approach to tackle suboptimal procedural results and/or complications in patients who have failed stent deployment with the standard sheathed stent delivery system currently available in the United States.
Assuntos
Angioplastia Coronária com Balão/métodos , Doença das Coronárias/terapia , Isquemia Miocárdica/terapia , Stents , Estudos de Coortes , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Vasos Coronários/lesões , Desenho de Equipamento , Humanos , Isquemia Miocárdica/diagnóstico por imagem , Stents/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: We examined the effects of intracoronary irradiation delivered at a high dose rate on neointimal hyperplasia after injury induced by two methods: balloon overstretch injury, and stent implantation in a porcine model of coronary restenosis. METHODS AND MATERIALS: In 34 Hanford miniature swine, a segment of each coronary artery was targeted for injury and treatment. The artery segments were treated with 192Ir at doses of 10 Gy over 4 min (eight animals), 15 Gy over 6 min (nine animals), 25 Gy over 10 min (nine animals) or control (simulation wire only; eight animals). The treated segments were subjected to stent implantation (left anterior descending and right coronary artery) or balloon overstretch (circumflex) injury. Twenty-eight days later, repeat coronary angiography and sacrifice were done. Quantitative coronary angiography, morphometry, and extensive histopathologic analyses were carried out in a blinded fashion. RESULTS: The change in minimal lumen diameter from postinjury to presacrifice in the stent-injured left anterior descending was -0.79 +/- 0.34 (mean: +/- SD) mm in the control group, compared to -0.43 +/- 0.35 mm in the 15 Gy (p = 0.04) and -0.21 +/- 0.50 mm in the 25 Gy (p = 0.01) groups; and in the balloon-injured circumflex was -0.31 +/- 0.22 mm in the control group compared to -0.03 +/- 0.18 mm in the 10 Gy (p = 0.05) and 0.00 +/- 0.33 in the 15 Gy (p = 0.01) groups. Percent area stenosis in the left anterior descending was 36 +/- 9% in the control group compared to 18 +/- 12% in the 15 Gy (p = 0.003) and 11 +/- 11% in the 25 Gy (p < 0.001) groups; and in the circumflex was 16 +/- 10% in the control groups, compared to 5 +/- 5% in the 15 Gy (p = 0.02) and 2 +/- 2% in the 25 Gy (p = 0.009) groups. Histopathology showed a striking reduction in the amount of neointima in the irradiated arteries compared with control vessels. Other radiation effects were stromal fibrin exudate, thinning of the media, and adventitial fibrosis and leukocyte infiltration in the radiated arterial segments. CONCLUSIONS: High dose rate intracoronary irradiation with 192Ir effectively inhibits intimal proliferation after stent-induced as well as balloon-overstretch injury. This shorter treatment time (4 to 10 min) may provide a clinically practical approach to the prevention of restenosis after angioplasty.
Assuntos
Braquiterapia/métodos , Doença das Coronárias/radioterapia , Vasos Coronários/efeitos da radiação , Dosagem Radioterapêutica , Túnica Íntima/efeitos da radiação , Angioplastia Coronária com Balão , Animais , Doença das Coronárias/patologia , Doença das Coronárias/terapia , Vasos Coronários/lesões , Vasos Coronários/patologia , Recidiva , Stents , Suínos , Porco Miniatura , Túnica Íntima/lesões , Túnica Íntima/patologiaRESUMO
OBJECTIVES: This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) in patients undergoing elective coronary angioplasty. BACKGROUND: Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes. METHODS: Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 mumol/liter ADP, 5 micrograms/ml collagen and 7.5 and 15 mumol/liter TRAP were assessed. RESULTS: Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h. Platelet aggregation in response to 20 mumol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 mumol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mumol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 mumol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 mumol/liter TRAP-induced aggregation. CONCLUSIONS: After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.
