ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundMethylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine.Methods and ResultsTo assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations (< 15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater (P < .05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels greater or equal to 15.4 nmol/L.ConclusionsIndividuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons. (Circulation. 1996;93:7-9.)Key Wordsenzymes, homocysteine, amino acids, metabolism, genetics.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundProstacyclin is an important vasoprotective molecule. It inhibits platelet aggregation, monocyte interaction with endothelium, and smooth muscle cell lipid accumulation. Vascular cyclooxygenase-1 (COX-1) is the rate-limiting step in prostacyclin synthesis. The objective of this study was to determine whether adenovirus-mediated transfer of COX-1 could restore COX-1 activity, augment prostacyclin synthesis, and prevent thrombus formation in a porcine carotid angioplasty model.Methods and ResultsHuman COX-1 cDNA driven by a cytomegalovirus promoter was constructed into a replication-defective adenovirus 5 vector by homologous recombination. Recombinant adenovirus without a foreign gene (Ad-RR) and buffer were included as controls. Recombinant Ad-LacZ was used for marking the transfected cells in vivo. In the in vitro experiments, cultured human endothelial cells (ECs) and porcine arterial smooth muscle cells (SMCs) were incubated with Ad-COX-1 for 2 hours and 6-keto-PGF1alpha level and the transgene expression were determined 72 hours after infection. In the in vivo experiments, recombinant adenoviruses were directly instilled into angioplasty-injured porcine carotid arteries for 30 minutes. Cyclic flow changes were monitored for 10 days and thrombus formation was examined histologically thereafter. Transgene expression and prostaglandin I2(PGI2) synthesis by the injured arteries were determined. Cultured ECs infected with Ad-COX-1 produced a fivefold to eightfold increase in PGI2, and the transgene expression in cultured porcine SMCs was demonstrated by Northern analysis. Direct administration of Ad-COX-1 at a dose of 3 x 1010pfu completely inhibited carotid cyclic flow changes and thrombus formation accompanied by a fourfold increase in PGI2synthesis by the injured arteries 10 days after infection, whereas Ad-COX-1 at a lower dose, 5 x 109pfu, had no antithrombotic effects when compared with Ad-RR vector and buffer controls.ConclusionsAdenovirus-mediated transfer of COX-1 to angioplasty-injured carotid arteries was efficacious in augmenting PGI2synthesis and was associated with an inhibition of thrombosis when a relatively high titer of adenovirus was instilled. (Circulation. 1996;93:10-17.)Key Wordsthrombosis, prostaglandins, gene transfer, angioplasty.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundAfter experimental angioplasty, partial or complete reendothelialization of the denuded surface occurs; the function of the regenerated endothelium has, however, been shown to be abnormal. Basic fibroblast growth factor (bFGF) is mitogenic for endothelial cells in vitro and in vivo. We investigated whether chronic administration of bFGF in a rabbit model of balloon denudation might not only improve endothelial regrowth but also restore normal physiological responses to endothelium-dependent agonists.Methods and ResultsThirty-nine New Zealand White rabbits underwent balloon denudation of the right iliac artery. Twenty rabbits received intravenous administration of bFGF (2.5 micro gram twice a week for 2 weeks). Nineteen rabbits receiving saline injections served as controls. Animals were killed on day 28 for assessment of reendothelialization and neointimal thickening and for analysis of in vitro vasoreactivity. Animals in the bFGF group had a significantly (P < .005) greater degree of reendothelialization than controls (115 plus/minus 13 versus 55 plus/minus 6 mm2). Neointimal thickening was similar in the two groups. Four weeks after denudation, endothelium-independent responses did not differ significantly between the two groups. In contrast, the maximal endothelium-dependent acetylcholine-induced relaxation of the bFGF-treated animals (Emax, 40 plus/minus 7%) was significantly greater than that of the control group (Emax, 11 plus/minus 9%; P < .05).ConclusionsSystemic administration of bFGF restores, in large part, the responses of previously denuded arterial segments to endothelium-dependent vasodilators. Angiogenic growth factors may help to reestablish normal endothelial cell function in patients who have undergone angioplasty. (Circulation. 1996;93:18-22.)Key Wordsendothelium, angioplasty, growth substances, vasodilation.