Asunto(s)
Enfermedades Cardiovasculares , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Niacina/farmacología , Triglicéridos/sangre , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos como Asunto , Humanos , Hipolipemiantes/farmacología , Factores de Riesgo , Resultado del TratamientoRESUMEN
Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health.Key messagesHigh-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries).Knowledge on the activity of high-density lipoproteins on health have however significantly widened.HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.
Asunto(s)
Aterosclerosis/terapia , Insuficiencia Cardíaca/terapia , Lipoproteínas HDL , Terapia Molecular Dirigida , Animales , Materiales Biocompatibles , Terapia Genética , Humanos , Intervención Coronaria Percutánea , StentsRESUMEN
The number of patients receiving dual antiplatelet therapy with an additional indication for long-term oral anticoagulation has substantially increased over time. This population is facing an unacceptable risk of bleeding events, particularly among elderly individuals, who are especially vulnerable to complications. Further strategies to minimize this bleeding risk, including various drug combinations, different dosage regimens and even numerous attempts to find the appropriate duration of the treatment, have been evaluated in a multitude of randomized control trials. Moreover, the recent incorporation of the direct oral anticoagulants (DOACs) to the therapeutic armamentarium may represent an alternative to treat such patients, since they have demonstrated to be noninferior to the classic vitamin K antagonists and with lower bleeding rates. The aim of this review is to summarize the most recent literature on the use of DOACs in patients with an indication for dual antiplatelet therapy (mostly subjects with coronary artery disease) and also an established indication for chronic anticoagulation (chiefly individuals with nonvalvular atrial fibrillation). The role of DOACs in ischemic heart disease alone is also discussed.
Asunto(s)
Anticoagulantes/uso terapéutico , Fibrinolíticos/uso terapéutico , Trombosis/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Atherosclerotic cardiovascular disease is the leading cause of death all over the world. Its etiopathogenesis involves many correlated processes, with hypercholesterolemia being one of the main risk factors. Several large clinical trials have established the association between low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. With the aim to take control over high LDL-C levels, several drugs with different targets in the cholesterol pathway have been developed. Statins are the cornerstone of pharmacological lipid-lowering treatment, although they are not always successful in attaining the recommended LDL-C levels. Therefore, newer and more potent therapies have been developed, being prominent among them ezetimibe and especially the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recent trials with these new therapies have reaffirmed the theory of 'the lower, the better' when it comes to LDL-C levels, and 'the earlier, the better' when it comes to atherosclerotic physiopathology.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , LDL-Colesterol/antagonistas & inhibidores , Inhibidores de PCSK9 , Subtilisinas/antagonistas & inhibidores , Aterosclerosis/prevención & control , Enfermedades Cardiovasculares/prevención & control , HumanosRESUMEN
BACKGROUND: Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-kappaBeta ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. MATERIALS AND METHODS: Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0.2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (microCT) and molecular analysis of the vascular tissue. RESULTS: Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3), P = 0.042, and 94 +/- 26 vs. 33 +/- 7 particles cm(-3), P = 0.046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 +/- 7 degrees vs. SHAM 33 +/- 5 degrees , P = 0.99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0.029, primarily by decreasing RANKL (P = 0.019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. CONCLUSIONS: In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women.
Asunto(s)
Aterosclerosis/patología , Calcinosis/etiología , Ovariectomía/efectos adversos , Ligando RANK/metabolismo , Animales , Enfermedades de la Aorta/inducido químicamente , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Aterosclerosis/inducido químicamente , Aterosclerosis/metabolismo , Western Blotting , Calcinosis/patología , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Imagen por Resonancia Magnética , Conejos , Transducción de SeñalRESUMEN
The role of thrombosis in various acute coronary syndromes has been established. However, the basic mechanism by which plaque rupture leads to a growing thrombus in the vicinity of stenotic lesions is not well understood. Using a characterized flow chamber in a rheologically controlled system, we have mimicked stenotic vessels and studied for the first time cell-vessel wall interaction in nonparallel streamlines. Stenoses ranging from 0 to 80% were produced with stripped tunica media to mimic severe vessel wall damage, and perfused with heparinized flowing blood. This perfusion device was placed within an extracorporeal system in swine, and blood was perfused for selected times from 1 to 30 min. Platelet deposition on the surface was evaluated by 111Indium-labeled platelets. As percent stenosis increased, platelet deposition significantly increased (P less than 0.001), indicating a shear-induced cell activation. Analysis of the axial distribution of platelet deposition indicated that the apex, and not the flow recirculation zone distal to the apex, was the segment of greater platelet accumulation within 30 min of blood perfusion (P less than 0.001). These results also indicate that the severity of the acute platelet response to plaque rupture probably depends on the location of the rupture with relation to the apex of the plaque.
