Assuntos
Angina Instável/sangue , Fator Natriurético Atrial/sangue , Infarto do Miocárdio/sangue , Proteína Plasmática A Associada à Gravidez/análise , Doença Aguda , Angina Instável/diagnóstico , Biomarcadores/análise , Doença da Artéria Coronariana/patologia , Humanos , Infarto do Miocárdio/diagnóstico , Miocárdio/patologia , Peptídeo Natriurético Encefálico , Necrose , Prognóstico , Medição de RiscoRESUMO
BACKGROUND: Rapamycin is a potent inhibitor of smooth muscle cell (SMC) proliferation and migration. Rapamycin-mediated inhibition of SMC proliferation is associated with upregulation of the cyclin-dependent kinase inhibitor p27(Kip1). Previously, we showed that mixed embryonic fibroblasts obtained from p27(Kip1)(-/-) mice were relatively rapamycin-resistant, suggesting that p27(Kip1) plays an integral role in modulating the antiproliferative effects of rapamycin. We hypothesized that the antimigratory effect of rapamycin may also be mediated by p27(Kip1). METHODS AND RESULTS: Rapamycin (1 to 10 nmol/L) inhibited basic fibroblast growth factor-induced migration of wild-type (WT) but not p27(Kip1)(-/-) SMCs in a dose-dependent manner (P<0.05) in a modified Boyden chamber. The effects of rapamycin on aortic SMC explant migration were also studied with WT, p27(+/-), and p27(-/-) mice. Rapamycin 4 mg. kg(-1). d(-1) IP for 5 days inhibited SMC migration by 90% in the WT and p27(Kip1)(+/-) (P<0.05) but not p27(Kip1)(-/-) animals. CONCLUSIONS: Lack of p27(Kip1) reduces rapamycin-mediated inhibition of SMC migration. These novel findings suggest a role for p27(Kip1) in the signaling pathway(s) that regulates SMC migration.
Assuntos
Toxinas Botulínicas , Quinases relacionadas a CDC2 e CDC28 , Proteínas de Ciclo Celular , Movimento Celular/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Liso Vascular/metabolismo , Proteínas Proto-Oncogênicas , Proteínas Supressoras de Tumor , ADP Ribose Transferases/farmacologia , Animais , Aorta , Adesão Celular/efeitos dos fármacos , Contagem de Células , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p27 , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Cultura em Câmaras de Difusão , Relação Dose-Resposta a Droga , Fator 2 de Crescimento de Fibroblastos/farmacologia , Heterozigoto , Homozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sirolimo/antagonistas & inibidores , Sirolimo/farmacologia , Tacrolimo/farmacologia , Proteína 1A de Ligação a Tacrolimo/metabolismoRESUMO
Hemostatic and immunologic factors have been implicated in future cardiac events in patients with coronary artery disease. The role of these factors and their interaction is less established in cardiac transplant recipients. We sought to characterize the role of these factors in these patients. Cardiac transplant patients who presented for surveillance coronary angiography and/or endomyocardial biopsy were eligible for enrollment. Ninety-nine consecutive patients were enrolled. Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1, von Willebrand factor, fibrin D-dimer, and anti-t-PA antibody were determined by enzyme-linked immunosorbent assays. Anti-THP-1 cell antibodies directed against a monocytic leukemia cell line were detected by incubating patient plasma with THP-1 cells. Bound antibody was detected using goat peroxidase-labeled immunoglobulin G directed against human immunoglobulins. Lipids were measured by enzymatic methods. Multivariate analysis identified the presence of anti-THP-1 cell antibodies (risk ratio 4.41, p = 0.002), t-PA antigen (risk ratio 1.10, p = 0.033), donor age 20 to 26 years (risk ratio 8.83, p = 0.042), and donor age >36 years (risk ratio 15.53, p = 0.009) as predictors of allograft failure. Altered hemostatic function, as demonstrated by elevated plasma t-PA antigen levels, is predictive of subsequent allograft failure in cardiac transplant recipients. In addition, the presence of anti-THP-1 cell antibodies in these patients is predictive of allograft failure.
Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangue , Distribuição de Qui-Quadrado , Ensaio de Imunoadsorção Enzimática , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hemostasia , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fator de von Willebrand/análiseRESUMO
BACKGROUND: T-lymphocytes are present in significant numbers in the atherosclerotic plaque, but their role in the progression and pathogenesis of coronary syndromes remains poorly understood. HYPOTHESIS: We sought to determine the relationship between T-lymphocyte activation and ischemic heart disease by measuring plasma levels of cytokines related to T-lymphocyte function in patients with stable and unstable angina. METHODS: Plasma levels of interleukin-2 (IL-2) and soluble IL-2 receptor (sIL-2R) were measured in 105 patients: 66 with stable angina, 24 with unstable angina, and 15 healthy controls. Patients who presented to the cardiac catheterization laboratory with unstable or stable anginal syndromes for coronary angiography or percutaneous coronary intervention enrolled in the study. RESULTS: Mean levels of IL-2 were significantly higher in patients with stable angina than in those with unstable angina. The differences between stable angina and control groups, or between unstable angina and control groups, were not statistically significant. Mean levels of slL-2R were significantly higher in patients with stable angina than in either patients with unstable angina or control patients. CONCLUSIONS: Levels of IL-2 and sIL-2 receptor are significantly elevated in patients with stable angina, but not in patients with unstable angina. The contribution of T-lymphocytes to the development of both stable and unstable angina requires further investigation.
Assuntos
Angina Pectoris/sangue , Angina Instável/sangue , Interleucina-2/sangue , Ativação Linfocitária , Receptores de Interleucina-2/sangue , Linfócitos T/fisiologia , Adulto , Idoso , Angina Pectoris/imunologia , Angina Instável/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SolubilidadeRESUMO
BACKGROUND: Inflammation may be involved in the origin of transplant coronary artery disease. We hypothesized that plasma levels of C-reactive protein (CRP) and interleukin-6 (IL-6), markers for systemic inflammation, would correlate with cardiac transplant graft survival. METHODS AND RESULTS: We studied 99 consecutive cardiac transplant recipients who were referred for routine endomyocardial biopsy and/or surveillance coronary angiography. Plasma levels of CRP and IL-6 were measured by their respective ELISAs. Patients were divided into 2 groups: those who died or required retransplantation and those who survived without the need for retransplantation. During the follow-up period of 5.0+/-2.7 years (range, 0.2 to 15.1 years) after transplant, 20 patients died and 9 required retransplantation. There was no significant difference in age, race, sex, cause of native myopathy, presence of diabetes, or use of aspirin, statins, or calcium channel blockers between the 2 groups. Although IL-6 did not relate to graft failure, CRP level was predictive of allograft failure (P:=0.003). The risk of allograft failure increased 36% for every 2-fold increase in CRP level. Moreover, CRP levels also correlated significantly with the frequency of grade 3 rejection (P:=0.02). In multivariate analysis, when combined with other significant predictors such as donor age and sex mismatching of the graft, CRP still significantly predicted graft failure (P:=0.025) with a 32% increase in the risk of graft failure for every 2-fold increase in CRP level. CONCLUSIONS: These findings suggest that elevated plasma levels of CRP are associated with subsequent allograft failure in cardiac transplant recipients.
Assuntos
Proteína C-Reativa/metabolismo , Sobrevivência de Enxerto , Transplante de Coração , Biomarcadores , Feminino , Transplante de Coração/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transplante Homólogo/efeitos adversosRESUMO
OBJECTIVES: To determine whether addition of basic fibroblast growth factor (bFGF), an angiogenic growth factor, enhances the angiogenic effects of transmyocardial laser revascularization (TMR). BACKGROUND: TMR is an investigational therapy for treating patients with medically refractory angina not amenable to traditional therapies. Histologic and blood flow studies in animals have suggested that TMR enhances angiogenesis above that normally seen in ischemic myocardium. We tested the hypothesis that bFGF administered into TMR channels further enhance the angiogenic effects of TMR. METHODS: Chronic ischemia was created in 3 groups of dogs using an ameroid constrictor on the proximal LAD. In the bFGF group (n = 5) non-transmyocardial channels were created in the LAD territory and bFGF, (100 ng/ml) dissolved in pluronic gel was injected into the each channel. In the TMR group (n = 7), transmyocardial channels were created without bFGF. A control group (n = 7) had ischemia without TMR of bFGF. 5-bromo-2'-deoxyuridine (BrdU) was administered to mark proliferating cells. After 8 weeks survival, colored microspheres were injected to assess the regional myocardial blood flow. RESULTS: TMR and TMR+bFGF increased total vascular density by approximately 40% over that observed in the control group. However, the number of large vessels (internal diameter > or = 50 microm) was doubled by the addition of bFGF, and this correlated with a 50% increase in the density of proliferating vascular cells and a tripling of the total estimated vascular cross sectional area. Blood flow to the LAD territory was increased by TMR compared to controls, with no further benefit observed in the bFGF group. CONCLUSIONS: On a histologic basis, basic fibroblast growth factor further enhances angiogenesis following TMR in ischemic myocardium mainly by increasing the size but not the total number of vessels.