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundCardiac reperfusion initiates release of inositol 1,4,5-triphosphate [Ins(1,4,5)P3] and arrhythmogenesis via norepinephrine stimulation of alpha1-adrenergic receptors. The present study examines arrhythmogenic effects of thrombin-stimulated Ins(1,4,5)P3release under these conditions.Methods and Results[sup 3 H]Ins(1,4,5)P3release was measured in [sup 3 H]inositol-labeled rat hearts by high-performance liquid chromatography. Arrhythmia studies were performed in buffer-perfused rat hearts. Two-minute reperfusion after 20 minutes of global ischemia increased [sup 3 H]Ins(1,4,5)P3from 1123 plus/minus 77 to 2238 plus/minus 44 cpm/mg tissue. No increase was observed in catecholamine-depleted hearts (755 plus/minus 89 cpm/mg). The addition of thrombin (5 IU/mL) or thrombin receptor agonist peptide (TRAP1-6, 50 micro mol/L) restored the reperfusion Ins(1,4,5)P3response (thrombin, 1518 plus/minus 68 cpm/mg and TRAP1-6, 1755 plus/minus 128 cpm/mg). Ins(1,4,5)P3release initiated by norepinephrine or thrombin was inhibited by gentamicin (150 micro mol/L; 986 plus/minus 52 and 868 plus/minus 125 cpm/mg, respectively). The thrombin response was inhibited by the phospholipase C inhibitor U-73122 (5 micro mol/L; 394 plus/minus 59 cpm/mg) but not by its inactive isomer U-73343. The norepinephrine response was not inhibited by U-73122 (2126 plus/minus 74 cpm/mg). Ventricular tachycardia and ventricular fibrillation were observed in intact hearts but not in hearts from catecholamine-depleted rats (ventricular fibrillation duration, 110 plus/minus 19 versus 0 plus/minus 0 seconds). The addition of thrombin or TRAP1-6 increased arrhythmias in catecholamine-depleted hearts (112 plus/minus 32 and 89 plus/minus 28 seconds, respectively). Gentamicin and U-73122 but not U-73343 prevented thrombin-induced arrhythmias. Gentamicin inhibited norepinephrine-initiated arrhythmias, but U-73122 was ineffective.ConclusionsThis study demonstrates that the development of reperfusion arrhythmias under these conditions depends on the release of Ins(1,4,5)P3. (Circulation. 1996;93:23-26.)Key Wordsarrhythmia, enzymes, receptors, adrenergic, alpha, thrombin, inositol phosphates.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundSince 1989, New York State has disseminated comparative information on outcomes of coronary bypass surgery to the public. It has been suggested that this program played a significant role in the 41% decrease in the risk-adjusted mortality rate between 1989 and 1992. We hypothesized that some high-risk patients had migrated out of state for surgery.Methods and ResultsWe reviewed 9442 isolated coronary bypass operations performed from 1989 through 1993 to assess referral patterns of case-mix and outcome. Expected and risk-adjusted mortality rates were computed using logistic regression models derived from the Cleveland Clinic and New York State databases. A mortality comparison was performed using the 1980 to 1988 time period as a historical control. Patients from New York (n = 482) had a higher frequency of prior open heart surgery (44.0%) than patients from Ohio (n = 6046) (21.5%, P < .001), other states (n = 1923) (37.4%, P = .008), and other countries (n = 991) (17.3%, P < .001). They were also more likely to be in NYHA functional class III or IV (47.6% versus Ohio 42.7%, P = .037; other states, 41.2%, P = .011; other countries, 34.1%, P = .001). The expected mortality rate was thus higher than among other referral cohorts. The observed 5.2% mortality rate among these patients was significantly greater than the 2.9%, 3.1%, and 1.4% mortality rates observed for patients from Ohio (P = .004), other states (P = .028), and other countries (P < .001). These differences in outcome were not apparent between 1980 and 1988 among referrals from within the United States.ConclusionsPublic dissemination of outcome data may have been associated with increased referral of high-risk patients from New York to an out-of-state regional medical center. (Circulation. 1996;93:27-33.)Key Wordsmortality, bypass, coronary disease, surgery, revascularization.