Asunto(s)
Arterias/fisiopatología , Plaquetas , Trombosis/fisiopatología , Animales , Modelos Animales de Enfermedad , PorcinosRESUMEN
The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34 +/- 4% in group 1, 38.8 +/- 5% in group 2, and 17.8 +/- 4% in group 3 (P less than 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration.
Asunto(s)
Arteriosclerosis/terapia , Colesterol en la Dieta/efectos adversos , Lipoproteínas HDL/administración & dosificación , Animales , Aorta/metabolismo , Arteriosclerosis/etiología , Arteriosclerosis/patología , Colesterol/sangre , Metabolismo de los Lípidos , ConejosRESUMEN
Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty and accelerated arteriopathy after cardiac transplantation. Previously, we reported that the macrolide antibiotic rapamycin, but not the related compound FK506, inhibits both human and rat aortic SMC proliferation in vitro by inhibiting cell cycle-dependent kinases and delaying phosphorylation of retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, and A.R. Marks. 1995. Circ. Res. 362:801). In the present study the effects of rapamycin on SMC migration were assayed in vitro using a modified Boyden chamber and in vivo using a porcine aortic SMC explant model. Pretreatment with rapamycin (2 ng/ml) for 48 h inhibited PDGF-induced migration (PDGF BB homodimer; 20 ng/ml) in cultured rat and human SMC (n = 10; P < 0.0001), whereas FK506 had no significant effect on migration. Rapamycin administered orally (1 mg/kg per d for 7 d) significantly inhibited porcine aortic SMC migration compared with control (n = 15; P < 0.0001). Thus, in addition to being a potent immunosuppressant and antiproliferative, rapamycin also inhibits SMC migration.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Inmunosupresores/farmacología , Músculo Liso/fisiología , Polienos/farmacología , Administración Oral , Secuencia de Aminoácidos , Animales , Aorta/citología , Secuencia de Bases , Northern Blotting , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Proteínas Portadoras/fisiología , Movimiento Celular/fisiología , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/fisiología , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/inmunología , Proteínas de Choque Térmico/fisiología , Humanos , Immunoblotting , Inmunosupresores/administración & dosificación , Datos de Secuencia Molecular , Músculo Liso/citología , Sistemas de Lectura Abierta , Factor de Crecimiento Derivado de Plaquetas/fisiología , Polienos/administración & dosificación , ARN/análisis , Ratas , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Sirolimus , Porcinos , Tacrolimus/farmacología , Proteínas de Unión a TacrolimusRESUMEN
Atherosclerotic disease is a pathological process characterized by the deposition of lipid and other blood-borne material within the arterial wall. The deposition of these materials and the subsequent thickening of the wall may significantly compromise the vessel lumen. Atherosclerosis is a diffuse disease with focal clinical manifestations that are the consequence of thrombotic complications on disrupted atherosclerotic lesions. Until recently, atherosclerosis development was envisaged as an incessant progressing process; however, new evidence has shown that atherosclerotic plaque homeostasis is not necessarily a constantly progressing process. There are many data showing that atherosclerotic plaque formation can be slowed, stopped or even reversed. Comprehension of the underlying mechanisms involved in the homeostasis of atherosclerotic plaque (progression/regression) should allow the development of interventions enhancing the regression pathway. Novel imaging technology has allowed the accurate evaluation of plaque progression, vital in the assessment of the efficacy of interventions. In this review we discuss the processes involved in the formation and progression of atherosclerotic lesions, the triggers for plaque disruption, as well as new therapies. We also deal with the potential pathways of plaque regression, as well as tools for accurate serial atherosclerotic quantification.