Assuntos
Fator 2 de Crescimento de Fibroblastos/farmacologia , Terapia a Laser , Isquemia Miocárdica/cirurgia , Revascularização Miocárdica/métodos , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Circulação Coronária , Cães , Imuno-Histoquímica , Isquemia Miocárdica/patologiaRESUMO
BACKGROUND: Multiple studies support a role for inflammation in the pathogenesis of coronary atherosclerosis and unstable cardiac syndromes. However, of the known proinflammatory cytokines, only elevated plasma levels of interleukin-6 have been linked to unstable angina. We sought to examine the plasma levels of other major proinflammatory cytokines in similar clinical settings and to determine the extent of the relationship between inflammation and unstable coronary syndromes by measuring the levels of various proinflammatory cytokines in patients with stable and unstable angina. METHODS: We measured plasma levels of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) in 97 patients: 67 with stable angina, 24 with unstable angina, and 15 healthy controls. RESULTS: Mean levels of IL-1beta were significantly higher in patients with unstable angina as compared to patients with stable angina (p =.009). Levels of IL-6 were significantly higher than control patients for both stable angina and unstable angina patients (p =.031 and.006, respectively). No significant differences were found in the levels of TNF-alpha. CONCLUSIONS: Our results suggest that both IL-1beta and IL-6 contribute to the pathogenesis of unstable angina, and that the profile of circulating plasma levels of proinflammatory cytokines differs in unstable angina from that in stable angina. Abbreviated Abstract. Multiple studies support a role for inflammation in the pathogenesis of coronary atherosclerosis and unstable cardiac syndromes. We measured plasma levels of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) in patients with stable and unstable coronary syndromes. Levels of IL-1beta and IL-6 were found to be elevated in patients with unstable coronary syndromes. No significant differences were found in the levels of TNF-alpha. Our results suggest that both IL-1beta and IL-6 contribute to the pathogenesis of unstable angina.
Assuntos
Angina Pectoris/sangue , Angina Instável/sangue , Interleucina-1/sangue , Adulto , Idoso , Angina Pectoris/tratamento farmacológico , Angina Instável/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Restenosis after percutaneous transluminal coronary angioplasty (PTCA) and coronary stenting remains a major clinical problem. Vascular smooth muscle cell (SMC) proliferation and migration from the arterial wall media into the intima are believed to play a critical role in the pathogenesis of restenosis. Several studies have demonstrated that phosphorothioate (PS) oligodeoxynucleotides targeted against genes involved in SMC proliferation inhibit in vitro SMC proliferation and migration. Moreover, PS oligodeoxynucleotides targeted against the genes c-myb, c-myc, cdc2 kinase, cdk2 kinase, and proliferating cell nuclear antigen (PCNA) when delivered adventitially or intraluminally inhibit in vivo neointimal formation after balloon injury in both the rat carotid and porcine coronary artery models. The inhibitory effects of these PS oligodeoxynucleotides may be the result of their suppression of migration of medial SMC rather than suppression of medial or intimal cell proliferation. Other studies have demonstrated the presence of the potent guanosine or G-quartet aptameric inhibitory effect of the PS oligodeoxynucleotides. Experiments with cytidine homopolymers such as S-dC28, which lack guanosines, reveal the presence of potent non-G-quartet, non-sequence-specific inhibitory effects on in vitro SMC proliferation, migration, and adhesion as well as in vivo neointimal formation after rat carotid artery balloon injury. This is owing to the avid binding of these PS oligodeoxynucleotides to the SMC mitogens and chemoattractants platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). The extent to which hybridization-dependent antisense, G-quartet aptameric, or non-G-quartet, non-sequence-specific inhibitory effects occurs is the result of PS oligodeoxynucleotide sequence, length, and concentration. The 18-mer guanosine-rich PS oligodeoxynucleotide ZK10 is a more potent in vitro SMC proliferation inhibitor than S-dC28, although both compounds manifest comparable in vivo inhibitory effects on neointimal formation in the rat