ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundRemnant lipoproteins are atherogenic, but assays of remnants have not been available in routine clinical laboratories because of the lack of practical and validated methods. A simple and reliable method for such an assay, using an immunochemical approach, has recently been developed. This study prospectively examined whether remnant lipoprotein levels in fasting serum, measured by our method, may have prognostic value in patients with coronary artery disease (CAD).5.1 mg cholesterol/dL; 75th percentile of distribution of remnant levels) than in those with the lowest tertile of remnant levels (<or=to3.3 mg cholesterol/dL; 50th percentile of the distribution). Higher levels of remnants were a significant and independent predictor of developing coronary events in multivariate Cox hazard analysis including the following covariates: extent of coronary artery stenosis, age, sex, smoking, hypertension, diabetes mellitus, hypercholesterolemia, low HDL cholesterol, and hypertriglyceridemia.ConclusionsHigher levels of remnant lipoproteins in fasting serum predict future coronary events in patients with CAD independently of other risk factors. Thus, measurement of fasting remnant levels, assessed by the current immunoseparation method, may be helpful in assessment of CAD risk. (Circulation. 1999;99:2858-2860.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundPlatelet-activating effects have been reported with high-dose heparin in acute thrombotic disorders. Recent studies have shown that increased platelet aggregation is due to reduced nitric oxide (NO) production in endothelial cells cultured in the presence of high-dose heparin. The aim of this study was to determine whether heparin can affect the NO pathway and the regulation of the vascular tone in vivo.Methods and Results-Anesthetized and mechanically ventilated Sprague-Dawley rats were treated with high-dose heparin. After 4 hours, the endothelial constitutive NO synthase (ecNOS) protein content in the aorta decreased (36% reduction, P<0.05), as detected by immunoblotting, and NO-dependent vascular reactivity was impaired. In fact, the increase in mean arterial blood pressure after inhibition of ecNOS with NG-nitro-L-argininemethyl ester (30 mg/kg) was smaller in heparin-treated animals than in controls (+26.9 +/- 4.8 versus +48.3 +/- 9.1 mm Hg, P<0.05), and further infusion of the biological ecNOS substrate L-arginine (0.5 g/kg) was ineffective in reversing systemic vasoconstriction (-1% versus 28% vasodilatation, P<0.001).ConclusionsHigh-dose heparin can significantly affect vascular reactivity in vivo by downregulation of ecNOS protein expression. (Circulation. 1999;99:2861-2863.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundCoronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm.Methods and Results-We searched for the possible mutations in the endothelial nitric oxide synthase (eNOS) gene in patients with coronary spasm. In this study, we demonstrate the existence of 3 linked mutations in the 5[prime]-flanking region of the eNOS gene (T-786[right arrow]C, A-922[right arrow]G, and T-1468[right arrow]A). The incidence of the mutations was significantly greater in patients with coronary spasm than in the control group (P<0.0001). Multiple logistic regression analysis with forward stepwise selection using the environmental risk factors and the eNOS gene variant revealed that the most predictive independent risk factor for coronary spasm was the mutant allele (P<0.0001). As assessed by luciferase reporter gene assays, the T-786[right arrow]C mutation resulted in a significant reduction in eNOS gene promoter activity (P<0.05), whereas neither the A-922[right arrow]G nor the T-1468[right arrow]A mutation had any affect.ConclusionsTaken together, these findings strongly suggest that the T-786[right arrow]C mutation in the eNOS gene reduces the endothelial NO synthesis and predisposes the patients with the mutation to coronary spasm. (Circulation. 1999;99:2864-2870.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundEarly stages of coronary atherosclerosis are characterized by a mainly functional impairment of coronary vasodilator capacity under the impact of such risk factors as hypercholesterolemia. The goal of this study was to determine whether 6-month cholesterol-lowering therapy improves coronary flow reserve in patients with angina, reduced flow reserve despite minimally diseased coronary vessels or even normal angiogram, and mild to moderately elevated LDL levels on average.Methods and Results-We noninvasively investigated 23 consecutive patients (18 men, 5 women; mean age, 56 +/- 7.6 years) with a mean LDL level of 165 +/- 34 mg/dL at baseline by PET for myocardial blood flow measurement with [(13) N]ammonia at rest and under