Asunto(s)
Aterosclerosis/patología , Trombosis/patología , Aterosclerosis/diagnóstico , Progresión de la Enfermedad , Humanos , Trombosis/diagnósticoRESUMEN
BACKGROUND: Platelet and endothelial production of nitric oxide (NO) is known to be impaired in coronary artery disease patients. Compounds that release NO (e.g. nitrates) have antiplatelet effects, but at supratherapeutic doses with hypotensive side effects. OBJECTIVES: To investigate the antithrombotic effect on human blood of a novel NO donor (LA419) with known anti-ischemic properties but without hypotensive side effects and to compare with abciximab. PATIENTS/METHODS: Healthy subjects (n = 8; 32 +/- 3 years) received daily aspirin starting three days prior to the study day. Treatments (LA419 10 and 20 microm, and abciximab 4 microm) were added ex vivo to non-anticoagulated blood, and the antithrombotic properties were assessed by measuring changes in thrombus size from pretreatment baseline in the Badimon perfusion chamber at low and high shear rates. Platelet surface adhesion using a Cone and Platelet Analyzer (CPA) and platelet fibrinogen-receptor activation with flow cytometry were also evaluated. RESULTS: At low shear rates, LA419 displayed a reduction in thrombus area of 43% +/- 8% (10 microm) and 56% +/- 6% (20 microm), whereas at high shear rates the reductions were 44% +/- 3% (10 microm) and 62% +/- 6% (20 microm). Platelet surface adhesion with the CPA was also reduced. Abciximab exhibited a strong inhibitory effect on thrombus formation, platelet surface adhesion and fibrinogen receptor activation. CONCLUSIONS: The novel NO donor, LA419, shows a strong antithrombotic effect in human blood, which is comparable to abciximab, especially under high shear rate conditions. Our observations suggest that the availability of an NO donor could prove beneficial in the prevention of thrombotic complications of cardiovascular disease. Further clinical studies are warranted.
Asunto(s)
Dinitrato de Isosorbide/análogos & derivados , Donantes de Óxido Nítrico/farmacología , Trombosis/prevención & control , Abciximab , Adulto , Anticuerpos Monoclonales/farmacología , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/farmacología , Técnicas In Vitro , Dinitrato de Isosorbide/farmacología , Masculino , Activación Plaquetaria/efectos de los fármacos , Adhesividad Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Receptores Fibrinógenos/efectos de los fármacosRESUMEN
BACKGROUND: Aspirin (ASA) + clopidogrel are commonly used in acute coronary syndrome (ACS), but persistent antiplatelet effects may complicate surgery. METHODS AND RESULTS: To study the possibility of normalizing platelet reactivity after ASA + clopidogrel treatment, 11 healthy subjects received a 325-mg ASA + clopidogrel loading dose (300 or 600 mg dependent on study arm), followed by 81 mg of ASA + 75 mg of clopidogrel daily for 2 days. Platelet reactivity was assessed by light transmittance aggregometry (LTA) [challenged by adenosine diphosphate (ADP), arachidonic acid (AA), collagen, and thrombin receptor activating peptide (TRAP)] and flow cytometry for platelet activation by GPIIb/IIIa receptor exposure pretreatment, 4 and 72 h postload. To normalize platelet reactivity, increasing amounts of pooled platelets from five untreated volunteers [volunteers (V)-platelet-rich plasma (PRP)] were added ex vivo to the subject's PRP (S-PRP). At both 4 and 72 h, 40% and 50% V-PRP were needed to overcome platelet disaggregation in the 300 or 600 mg arms, respectively, after ADP challenge; an additional 10% V-PRP fully normalized aggregation. Recovery of function was linear with each incremental increase of V-PRP. ADP-induced GPIIb/IIIa activation showed the same pattern as LTA (r = 0.74). Forty percent V-PRP was required to normalize platelet function to AA, collagen, and TRAP. CONCLUSION: Our results suggest that the pre-operative transfusion of 10 platelet concentrate units (the equivalent of 40% V-PRP) after a 300-mg clopidogrel loading or 12.5 units (50% V-PRP) after a 600 mg loading may adequately reverse clopidogrel-induced platelet disaggregation to facilitate postoperative hemostasis. An additional 2.5 units fully normalized platelet function. The potential clinical implications of our observations could include shorter hospitalizations and reduced bleeding complications. But these observations should be fully explored in an in vivo clinical setting with clopidogrel-treated patients before and after surgery.