carotid artery model of balloon injury. PS oligodeoxynucleotides also possess non-sequence-specific immunomodulatory effects, including the induction of interferon-gamma and the unmethylated CpG motif, which exhibits numerous immunomodulatory effects. Novel strategies to inhibit restenosis include the development of E2F transcription decoys that inhibit several cell cycle regulatory genes and diminish neointimal lesion formation. In addition, antisense oligonucleotides targeted against the anti-apoptotic gene bcl-xL, which when transfected into the vessel wall inhibits bcl-xl expression, induce a five-fold increase in apoptotic SMC intimal cells, and effect a marked attenuation of in vivo lesion dimensions, thereby suggesting frank vascular lesion regression.
Assuntos
Doença das Coronárias/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Animais , Constrição Patológica/fisiopatologia , Constrição Patológica/prevenção & controle , Doença das Coronárias/fisiopatologia , Humanos , Ratos , RecidivaRESUMO
BACKGROUND: Prior studies, usually conducted with the use of insurance databases, have shown differences in the use of cardiac procedures between black patients and white patients hospitalized with various types of coronary artery disease. However, few data are available in prospectively collected cohorts of patients with unstable angina or on the use of appropriate medications or interventions. METHODS AND RESULTS: We evaluated 2948 consecutive patients with unstable angina admitted to 35 hospitals across the United States in 1996, comparing nonwhite and white patients. Seventy-seven percent of patients were white, 14% were black, 4% were Hispanic, 1% were Asian, and 3% were other or unknown race. Differences were seen in coronary risk profile, with a higher incidence of hypertension and diabetes mellitus in nonwhites. Cardiac catheterization was performed less often in nonwhites compared with whites (36% vs 53%, P =.001). Even in patients meeting the criteria for appropriate catheterization in the Agency for Health Care Policy Research unstable angina guidelines, fewer nonwhites underwent catheterization (44% vs 61%, P =.001), but among these, fewer nonwhites had significant coronary stenosis (72% vs 90%, P =.001). However, among patients catheterized who had indications for revascularization, angioplasty and coronary artery bypass grafting were performed equally often in nonwhites and whites. CONCLUSIONS: Current guidelines would recommend more aggressive use of cardiac catheterization for nonwhite patients. However, our findings suggest that racial differences may need to be included in the diagnostic and interventional algorithms.
Assuntos
Angina Instável/terapia , Etnicidade/estatística & dados numéricos , Sistema de Registros , Idoso , Cateterismo Cardíaco , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estados UnidosRESUMO
Few data are available in prospectively collected cohorts of patients with unstable angina pectoris or on the use of appropriate medications or interventions. Accordingly, we evaluated 2,948 consecutive patients with unstable angina admitted to 35 hospitals in the United States in 1996, and comparing men and women (39% of the patients were women). Differences were seen in coronary risk profiles with a higher incidence of systemic hypertension, diabetes mellitus, and a family history of coronary disease in women. Women were less likely to receive Agency for Health Care Policy Research (AHCPR) recommended pharmacologic treatment than men. Cardiac catheterization, coronary angioplasty, and bypass was performed less often in women compared with men (44% vs. 53%, p = 0.002; 12% vs. 18%, p = 0.02; 7% vs. 10%, p = 0.001, respectively). At catheterization, women were more likely to have no significant coronary artery disease (25% vs. 14%, p = 0.001). Although fewer women than men fulfilled the AHCPR criteria for cardiac catheterization (54% vs. 64%, p = 0.001), a similar rate of men and women with positive criteria underwent catheterization and angioplasty. However, fewer women with positive criteria underwent bypass surgery (36% vs. 46%, p = 0.03). More men "ruled-in" for a myocardial infarction at admission (13% vs. 8%, p = 0.001), but there was no difference in recurrent angina, in-hospital myocardial infarction, or death. Despite different epidemiologic profiles and less evidence of coronary artery disease by noninvasive and invasive tests, women and men had similar outcomes.
Assuntos
Angina Instável/diagnóstico , Angina Instável/terapia , Padrões de Prática Médica , Adulto , Idoso , Angina Instável/epidemiologia , Angioplastia Coronária com Balão/estatística & dados numéricos , Cateterismo Cardíaco/estatística & dados numéricos , Ponte de Artéria Coronária/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores Sexuais , Resultado do TratamentoRESUMO
Phosphorothioate (PS) oligodeoxynucleotides (ODN) inhibit vascular smooth muscle cell proliferation through antisense and G-quartet aptameric mechanisms. PS-ODN such as the cytidine homopolymers, have been demonstrated to have non-G-quartet, nonsequence-specific inhibitory effects in a rat carotid balloon injury model of neointimal proliferation. We sought to test the efficacy of S-dC28, a cytidine homopolymer lacking G-quartets, on neointimal proliferation in the porcine coronary artery model of balloon injury. A total of 23 animals (11 controls, 12 treated) were subjected to balloon injury in a coronary artery, followed by infusion of control solution or S-dC28 via porous balloon, the Scimed Dispatch Coronary Infusion Catheter. After a mean interval of 49 days, the animals were killed, and the target coronary segments were examined histologically. S-dC28 did not significantly inhibit neointimal formation. Fluorescein isothiocyanate (FITC)-labeled S-dC28 was present in the intima and media immediately after administration but was present mainly within the adventitia 3 hours after administration. S-dC28, when delivered by a Scimed Dispatch Coronary Infusion Catheter (Maple Grove, MN), did not significantly affect neointimal proliferation after balloon injury in a porcine coronary artery model.
Assuntos
Vasos Coronários/lesões , Oligodesoxirribonucleotídeos/administração & dosagem , Angioplastia Coronária com Balão/efeitos adversos , Animais , Divisão Celular , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Modelos Animais de Doenças , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Músculo Liso Vascular/patologia , Oligodesoxirribonucleotídeos/genética , Ratos , Suínos , Tionucleotídeos/administração & dosagem , Tionucleotídeos/genéticaRESUMO
BACKGROUND: Inflammatory markers have been shown to be elevated in acute coronary syndromes. Recently, interleukin-6 was demonstrated to be elevated in unstable angina compared with stable angina. However, the effect of percutaneous coronary interventions on the levels of inflammatory markers is less well known. METHODS AND RESULTS: In this study, we measured the levels of interleukin-6 and interleukin-1 by using enzyme-linked immunosorbent assays in patients with angina pectoris undergoing coronary interventions and in healthy control subjects. Interleukin-6 was significantly elevated in patients with unstable angina compared with patients with stable angina (P= .01). There were no significant differences between the levels of interleukin-1 in patients with unstable angina versus patients with stable angina and healthy control subjects. Furthermore, at 1-month follow-up after percutaneous coronary interventions, there were no longer any significant differences between the levels of interleukin-6 in patients with unstable angina versus patients with stable angina and healthy control subjects. CONCLUSIONS: These data suggest that interleukin-6 levels may correlate with instability of atheromatous plaques and that the decrease of interleukin-6 levels after percutaneous coronary interventions may represent plaque reendothelialization and stabilization.
Assuntos
Angina Pectoris/imunologia , Angina Instável/imunologia , Angioplastia Coronária com Balão , Doença da Artéria Coronariana/imunologia , Interleucina-1/sangue , Interleucina-6/sangue , Stents , Adulto , Idoso , Angina Pectoris/terapia , Angina Instável/terapia , Doença da Artéria Coronariana/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Phosphorothioate oligodeoxynucleotides (PS oligos) manifest antisense and G-quartet aptameric inhibitory effects on vascular smooth muscle cell (SMC) proliferation. PS oligo cytidine homopolymers also have nonsequence-specific, non-G-quartet inhibitory effects on in vitro and in vivo SMC proliferation. In this study, we compared the effects of S-dC18 and S-dC28, 18-mer and 28-mer cytidine homopolymers, respectively, which lack guanosines, with those of ZK10, a G-tetrad forming compound, on in vitro SMC proliferation and in vivo neointimal formation. ZK10 significantly inhibited in vitro human aortic SMC proliferation. At the same molar concentration, ZK10 had significantly greater inhibitory potency on SMC proliferation than either S-dC18, S-dC28, or 7DG-ZK10, which is a modified ZK10 with ten 7-deaza guanosine substitutions. ZK10 was significantly more potent than S-dC18 and S-dC28 in inhibiting PDGF-induced in vitro SMC migration. S-dC18, S-dC28, and ZK10 treatment significantly reduced the intima/media area ratio after rat carotid artery balloon injury compared with the values of the control groups. ZK10 was a more potent inhibitor of neointimal formation than the same chain length S-dC18. ZK10 formed higher-order structures, as shown on gel electrophoresis, in contrast to S-dC28 and 7DG-ZK10. Therefore, the 18-mer ZK10 has comparable in vivo SMC inhibitory effects to the 28-mer S-dC28, a fact that may have ramifications for the development of optimal PS oligos to inhibit angioplasty restenosis.
Assuntos
Citidina/farmacologia , Guanosina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Oligodesoxirribonucleotídeos/farmacologia , Tionucleotídeos/farmacologia , Angioplastia com Balão , Animais , Artérias Carótidas/citologia , Lesões das Artérias Carótidas , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Músculo Liso Vascular/citologia , Ratos , Endonucleases Específicas para DNA e RNA de Cadeia SimplesRESUMO
OBJECTIVES: The objectives of this study were to define the hemostatic profiles of patients with unstable angina compared with patients with stable angina and to investigate the effect of percutaneous interventions on the follow-up hemostatic profiles of these patients. BACKGROUND: Disturbances in hemostatic factors have been shown to be present in various clinical syndromes involving coronary artery disease. However, their role in stable angina versus unstable angina is less well defined. METHODS: We studied 61 patients with either stable or unstable angina undergoing percutaneous coronary interventions. Blood samples were drawn immediately before the intervention and at 1-month follow-up. Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF) were measured by enzyme-linked immunosorbent assays. RESULTS: Patients with unstable angina had significantly higher t-PA levels (mean [+/-SE] 23.7 +/- 3.4 vs. 14.3 +/- 1.4 ng/ml, respectively, p = 0.02) and vWF antigen concentrations (2,231 +/- 157 vs. 1,792 +/- 108 mU/ml, respectively, p = 0.03) than patients with stable angina. No statistically significant differences were observed in the PAI-1 levels between the two groups (27.9 +/- 5.5 vs. 21.4 +/- 2.5 ng/ml, respectively, p = 0.25). At 1-month follow-up, there were no longer any significant differences in the t-PA or vWF levels between the two groups (15.7 +/- 1.2 vs. 13.6 +/- 0.6 ng/ml, p = 0.13; 1,962 +/- 170 vs. 1,809 +/- 88 mU/ml, p = 0.39, respectively). There were no significant differences between the hemostatic profiles of patients undergoing percutaneous transluminal coronary angioplasty or coronary stenting initially and at 1-month follow-up. CONCLUSIONS: These data suggest that elevated plasma levels of t-PA and vWF may correlate with instability of atheromatous plaques, and that their decrease after coronary interventions may reflect plaque reendothelialization and stabilization.
Assuntos
Angina Pectoris/sangue , Angina Instável/sangue , Angioplastia Coronária com Balão , Hemostasia , Stents , Ativador de Plasminogênio Tecidual/sangue , Fator de von Willebrand/análise , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hemostatic factors are involved in the pathogenesis of native coronary artery disease. However, their role in transplant coronary artery disease is less established. To assess the role of hemostatic factors in transplant coronary artery disease we studied 52 consecutive cardiac transplant patients. The presence of transplant coronary artery disease was determined by angiography. Plasma levels of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von Willebrand Factor (vWF), and fibrin D-dimer were determined by enzyme-linked immunosorbent assays. Serum lipids were measured by enzymatic methods. Patients with transplant coronary artery disease had higher circulating t-PA (8.6 +/- 0.8 vs. 5.4 +/- 0.6 ng/ml, p = 0.021) and PAI-1 antigen concentrations (38.0 +/- 3.4 vs 25.8 +/- 2.2 ng/ml, p = 0.037). t-PA and PAI-1 antigen concentrations correlated with the severity of angiographic disease (R = 0.34; p = 0.014 for t-PA, and R = 0.45; p = 0.001 for PAI-1). Serum cholesterol levels were higher in patients with transplant coronary artery disease (221 +/- 7.6 vs 191 +/- 9.2 mg/dl, p = 0.039). Serum triglycerides were also higher in patients with transplant coronary artery disease by angiography (246 +/- 38.3 vs 139 +/- 20.8 mg/dl, p = 0.050). Multivariate analysis identified t-PA antigen (p = 0.003) and triglyceride levels (p = 0.038) as independent predictors for the presence of transplant coronary artery disease. We conclude that cardiac transplant patients with evidence of transplant coronary artery disease on coronary angiography have altered hemostatic function which is reflected by elevated levels of circulating t-PA and PAI-1 antigens. The interaction of the hemostatic system and serum lipids in the development of transplant coronary artery disease warrants further study.
Assuntos
Doença das Coronárias/sangue , Transplante de Coração/fisiologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangue , Colesterol/sangue , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Masculino , Triglicerídeos/sangue , Fator de von Willebrand/análiseRESUMO
We sought to examine phosphorothioate oligodeoxynucleotide (PS oligo) non-G-quartet, nonsequence specific effects on smooth muscle cell (SMC) adhesion by using S-dC28, a 28-mer cytidine homopolymer that lacks contiguous guanosine residues. Human aortic SMC were incubated with vehicle or various doses of S-dC28, and the number of SMC adhered to noncoated plates was determined using a Coulter Counter. S-dC28 significantly inhibited SMC adhesion. SMC adhesion dramatically improved with S-dC28 in fibronectin-coated plates. When laminin-coated plates were used, the inhibition of SMC adhesion by S-dC28 was completely reversed. Replacement of serum-free medium with 5% fetal bovine serum medium for SMC cultured on non-coated plates also greatly attenuated inhibition of adhesion by S-dC28. Human SMC TPA, UPA, and PAI-1 antigen levels were determined by ELISAs. PDGF significantly induced SMC TPA antigen production measured by an ELISA. Coincubation of PDGF with S-dC28 significantly attenuated SMC TPA antigen levels. SMC UPA antigen levels after coincubation with PDGF and S-dC28 were significantly greater than the values observed in SMC incubated in medium containing PDGF alone. SMC PAI-1 antigen levels were not altered by the addition of S-dC28. We conclude that S-dC28 inhibits human SMC adhesion and that this inhibition can be diminished by fibronectin or laminin coating of culture plates or by the presence of serum in the culture medium. Furthermore, S-dC28 attenuates SMC TPA production, thereby inhibiting SMC migration, whereas S-dC28 augments SMC UPA production, thus diminishing SMC cellular adhesion.
Assuntos
Adesão Celular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Oligodesoxirribonucleotídeos/farmacologia , Tionucleotídeos/farmacologia , Ativador de Plasminogênio Tecidual/biossíntese , Análise de Variância , Aorta , Meios de Cultura , Ensaio de Imunoadsorção Enzimática , Fibronectinas , Humanos , Laminina , Músculo Liso Vascular/citologia , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Ativador de Plasminogênio Tecidual/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/biossínteseRESUMO
Smooth muscle cell (SMC) fibrinolysis is necessary for SMC migration. To determine whether the T cell lymphokines interleukin 4 (IL-4) and interferon-gamma (IFN-gamma) modulate SMC fibrinolysis and migration induced by basic fibroblast growth factor (bFGF), we examined the effects of IL-4 and IFN-gamma on human SMC tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (UPA), and plasminogen activator inhibitor 1 (PAI-1) antigen production, determined by enzyme-linked immunosorbent assays. Although IL-4 had no effects on SMC tPA, UPA, and PAI-1 production, it potentiated bFGF-induced tPA, UPA, and PAI-1 antigens. IL-4 plus bFGF resulted in a net increase in SMC fibrinolytic activity. IFN-gamma did not significantly affect bFGF induction of SMC tPA and PAI-1 antigens. However, IFN-gamma significantly decreased bFGF-mediated induction of SMC UPA antigen. IFN-gamma decreased the IL-4 plus bFGF induction of both tPA and UPA antigens. IL-4 increased and IFN-gamma abrogated bFGF induction of in vitro SMC migration through a modified micro-Boyden chamber. Therefore, IL-4 and IFN-gamma modulate bFGF-mediated induction of in vitro vascular SMC fibrinolysis and migration.
Assuntos
Fibrinólise/fisiologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Linfocinas/fisiologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Linfócitos T/metabolismo , Antígenos/análise , Movimento Celular/fisiologia , Humanos , Interferon gama/farmacologia , Interleucina-4/farmacologia , Músculo Liso Vascular/citologia , Inibidor 1 de Ativador de Plasminogênio/imunologia , Proteínas Recombinantes , Ativador de Plasminogênio Tecidual/imunologia , Ativador de Plasminogênio Tipo Uroquinase/imunologiaRESUMO
Phosphorothioate oligodeoxynucleotides (PS oligos) manifest both antisense and G-quartet aptameric inhibitory effects on vascular smooth muscle cell (SMC) proliferation. In this study, we examined the effects of three cytidine (S-dC) homopolymers lacking any guanosines of various chain length-S-dC28, S-dC18 and S-dC12-on in vitro SMC proliferation and in vivo neointimal formation. S-dC18 significantly inhibited human vascular SMC proliferation, although it had only half the potency as the same dose of S-dC28. Furthermore, S-dC12 at the same concentrations as S-dC18 did not significantly inhibit vascular SMC proliferation. S-dC28 and S-dC18 inhibited PDGF-induced in vitro SMC migration, whereas D-dC12 had no significant effect on PDGF-induced in vitro SMC migration. We determined the effects of S-dC28, S-dC18, and S-dC12 on neointimal SMC formation in the rat carotid balloon injury model. Rat carotid artery neointimal formation after balloon injury was significantly attenuated by S-dC28 treatment compared with the control group and by S-dC18 treatment compared with the control group. S-dC28 and S-dC18 treatment significantly reduced the intima/media area ratio compared with the values of the control groups. However, S-dC12 did not significantly inhibit neointimal formation. We investigated the time course of the inhibitory effects of S-dC28 on rat carotid artery neointimal formation. S-dC28 significantly inhibited rat carotid artery intimal area and intima/media area ratio at 4 weeks and 8 weeks. Fluoresceinated S-dC28 (FITC-S-dC28) was found to be present throughout the rat carotid arterial wall within 6 hours after balloon injury. Taken together, the potent non-G-quartet, nonsequence-specific inhibitory effects of S-dC compounds on in vitro SMC proliferation and in vivo neointimal formation in the rat carotid balloon injury model are chain length dependent and long lasting.
Assuntos
Divisão Celular/efeitos dos fármacos , Citidina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Angioplastia com Balão , Animais , Biopolímeros , Artérias Carótidas/citologia , Artérias Carótidas/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Citidina/química , Endotélio Vascular/citologia , Fluoresceína-5-Isotiocianato , Humanos , RatosRESUMO
Magnesium possesses numerous salutary effects for the treatment of acute myocardial infarction (AMI). It is a coronary vasodilator, calcium antagonist, afterload reducer, antiarrhythmic, and antiplatelet drug that modulates autonomic function and limits reperfusion injury when administered early in infarction. Various clinical trials of magnesium therapy for AMI have proffered conflicting results as to the efficacy of magnesium therapy because of significant differences in the timing of magnesium administration. Additional clinical trials that focus on early administration of magnesium are warranted to delineate the role of magnesium therapy for AMI.