Assuntos
Difosfato de Adenosina/farmacologia , Anticorpos Monoclonais/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Oligopeptídeos/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas , Receptores de Superfície Celular/antagonistas & inibidores , Abciximab , Adulto , Idoso , Angioplastia Coronária com Balão , Anticorpos Monoclonais/farmacologia , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Integrina alfa2 , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidoresRESUMO
BACKGROUND: The omega-3 polyunsaturated fatty acids derived from fish oils have been shown to modulate many factors believed to affect the pathogenesis of atherosclerosis. Because certain features of restenosis following angioplasty mimic some of the early changes of atherogenesis, some researchers have suggested that fish oil might prevent restenosis following angioplasty. We report the effects of omega-3 fatty acids on the rate of restenosis following percutaneous intraluminal coronary angioplasty (PTCA). METHODS AND RESULTS: From August 1989 through September 1992, 551 patients were randomized to start receiving a daily dietary supplement of ten 1.0-g capsules containing 80.6% ethyl esters of omega-3 fatty acids providing 4.1 g eicosapentaenoic acid (EPA) and 2.8 g docosahexaenoic acid (DHA) for 6 months or an equal amount of an ethyl ester of corn oil. Four hundred seventy subjects who were well matched for risk factors completed successful angioplasty of one or multiple lesions in native coronary vessels and constituted the study cohort, of whom 447 were evaluable at 6 months after PTCA. The criteria for restenosis were that the quantitative coronary angiography at 6 months show a > 30% increase in narrowing at the stenosis site or loss of at least half of the gain achieved at the time of PTCA and final restenosis with < 50% luminal diameter remaining. In 93% of the patients, the end point was determined by angiography and in all except 1% of these by quantitative coronary angiography. Compliance with the fish oil supplement was good as judged by incorporation of EPA and DHA in plasma and red blood cell phospholipids. The restenosis rate among analyzable patients was 46% for corn oil and 52% for fish oil (P = .37). The addition of 200 mg alpha-tocopherol for all subjects during the study had no effect on restenosis rates. CONCLUSIONS: This was the largest of such trials to date, and a supplement of 8 g/d of omega-3 fatty acids failed to prevent the usual high rate of restenosis after PTCA. No adverse effects were attributable to this large daily supplement of omega-3 fatty acids.
Assuntos
Angioplastia Coronária com Balão , Doença das Coronárias/prevenção & controle , Óleos de Peixe/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Fumar/efeitos adversosRESUMO
BACKGROUND: Gene therapy has been proposed as a possible solution to the problem of restenosis after coronary angioplasty. The current study was undertaken to assess conventional methods of gene transfer and to develop percutaneous techniques for introducing genes directly into the coronary arteries of large mammals. Since the anticipated targets of gene therapy against restenosis include atherosclerotic and previously instrumented arteries, we also evaluated gene transfer in atherosclerotic coronary arteries and in two porcine models of restenosis: one using intracoronary stents and a second using balloon overstretch angioplasty. METHODS AND RESULTS: The conventional method of using perforated balloon catheters to deliver Lipofectin-DNA complexes directly into the coronary arteries of intact animals was applied to 18 porcine coronary arteries including normal arteries, hypercholesterolemic arteries, and those simulating restenosis. The results of this study were consistent with previously published results indicating that only low levels of luciferase gene expression could be obtained by Lipofectin-mediated gene transfer. We therefore undertook a second, parallel study to evaluate percutaneous transluminal in vivo gene transfer using a replication-deficient adenoviral vector. A comparison of the two studies revealed that the mean level of reporter gene expression in the cohort undergoing adenoviral infection was 100-fold higher than in the cohort undergoing Lipofection. Analysis of luciferase activity over time in normal arteries revealed that recombinant gene expression was half-maximal after 1 day, peaked within 1 week, was still half-maximal at 2 weeks, and declined to low levels by 4 weeks. Histochemical analysis of coronary arteries treated with a second adenovirus expressing a nuclear-localized beta-galactosidase gene demonstrated gene transfer to a limited number of cells in the media and adventitia. Immunohistochemical analysis of Ad5-infused arteries using a monoclonal antibody directed against CD44 identified a periadventitial infiltrate composed of leukocytes. CONCLUSIONS: The recombinant adenoviral vectors proved to be far more effective than Lipofectin at delivering foreign genes directly into the coronary arteries of living mammals. Furthermore, the influences of hypercholesterolemia and arterial injury appeared to have little effect on the levels of gene expression obtained using either method. The results demonstrate that low-level recombinant gene expression, the major obstacle impeding gene therapy for the prevention of restenosis, can potentially be overcome by using adenoviral vectors to mediate coronary gene transfer in vivo. The duration of gene expression provided by these vectors and their effective deployment in atherosclerotic, balloon-overstretched, and stented coronary arteries suggest that recombinant adenovirus may have potential for evaluating gene therapy in the clinically informative porcine models of coronary restenosis.
Assuntos
Adenoviridae/genética , Doença da Artéria Coronariana/metabolismo , Doença das Coronárias/metabolismo , Vasos Coronários/metabolismo , Técnicas de Transferência de Genes , Animais , Doença da Artéria Coronariana/terapia , Doença das Coronárias/terapia , Modelos Animais de Doenças , Expressão Gênica , Terapia Genética , Óperon Lac , Luciferases/genética , Masculino , Fosfatidiletanolaminas/farmacologia , Suínos , Porco MiniaturaRESUMO
BACKGROUND: Restenosis after coronary angioplasty might be prevented by locally delivered gene therapy in conjunction with percutaneous transluminal coronary angioplasty (PTCA), since this approach should provide a sustained source of therapeutic protein within the dilated lesion. However, the potential application of gene therapy is limited by the technical barrier of efficiently transferring genes to vascular cells. METHODS: We used cultured coronary smooth muscle cells of human, porcine, and canine origin to evaluate three methods of gene transfer: recombinant adenovirus, liposomal complexes (Lipofectin), and Lipofectin supplemented with hemagglutinin. We then compared Lipofectin- and adenovirus-mediated direct gene transfer in canine and porcine coronary arteries. RESULTS: The lipofection of cultured smooth muscle cells was enhanced by adding hemagglutinin, yielding luciferase levels that were 631-fold (human), ninefold (porcine), and sevenfold (canine) higher than with Lipofectin alone. However, the recombinant adenovirus directed even higher levels of gene expression, yielding luciferase levels that were 113,000-fold (human), 450-fold (porcine), and 230-fold (canine) higher than with Lipofectin alone. After percutaneous transluminal local delivery to intact canine coronary arteries, the adenovirus produced 55 times more luciferase than did Lipofectin. In living porcine coronary arteries, adenovirus produced 95 times more luciferase than did Lipofectin. CONCLUSION: Recombinant adenovirus produces far more recombinant protein than does Lipofectin after percutaneous transluminal direct gene transfer to canine and porcine coronary arteries. Adenoviral vectors may therefore prove useful in evaluating the potential of gene therapy in large animal models of coronary restenosis.
Assuntos
Adenoviridae/genética , Técnicas de Transferência de Genes , Fosfatidiletanolaminas , Transfecção , Animais , Células Cultivadas , Vasos Coronários/enzimologia , Cães , Vetores Genéticos , Hemaglutininas , Humanos , Luciferases/metabolismo , Modelos Genéticos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologia , Proteínas Recombinantes/metabolismo , SuínosRESUMO
A series of angioplasty cases is presented in which dynamic alterations in coronary artery configuration developed. These changes were suggestive of extensive, complex dissections. Several common features emerged in these cases of which interventional cardiologists should be aware. These features included complex vessel morphology (tortuous segments, anomalous takeoffs, and complex stenoses) and the use of certain types of PTCA hardware (Amplatz guiding catheters and 0.018-inch wires). This phenomenon, termed pseudo narrowing, remains largely unrecognized. Identification of these characteristics and employment of proper management strategies will ensure a good outcome in these situations when they arise.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Angioplastia com Balão a Laser/instrumentação , Dissecção Aórtica/diagnóstico por imagem , Aneurisma Coronário/diagnóstico por imagem , Angiografia Coronária , Doença das Coronárias/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Idoso , Ponte de Artéria Coronária , Doença das Coronárias/diagnóstico por imagem , Diagnóstico Diferencial , Falha de Equipamento , Feminino , Oclusão de Enxerto Vascular/diagnóstico por imagem , Oclusão de Enxerto Vascular/cirurgia , Humanos , Masculino , Complicações Pós-Operatórias/cirurgia , ReoperaçãoRESUMO
BACKGROUND: Abrupt vessel closure and early reocclusion remain the principal vascular events underlying early recurrent ischemia complicating elective percutaneous transluminal coronary angioplasty (PTCA). Intracoronary stenting has been used to circumvent emergency bypass surgery after acute vessel closure and as an adjunct for the elective treatment of restenosis. The initial multicenter experience with the Gianturco-Roubin stent is presented, and predictors for early recurrent ischemic events are identified. METHODS AND RESULTS: Data accrued from 639 serial patients undergoing emergency stenting for abrupt closure (n = 415; 65%) or elective deployment for restenosis (n = 224; 35%) from October 1989 through May 1991 were analyzed. The incidence of subsequent ischemic events, including death, nonfatal myocardial infarction, and bypass surgery referral within 90 days of the procedure, was higher after acute deployment (20%) compared with elective stenting (9%; P = .0004). Although mortality within the two cohorts was the same (3%; P = NS), there were significant differences in the incidence of nonfatal myocardial infarction (5% versus 0.5%; P = .002) and bypass surgery (12% versus 6%; P = .02) between the acutely and electively stented patients, respectively. These events were significantly more common when the stent was undersized to the target vessel diameter (stent:artery ratio for event, 0.95 +/- 0.14 versus no event, 1.04 +/- 0.22; P = .0001) or when there was less expansion of the lesion by the deployed device (stent-to-lesion diameter ratio for event, 6.6 +/- 9.2 versus no event, 11.0 +/- 21.4; P = .0001). In a stepwise logistic regression model, acute stenting (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3 to 2.4), multivessel disease (OR, 1.4; CI, 1.1 to 1.8), larger target lesion diameter (OR, 2.1; CI, 1.4 to 3.2), larger target vessel (OR, 2.9; CI, 1.7 to 4.7), and smaller stent size (OR, 6.1; CI, 3.0 to 12.3) were independent predictors of early, recurrent ischemic events. The presence of thrombus was associated with a higher event rate after elective stenting (OR, 2.3; CI, 1.06 to 5.4) but was not associated with a higher early event rate after acute stenting. CONCLUSIONS: Early ischemic events are more common after acute stenting for abrupt or threatened closure than after elective deployment. These events may be avoided with careful attention to morphometric characteristics to avoid undersizing the stent to the target vessel and ensure adequate lesion expansion.
Assuntos
Angioplastia Coronária com Balão , Doença das Coronárias/terapia , Isquemia Miocárdica/epidemiologia , Stents , Angiografia Coronária , Doença das Coronárias/epidemiologia , Emergências , Desenho de Equipamento , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Recidiva , Sistema de Registros , Aço Inoxidável , Fatores de TempoRESUMO
Restenosis continues to limit the efficacy of coronary angioplasty, despite the various mechanical and pharmaceutical interventions that have been employed. The migration, proliferation, and extracellular matrix production by vascular smooth muscle cells are processes integral to restenosis, and sustained local delivery of drugs at high concentration should curtail these vascular responses to balloon angioplasty. Our laboratory and others are exploring the potential of using somatic cell gene therapy to provide such treatment and thereby prevent restenosis. However, conventional methods of gene transfer fail to produce physiologic levels of recombinant protein in vivo. This obstacle might be overcome by using adenoviral vectors to mediate efficient direct gene transfer. Herein we summarize these developments and focus upon our laboratory's progress towards evaluating adenovirus-mediated gene therapy in porcine coronary arteries. Recombinant adenoviruses directing the expression of the beta-galactosidase and luciferase reporter genes were evaluated in cultured coronary vascular smooth muscle cells in vitro and in porcine coronary arteries in vivo. Following percutaneous transluminal gene transfer in vivo, recombinant adenoviruses were shown to produce 70- to 240-fold more reporter protein than that produced by Lipofectin-DNA complexes. Furthermore, the high levels of adenovirus-mediated gene expression were shown to persist for at least 14 days following catheterization. Additional histologic studies will be required to determine the cellular distribution of gene expression and to elucidate potential interactions between adenovirus and the host's immune system, but recombinant adenovirus appears to be a promising vector for evaluating gene therapy against coronary restenosis.
Assuntos
Doença das Coronárias/terapia , Terapia Genética , Adenoviridae/genética , Angioplastia Coronária com Balão/efeitos adversos , Animais , Células Cultivadas , Doença das Coronárias/etiologia , Técnicas de Transferência de Genes , Vetores Genéticos , Recidiva , SuínosRESUMO
OBJECTIVES: This study reports on the initial experience with the Gianturco-Roubin flexible coronary stent. The immediate and 6-month efficacy of the device and the incidence of the complications of death, myocardial infarction, emergency coronary artery bypass surgery and recurrent ischemic events are presented. BACKGROUND: Abrupt or threatened vessel closure after coronary angioplasty is associated with increased risk of myocardial infarction, emergency coronary artery bypass graft surgery and in-hospital death. When dissection or prolapse of dilated plaque into the lumen is unresponsive to additional or prolonged balloon catheter inflation, coronary stenting offers a nonsurgical mechanical means to rapidly restore stable vessel geometry and adequate coronary blood flow. METHODS: From September 1988 through June 1991, 518 patients underwent attempted coronary stenting with the 20-mm long Gianturco-Roubin coronary stent for acute or threatened vessel closure after angioplasty. In 494 patients, one or more stents were deployed. Thirty-two percent of patients received stents for acute closure and 69% for threatened closure. RESULTS: Successful deployment was achieved in 95.4% of patients. Overall, stenting resulted in an immediate angiographic improvement in the diameter stenosis from 63 +/- 25% before stenting to 15 +/- 14% after stenting. Emergency coronary artery bypass graft surgery was required in 4.3% (21 of 493 patients). The incidence of in-hospital myocardial infarction (Q wave and non-Q wave) was 5.5% (27 of 493 patients). At 6 months, myocardial infarction was infrequent, occurring in 1.6% (8 of 493 patients). The incidence of in-hospital death was 2.2% (11 of 493 patients). Late death occurred in 7 patients (1.4%) and 34 patients (6.9%) required later bypass graft surgery. Complications included blood loss, primarily from the arterial access site, and subacute thrombosis of the stented vessel in 43 patients (8.7%). CONCLUSIONS: The early multicenter experience suggests that this stent is a useful adjunct to coronary angioplasty to prevent or minimize complications associated with flow-limiting coronary artery dissections previously correctable only by surgery. Although this study was not randomized, it demonstrated a high technical success rate and encouraging results with respect to the low incidence of emergency coronary artery bypass graft surgery and myocardial infarction.