Asunto(s)
Plaquetas/efectos de los fármacos , Enfermedad Coronaria/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Transfusión de Plaquetas , Plasma Rico en Plaquetas/efectos de los fármacos , Ticlopidina/análogos & derivados , Adenosina Difosfato/farmacología , Adulto , Ácido Araquidónico/farmacología , Aspirina/farmacología , Plaquetas/metabolismo , Clopidogrel , Colágeno/farmacología , Enfermedad Coronaria/fisiopatología , Enfermedad Coronaria/terapia , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Fibrinógeno/metabolismo , Humanos , Masculino , Proyectos Piloto , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pruebas de Función Plaquetaria , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Hemorragia Posoperatoria/prevención & control , Receptores de Trombina/metabolismo , Recuperación de la Función , Valores de Referencia , Ticlopidina/farmacología , Ticlopidina/uso terapéutico , Factores de TiempoRESUMEN
Plaque disruption and subsequent thrombus formation play a critical role in the clinical manifestations of atherothrombosis. Vulnerable lesions are characterized by the existence of core rich in lipid, macrophages and tissue factor (TF). Plaque disruption facilitates the interaction between flowing blood with the inner components (TF) of disrupted atherosclerotic lesions triggering the coagulation cascade. TF, thrombin, platelets, fibrin and inflammatory cells are involved in this process of acute thrombus formation. This pathologic process is significantly accelerated by several "cardiovascular risk factors" such as diabetes, smoking, dyslipemia, etc. We will review on the role of TF, plaque cell apoptosis and blood thrombogenicity acting as a thread of inflammatory and prothrombotic mediators. We will also review the role of activated platelets as source for pro-inflammatory cytokines and enunciation of thrombotic process. Overall, we will try to emphasize the most recent understanding of the concepts involved in the interaction between inflammation and coagulation within the setting of atherothrombotic disease.
Asunto(s)
Aterosclerosis/patología , Trombosis/patología , Animales , Apoptosis , Humanos , Inflamación , Trombina/metabolismo , Tromboplastina/metabolismoRESUMEN
Metabolic syndrome is characterized by the clustering of a number of metabolic abnormalities in the presence of underlying insulin resistance with a strong association with diabetes and cardiovascular disease morbidity and mortality. The disorder is defined in different ways, but the pathophysiology is attributable to insulin resistance. An increased release of free fatty acids (FFAs) from adipocytes block insulin signal transduction pathway, induce endothelial dysfunction due to increased reactive oxygen species (ROS) generation and oxidative stress. Dyslipidemia, associated with high levels of triglycerides and low concentrations of high density lipoproteins (HDLs), contributes to a proinflammatory state. Inflammation, the key pathogenic component of atherosclerosis, promotes thrombosis, a process that underlies acute coronary event and stroke. Tissue factor, a potent trigger of the coagulation cascade, is increased in diabetes with poor glycemic control. Therapeutic lifestyle changes (weight loss and physical activity) along with pharmacological interventions are recommended to prevent the complications of metabolic syndrome. In addition to statins, metformin, blood pressure lowering medications, interventions to increase HDLs are other important approaches to decrease the risk of cardiovascular disease. Furthermore, the peroxisome proliferator activated receptor (PPAR)-alpha and gamma agonists are potent anti-inflammatory and anti-atherogenic agents that could both improve insulin sensitivity and the long-term cardiovascular risk. In this review we focus on the molecular and pathophysiological basis of metabolic syndrome, which augments diabetes (insulin resistance) and the contribution of neovascularization in the plaque progression in diabetes, leading to rupture and coronary thrombosis.
Asunto(s)
Aterosclerosis/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/complicaciones , Síndrome Metabólico/complicaciones , Animales , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , Angiopatías Diabéticas/patología , Angiopatías Diabéticas/fisiopatología , Humanos , Síndrome Metabólico/patología , Síndrome Metabólico/fisiopatología , Síndrome Metabólico/terapia , Neovascularización PatológicaRESUMEN
Despite significant progress in the management of atherosclerosis and its resultant complications, cardiovascular disease remains the principal cause of death in the world. The National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III) recognizes low levels of high-density lipoprotein cholesterol (HDL) as a risk factor for coronary heart disease (CHD) and high levels of HDL as a risk-reducing factor; however, the elevation of HDL as a specific therapeutic target for the prevention and treatment of CHD has yet to be accepted on the same level as low-density lipoprotein (LDL)-reducing therapies. Current HDL elevators including nicotinic acid, fibric acid derivatives, peroxisome proliferator activated receptor (PPAR) agonists and statins also affect other lipid constituents which make interpretation of the clinical trials of these drugs difficult in teasing out the independent effect of HDL elevation. Ample laboratory investigation suggests that HDL elevation would reduce atherosclerotic burden through multiple independent mechanisms. In this review, we explore HDL biology, its potential mechanisms in the treatment of atherosclerotic disease, and promising new drugs with HDL-raising activity.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/terapia , HDL-Colesterol/metabolismo , Animales , Humanos , Metabolismo de los LípidosRESUMEN
Atherothrombotic vascular disease is a complex disorder in which inflammation and coagulation play a pivotal role. Rupture of high-risk, vulnerable plaques with the subsequent tissue factor (TF) exposure is responsible for coronary thrombosis, the main cause of unstable angina, acute myocardial infarction, and sudden cardiac death. Tissue factor (TF), the key initiator of coagulation is an important modulator of inflammation. TF is widely expressed in atherosclerotic plaques and found in macrophages, smooth muscle cells, extracellular matrix and acellular lipid-rich core. TF expression can be induced by various stimulants such as C-reactive protein, oxLDL, hyperglycemia and adipocytokines. The blood-born TF encrypted on the circulating microparticles derived from vascular cells is a marker of vascular injury and a source of procoagulant activity. Another form of TF, called alternatively spliced has been recently identified in human and murine. It is soluble, circulates in plasma and initiates coagulation and thrombus propagation. Evidence indicates that elevated levels of blood-borne or circulating TF has been associated with metabolic syndrome, type 2 diabetes and cardiovascular risk factors and is a candidate biomarker for future cardiovascular events. Therapeutic strategies have been developed to specifically interfere with TF activity in the treatment of cardiovascular disease.
Asunto(s)
Enfermedad de la Arteria Coronaria/etiología , Trombosis Coronaria/etiología , Diabetes Mellitus/metabolismo , Obesidad/metabolismo , Tromboplastina/fisiología , Enfermedad de la Arteria Coronaria/metabolismo , Trombosis Coronaria/metabolismo , Endotelio Vascular/metabolismo , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Obesidad/complicaciones , Tromboplastina/genéticaRESUMEN
BACKGROUND: Plaque disruption and subsequent thrombus formation lead to acute coronary syndromes and progression of atherosclerotic disease. Tissue factor (TF) appears to mediate plaque thrombogenicity. Tissue factor pathway inhibitor (TFPI) is the major physiological inhibitor of TF. This study analyzes the role of TF on thrombogenicity of disrupted human atherosclerotic plaques and the therapeutic possibilities of its specific inhibition. METHODS AND RESULTS: Human atherosclerotic and normal arterial segments were exposed to heparinized blood at flow conditions modeling medium-grade coronary stenosis in the Badimon perfusion chamber. The antithrombotic effects of the specific inhibition of plaque TF was assessed by reduction in the deposition of radiolabeled platelets and fibrin(ogen) and immunohistochemical analysis of perfused arteries. TF activity was inhibited by both recombinant TFPI and a polyclonal antibody against human TF. Human lipid-rich plaques were more thrombogenic than less advanced atherosclerotic plaques. Specific inhibition of TF activity reduced plaque thrombogenicity, inhibiting both platelet and fibrin(ogen) deposition (580 versus 194 plateletsx10(6)/cm2; P<0.01, and 652 versus 172x10(12) molecules of Fg/cm2; P<0.05, respectively) and thrombosis (immunohistochemistry). CONCLUSIONS: This study documents the key role of TF activity in acute arterial thrombosis after atherosclerotic plaque disruption and provides evidence of the benefit of blocking plaque TF activity. Therefore the inhibition of the TF pathway opens a new therapeutic strategy in the prevention of acute coronary thrombosis after plaque disruption.