dipyridamole stress (0.56 mg/kg) before and after lipid-lowering therapy with simvastatin for 6 months. Between baseline and the 6-month follow-up, total cholesterol concentration fell from 241 +/- 44 to 168 +/- 34 mg/dL, and the LDL level decreased from 165 +/- 34 to 95 +/- 26 mg/dL (P<0.001). Overall, coronary flow reserve increased from 2.2 +/- 0.6 to 2.64 +/- 0.6 (P<0.01). Maximal coronary flow increased significantly from 182 +/- 36 to 238 +/- 58 mL/minx100 g (P<0.001) at follow-up. Minimum coronary resistance declined significantly from 0.51 +/- 0.12 to 0.40 +/- 0.14 mm Hg[middle dot]mL-1[middle dot]minx100 g (P<0.001). Concomitantly, a regression of anginal symptoms was observed in most patients.ConclusionsOur results suggest that cholesterol-lowering therapy with simvastatin may improve overall coronary vasodilator capacity assessed noninvasively by PET in patients with mild to moderate hypercholesterolemia. Consequently, intensive lipid-lowering therapy is considered a vasoprotective treatment for selected patients in very early stages of coronary atherosclerosis with the potential of preventing further disease progression. (Circulation. 1999;99:2871-2875.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundGlycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) may play an important role in inflammation, because it can hydrolyze the GPI anchors of several inflammatory membrane proteins (eg, CD106, CD55, and CD59) and its hydrolytic products upregulate macrophage cytokine expression (eg, interleukin-1 and tumor necrosis factor-alpha). Because of its potential regulatory role in inflammatory reactions, we hypothesized that GPI-PLD might be expressed in atherosclerosis.Methods and Results-Immunohistochemistry using human GPI-PLD-specific rabbit polyclonal antiserum was performed on a total of 83 nonatherosclerotic and atherosclerotic human coronary arteries from 23 patients. Macrophages, smooth muscle cells, apoA-I, and oxidation epitopes also were identified immunohistochemically. Cell-associated GPI-PLD was detected in 95% of atherosclerotic segments, primarily on a subset of macrophages. Extracellular GPI-PLD was present in only 30% of atherosclerotic segments and localized to regions with extracellular apoA-I. In contrast, GPI-PLD was not detected in nonatherosclerotic segments. Expression of GPI-PLD mRNA by human macrophages was confirmed in vitro by reverse transcription/polymerase chain reaction. Further studies demonstrated that GPI-PLD-positive plaque macrophages contained oxidation epitopes, suggesting a link between oxidant stress and GPI-PLD expression. This possibility was supported by studies in which exposure of a macrophage cell line to H2O (2) led to a 50 +/- 3% increase in steady-state GPI-PLD mRNA levels.ConclusionsCollectively, these results suggest that oxidative processes may regulate GPI-PLD expression and suggest a role for GPI-PLD in inflammation and in the pathogenesis of atherosclerosis. (Circulation. 1999;99:2876-2882.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundSome animal studies suggest that transforming growth factor-beta (TGF-beta) protects vessels from atherosclerosis by preventing intima formation, but others indicate a role in vessel proteoglycan accumulation and lipoprotein retention. To distinguish between these possibilities in humans, immunohistochemical studies were performed examining the coexpression of TGF-beta isoforms and the TGF-beta receptors ALK-5 and T beta R-II in aorta during the various stages of atherosclerotic lesion development.Methods and Results-The spatial relationships between TGF-beta1, TGF-beta (3), ALK-5, and T beta R-II expression were compared in aortic segments from 21 subjects. Nonatherosclerotic intima contained predominantly TGF-beta1, low concentrations of T beta R-II, and barely detectable amounts of ALK-5. In contrast, fatty streaks/fibrofatty lesions contained high concentrations of both TGF-beta isoforms. Smooth muscle cells (SMCs), macrophages, and foam cells of macrophage and SMC origin contributed to these high levels. These lesions also contained high, colocalized concentrations of ALK-5 and T beta R-II. Despite fibrous plaques containing TGF-beta1, its receptors were at detection limits. We found no evidence for truncated T beta R-II expression in either normal intima or the various atherosclerotic lesions.ConclusionsTGF-beta appears to be most active in lipid-rich aortic intimal lesions. The findings support the hypothesis that TGF-beta contributes primarily to the pathogenesis of lipid-rich atherosclerotic lesions by stimulating the production of lipoprotein-trapping proteoglycans, inhibiting smooth muscle proliferation, and activating proteolytic mechanisms in macrophages. (Circulation. 1999;99:2883-2891.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID