In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement.
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OBJECTIVES: The purpose of this study was to target acoustically reflective liposomes to atherosclerotic plaques in vivo for ultrasound image enhancement. BACKGROUND: We have previously demonstrated the development of acoustically reflective liposomes that can be conjugated for site-specific acoustic enhancement. This study evaluates the ability of liposomes coupled to antibodies specific for different components of atherosclerotic plaques and thrombi to target and enhance ultrasonic images in vivo. METHODS: Liposomes were prepared with phospholipids and cholesterol using a dehydration/ rehydration method. Antibodies were thiolated for liposome conjugation with N-succinimidyl 3-(2-pyridyldithio) propionate resulting in a thioether linkage between the protein and the phospholipid. Liposomes were conjugated to antifibrinogen or anti-intercellular adhesion molecule-1 (anti-ICAM-1). In a Yucatan miniswine model, atherosclerosis was developed by crush injury of one carotid and one femoral artery and ingestion of a hypercholesterolemic diet. After full plaque development the arteries were imaged (20-MHz intravascular ultrasound catheter and 7.5-MHz transvascular linear probe) after injection of saline, unconjugated liposomes and antibody conjugated liposomes. RESULTS: Conjugated liposomes retained their acoustically reflective properties and provided ultrasonic image enhancement of their targeted structures. Liposomes conjugated to antifibrinogen attached to thrombi and fibrous portions of the atheroma, whereas liposomes conjugated to anti-ICAM-1 attached to early atheroma. CONCLUSIONS: Our data demonstrate that this novel acoustic agent can provide varying targeting with different antibodies with retention of intravascular and transvascular acoustic properties. (+info)
Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling.
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OBJECTIVES: The purpose of this study was to assess the effects of L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) on neointimal hyperplasia and vascular remodeling after balloon angioplasty in the hypercholesterolemic rabbit. BACKGROUND: Restenosis after balloon angioplasty is a consequence of both neointimal hyperplasia and vessel remodeling. Nitric oxide inhibits neointimal hyperplasia, but its effect on vessel remodeling is unknown. METHODS: Six weeks after induction of bilateral iliac atherosclerosis, 48 rabbits underwent successful angioplasty in 75 vessels. Eight rabbits (acute group) were sacrificed immediately after angioplasty. The remaining animals received either placebo (chronic control group), or a diet supplemented with either L-arginine (1.5 g/kg/day), or L-NAME (15 mg/kg/day) for 4 weeks after angioplasty. RESULTS: The intimal area was significantly greater in the chronic control group compared to the acute group (2.60+/-1.03 mm2 vs. 1.35+/-0.62 mm2). This increase in intimal area was lower in the L-arginine group (1.79+/-0.61 mm2), and greater in the L-NAME group (3.23+/-0.92 mm2). The area circumscribed by the internal elastic lamina (IEL) increased significantly in the control group compared to the acute group (from 2.52+/-0.66 to 3.33+/-0.85 mm2); a more marked increase occurred in the L-NAME group (3.90+/-0.85 mm2). By contrast, IEL area was unchanged in the L-arginine group (2.41+/-0.62 mm2). As a result, there was no significant difference in lumen area after 4 weeks in the chronic groups (control: 0.74+/-0.38 mm2; L-arginine: 0.50+/-0.43 mm2; L-NAME: 0.48+/-0.42 mm2). CONCLUSIONS: Our results demonstrate that L-arginine inhibits whereas L-NAME stimulates neointimal hyperplasia after experimental balloon angioplasty in the hypercholesterolemic rabbit. However, the lack of vessel enlargement in the L-arginine group resulted in a similar final lumen size in the L-NAME and L-arginine groups. (+info)
Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis.
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Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid beta peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders. (+info)
Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction.
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BACKGROUND: Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P-induced tPA release in vivo in humans. METHODS AND RESULTS: Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively. CONCLUSIONS: Cigarette smoking causes marked inhibition of substance P-induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity. (+info)
Mechanisms of death in the CABG Patch trial: a randomized trial of implantable cardiac defibrillator prophylaxis in patients at high risk of death after coronary artery bypass graft surgery.
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BACKGROUND: The CABG Patch trial compared prophylactic implantable cardiac-defibrillator (ICD) implantation with no antiarrhythmic therapy in coronary bypass surgery patients who had a left ventricular ejection fraction <0.36 and an abnormal signal-averaged ECG. There were 102 deaths among the 446 ICD group patients and 96 deaths among the 454 control group patients, a hazard ratio of 1.07 (P=0.63). The mechanisms of death were classified, and hypotheses were tested about the effects of ICD therapy on arrhythmic and nonarrhythmic cardiac deaths in the CABG Patch Trial and the Multicenter Automatic Defibrillator Implantation Trial (MADIT). METHODS AND RESULTS: The 198 deaths in the trial were reviewed by an independent Events Committee and classified by the method of Hinkle and Thaler. Only 54 deaths (27%) occurred out of hospital; 145 deaths (73%) were witnessed. Seventy-nine (82%) of the 96 deaths in the control group and 76 (75%) of the 102 deaths in the ICD group were due to cardiac causes. Cumulative arrhythmic mortality at 42 months was 6.9% in the control group and 4.0% in the ICD group (P=0. 057). Cumulative nonarrhythmic cardiac mortality at 42 months was 12. 4% in the control group and 13.0% in the ICD group (P=0.275). Death due to pump failure was significantly associated with death >1 hour from the onset of symptoms, dyspnea within 7 days of death, and overt heart failure within 7 days of death. CONCLUSIONS: In the CABG Patch Trial, ICD therapy reduced arrhythmic death 45% without significant effect on nonarrhythmic deaths. Because 71% of the deaths were nonarrhythmic, total mortality was not significantly reduced. (+info)
Oxidized low-density lipoprotein as a delivery system for photosensitizers: implications for photodynamic therapy of atherosclerosis.
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Photodynamic therapy is a promising new strategy in the treatment of cardiovascular diseases. Photodynamic therapy for vascular diseases may be improved by the specific delivery of photosensitizers to the atherosclerotic lesion. In this study, we studied whether oxidatively modified low-density lipoprotein (OxLDL) could be used as a specific carrier for photosensitizers, thereby using the scavenger receptor expressed on macrophages as a target. The photosensitizer aluminum phthalocyanine chloride (AlPc) was incorporated into OxLDL, and its photodynamic effects were studied. Macrophages (RAW 264.7) were incubated with various concentrations of OxLDL-AlPc for different periods. After illumination of the cells with red light, cytotoxicity was observed that was dependent on the time of illumination and incubation. Macrophages incubated with OxLDL-AlPc that were not illuminated revealed no cytotoxicity. The uptake of the OxLDL-AlPc complexes was mediated by scavenger receptors expressed on macrophages. In the presence of the polyanion polyinosinic acid, a specific ligand for scavenger receptors, no cytotoxicity could be observed. Serum incubations of the OxLDL-AlPc complexes revealed that these complexes stay intact after incubation. No redistribution of AlPc to other plasma (lipo-) proteins could be detected, and 80-90% of the AlPc remained associated with the OxLDL particle. These results indicate that OxLDL may function as a specific delivery system for photosensitizers to the scavenger receptors expressed on the macrophages in the atherosclerotic lesion, increasing the beneficial effects of photodynamic therapy for cardiovascular diseases. (+info)
Is normal pregnancy atherogenic?
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Serum cholesterol, triacylglycerols and low-density lipoprotein (LDL) subfractions were determined in 120 primagravid women during normal gestation (40 in each trimester) and in 20 non-pregnant age-matched controls. LDL subfractions were determined by PAGE, and an LDL score was calculated. The higher the score, the smaller the subfractions. The objective of the study was to determine the effects of the hyperlipidaemia, high oestrogen concentrations and insulin resistance known to exist in normal pregnancy on LDL subfraction formation. Pregnant women had an increased mean serum cholesterol concentration [5.78 (S.D. 1.09) mmol/l] in the first trimester compared with the non-pregnant controls [5.11 (0.77) mmol/l; P<0.01]. The serum cholesterol concentration increased progressively throughout gestation to a mean of 8.14 (1.39) mmol/l in the third trimester (P<0.001 compared with the second trimester). Triacylglycerol concentrations in the first trimester were similar to those of controls, and there was a non-significant increase by the second trimester to 1.32 (0.44) mmol/l. However, by the third trimester the mean triacylglycerol concentration had doubled [2.58 (0.98) mmol/l; P<0.001 compared with the first and second trimester]. During gestation the LDL score increased dramatically, from 1.17 (0.39) during the first trimester to 2.01 (0.37) in the second trimester (P<0.001) to 2.73 (0.48) in the third trimester (P<0.001 compared with the second trimester). Thus an atherogenic lipid profile develops during normal gestation. The significance of these changes remains unclear, but thay may have important implications for mother and foetus. (+info)
Serum lipoprotein(a) and apolipoprotein(a) phenotypes in patients with rheumatoid arthritis.
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OBJECTIVE: To determine serum lipoprotein(a) (Lp[a]) concentrations and to analyze the apolipoprotein(a) (Apo[a]) phenotype in patients with rheumatoid arthritis (RA). METHODS: The subjects included 131 patients with RA and 200 healthy control subjects. Serum Lp(a) concentrations were measured by enzyme-linked immunosorbent assay, and the Apo(a) phenotype was determined by immunoblotting. HLA-DR typing was also done. RESULTS: The mean serum Lp(a) level was significantly higher (P < 0.001) in the RA patients (27.5 mg/dl) than in the controls (15.0 mg/dl). The S3 allele was found in 70.0% of the patients versus 39.5% of the controls (P < 0.001). There was no significant difference in HLA-DR4 positivity between patients with and without the S3 phenotype. CONCLUSION: The serum Lp(a) level was increased in patients with RA, possibly partly because of S3 phenotype predominance. (+info)