Asunto(s)
Arteriosclerosis/complicaciones , Lipoproteínas/farmacología , Tromboplastina/antagonistas & inhibidores , Trombosis/prevención & control , Animales , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Plaquetas/fisiología , Cadáver , Humanos , Inmunohistoquímica , Metabolismo de los Lípidos , Persona de Mediana Edad , Perfusión , Proteínas Recombinantes , Valores de Referencia , Porcinos , Trombosis/etiologíaRESUMEN
BACKGROUND: Acyl-COA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters. The form of ACAT in macrophages, ACAT1, contributes to foam cell formation in the arterial wall and the development of atherosclerosis. Recent studies in a mouse model of atherosclerosis (the apolipoprotein E [apoE]-deficient mouse), however, have suggested that complete deficiency of ACAT1 activity is not antiatherogenic, in part because of toxicity resulting from adverse effects on tissue cholesterol homeostasis. We have tested whether partial inhibition of ACAT1 and ACAT2 (expressed in liver and intestine) activities reduces atherosclerosis development in apoE-deficient mice and avoids toxicity. METHODS AND RESULTS: ApoE-deficient mice were maintained for 17 weeks on a Western-type diet without (control) or with the ACAT inhibitor F-1394 (effective against ACAT1 and ACAT2) at doses of either 300 (low) or 900 (high) mg/kg. Intimal lesion area at the aortic sinus in controls was 0.69+/-0.06 mm(2). F-1394 treatment significantly decreased lesional area by 39% (low) or 45% (high). F-1394 treatment also reduced lesional immunostaining for macrophages by 61% (low) or 83% (high). En face analysis showed that surface lipid staining in control aortas was 20.0+/-2.8%; F-1394 treatment reduced this by 46% (low) or 62% (high). There were no obvious signs of systemic or vessel wall toxicity associated with F-1394 treatment. CONCLUSIONS: Partial ACAT inhibition by F-1394 had antiatherogenic effects in apoE-deficient mice that were achieved without obvious toxicity. Partial ACAT inhibition may have therapeutic potential in the clinical treatment of atherosclerosis.
Asunto(s)
Apolipoproteínas E/deficiencia , Arteriosclerosis/prevención & control , Ciclohexanos/farmacología , Dioxanos/farmacología , Inhibidores Enzimáticos/farmacología , Esterol O-Aciltransferasa/antagonistas & inhibidores , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Apolipoproteínas E/genética , Arteriosclerosis/enzimología , Arteriosclerosis/patología , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Femenino , Modelos Lineales , Metabolismo de los Lípidos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esterol O-Aciltransferasa/metabolismo , Túnica Íntima/efectos de los fármacos , Túnica Íntima/patologíaRESUMEN
BACKGROUND: Although percutaneous transluminal coronary angioplasty (PTCA) is a highly effective procedure to reduce the severity of stenotic coronary atherosclerotic disease, its long-term success is significantly limited by the high rate of restenosis. Several cellular and molecular mechanisms have been implicated in the development of restenosis post-PTCA, including vascular smooth muscle cell (VSMC) activation, migration, and proliferation. Recently, our group demonstrated that rapamycin, an immunosuppressant agent with antiproliferative properties, inhibits both rat and human VSMC proliferation and migration in vitro. In the present study, we investigated (1) whether rapamycin administration could reduce neointimal thickening in a porcine model of restenosis post-PTCA and (2) the mechanism by which rapamycin inhibits VSMCs in vivo. METHODS AND RESULTS: PTCA was performed on a porcine model at a balloon/vessel ratio of 1.7+/-0.2. Coronary arteries were analyzed for neointimal formation 4 weeks after PTCA. Intramuscular administration of rapamycin started 3 days before PTCA at a dose of 0.5 mg/kg and continued for 14 days at a dose of 0.25 mg/kg. Cyclin-dependent kinase inhibitor (CDKI) p27(kip1) protein levels and pRb phosphorylation within the vessel wall were determined by immunoblot analysis. PTCA in the control group was associated with the development of significant luminal stenosis 4 weeks after the coronary intervention. Luminal narrowing was a consequence of significant neointimal formation in the injured areas. Rapamycin administration was associated with a significant inhibition in coronary stenosis (63+/-3.4% versus 36+/-4.5%; P<0.001), resulting in a concomitant increase in luminal area (1.74+/-0.1 mm2 versus 3. 3+/-0.4 mm2; P<0.001) after PTCA. Inhibition of proliferation was associated with markedly increased concentrations of the p27(kip1) levels and inhibition of pRb phosphorylation within the vessel wall. CONCLUSIONS: Rapamycin administration significantly reduced the arterial proliferative response after PTCA in the pig by increasing the level of the CDKI p27(kip1) and inhibition of the pRb phosphorylation within the vessel wall. Therefore, pharmacological interventions that elevate CDKI in the vessel wall and target cyclin-dependent kinase activity may have a therapeutic role in the treatment of restenosis after angioplasty in humans.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Proteínas de Ciclo Celular , Vasos Coronarios/patología , Sirolimus/farmacología , Proteínas Supresoras de Tumor , Túnica Íntima/patología , Animales , División Celular/efectos de los fármacos , Movimiento Celular , Enfermedad Coronaria/etiología , Enfermedad Coronaria/metabolismo , Enfermedad Coronaria/patología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/lesiones , Vasos Coronarios/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Fosforilación , Ratas , Proteína de Retinoblastoma/metabolismo , Porcinos , Túnica Íntima/efectos de los fármacos , Túnica Íntima/lesiones , Túnica Íntima/metabolismoRESUMEN
BACKGROUND: High-resolution MRI has the potential to noninvasively image the human coronary artery wall and define the degree and nature of coronary artery disease. Coronary artery imaging by MR has been limited by artifacts related to blood flow and motion and by low spatial resolution. METHODS AND RESULTS: We used a noninvasive black-blood (BB) MRI (BB-MR) method, free of motion and blood-flow artifacts, for high-resolution (down to 0.46 mm in-plane resolution and 3-mm slice thickness) imaging of the coronary artery lumen and wall. In vivo BB-MR of both normal and atherosclerotic human coronary arteries was performed in 13 subjects: 8 normal subjects and 5 patients with coronary artery disease. The average coronary wall thickness for each cross-sectional image was 0.75+/-0.17 mm (range, 0.55 to 1.0 mm) in the normal subjects. MR images of coronary arteries in patients with >/=40% stenosis as assessed by x-ray angiography showed localized wall thickness of 4.38+/-0.71 mm (range, 3.30 to 5.73 mm). The difference in maximum wall thickness between the normal subjects and patients was statistically significant (P<0.0001). CONCLUSIONS: In vivo high-spatial-resolution BB-MR provides a unique new method to noninvasively image and assess the morphological features of human coronary arteries. This may allow the identification of atherosclerotic disease before it is symptomatic. Further studies are necessary to identify the different plaque components and to assess lesions in asymptomatic patients and their outcomes.
Asunto(s)
Enfermedad Coronaria/patología , Vasos Coronarios/anatomía & histología , Vasos Coronarios/patología , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Artefactos , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Tests developed to monitor glycoprotein (GP) IIb/IIIa blockade do not properly reflect platelet function in vivo and need a baseline (pretreatment) value. Because GP IIb/IIIa is essential in platelet aggregation and thrombosis under shear conditions, a flow-dependent approach to monitor its inhibition can be used. METHODS AND RESULTS: We compared a test based on flow-dependent platelet deposition, the Cone and Platelet Analyzer (CPA), with in vitro platelet aggregometry and the Rapid Platelet Function Assay (RPFA) on platelet function after GP IIb/IIIa inhibition. In vitro, increasing concentrations of abciximab (0% to 100% receptor occupancy) were tested. Ex vivo, platelet function was monitored with the CPA and with aggregometry for up to 1 week after abciximab administration. The CPA was better correlated with the percentage of free GP IIb/IIIa receptors than was aggregometry or the RPFA. Only the RPFA, when expressed as a ratio over baseline (pretreatment), was comparable to the CPA. Ex vivo, the CPA, but not aggregometry, showed prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade in the first week after abciximab administration. CONCLUSIONS: Platelet function assessment by shear-induced deposition is a reliable test to monitor a wide range of GP IIb/IIIa inhibition. Its accuracy does not require a baseline reference. The effects of GP IIb/IIIa blockade on platelet function should be examined under high shear conditions.