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundProgression of coronary artery disease is assumed to be a surrogate end point for clinical coronary events. Because no single method or measure for a coronary angiographic end point is uniformly accepted as optimal, the utility and validity of surrogate end points for predicting clinical coronary events remain unsettled.Methods and ResultsThe Cholesterol Lowering Atherosclerosis Study randomized 162 nonsmoking, 40- to 59-year-old men with previous coronary artery bypass graft surgery to colestipol/niacin plus diet or placebo plus diet. Atherosclerosis change on 2-year coronary angiograms was evaluated by a consensus panel and by quantitative coronary angiography (average per-subject change in percent diameter stenosis [%S] and minimum lumen diameter [MLD]). With all three end points, the benefit of colestipol/niacin treatment on coronary artery atherosclerosis has been reported. Annual follow-up for an average of 7 years (range, 6.3 months to 10 years) has been carried out on all subjects who completed the 2-year angiogram. Clinical coronary events (need for revascularization, nonfatal acute myocardial infarction, and coronary death) have been documented. Risk of clinical coronary events was positively related to coronary lesion progression for all three surrogate end points (P < .05). New lesion formation in bypass grafts (P = .02) and progression of mild/moderate lesions (< 50%S) were predictive of clinical coronary events (P < .01). Change in MLD contributed significantly to the prediction of clinical coronary events beyond a model with %S alone (P < .05).ConclusionsIn this population of nonsmoking men with previous bypass surgery, both the consensus panel- and quantitative coronary angiography-based end points of coronary artery disease progression predict clinical coronary events. Subjects who demonstrate greater coronary artery lesion progression have an increased risk of future clinical coronary events. Design of shorter, smaller trials of antiatherosclerotic agents is justified. (Circulation. 1996;93:34-41.)Key Wordsangiography, atherosclerosis, follow-up studies, coronary disease.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundThe long-term clinical effects of smoking and smoking cessation after venous coronary bypass surgery have not been well established.Methods and ResultsFour hundred fifteen patients who underwent venous coronary bypass surgery between April 1976 and April 1977 were followed up prospectively for 15 years. Multivariate Cox survival analysis revealed that patients who smoked at the time of surgery had no elevated risks for clinical events compared with nonsmokers. However, smoking behavior at 1 and 5 years after surgery appeared to be an important predictor of clinical events during the subsequent follow-up period. Compared with patients who stopped smoking since surgery, smokers at 1 year after surgery had more than twice the risk for myocardial infarction and reoperation. Patients who were still smoking at 5 years after surgery had even more elevated risks for myocardial infarction and reoperation and a significantly increased risk for angina pectoris compared with patients who stopped smoking since surgery and patients who never smoked. Patients who started to smoke again within 5 years after surgery had increased risks for reoperation and angina pectoris. No differences in outcome were found between patients who stopped smoking since surgery and nonsmokers.ConclusionsOur results show that smoking cessation after coronary bypass surgery may have important beneficial effects on clinical events during long-term follow-up. (Circulation. 1996;93:42-47.)Key Wordssmoking, bypass, follow-up studies.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

BackgroundMyocardial salvage is most likely to occur when thrombolytic therapy is administered within 4 to 6 hours of the onset of symptoms of myocardial infarction. The impact of delays within this early time period on final myocardial infarct size are unknown. The purpose of this study was to quantitate the relation between final myocardial infarct size and duration of symptoms before initiation of thrombolytic therapy in patients treated within 6 hours of symptom onset.Methods and ResultsThe findings from patients in four prospective randomized trials of thrombolytic therapy were combined for analysis. The study population consisted of 432 patients presenting within 6 hours of onset of symptoms of first acute myocardial infarction who met ECG criteria that allowed estimation of myocardial area at risk before treatment with thrombolytic therapy and who had thallium-201 myocardial infarct--size measurements performed several weeks after infarction. ECG analysis revealed no difference in myocardium at risk for infarction as a function of duration of symptoms before initiation of thrombolytic therapy. In contrast, univariate and multivariate analysis showed that final infarct size was highly dependent on duration of symptoms before initiation of therapy. Each 30-minute increase in symptom duration before thrombolytic therapy was associated with an increase in infarct size of 1% of the myocardium. Final infarct size in patients treated 4 to 6 hours after symptom onset was indistinguishable from patients who did not receive thrombolytic therapy.ConclusionsThese findings suggest that for patients treated within 4 to 6 hours of the onset of symptoms, there is a progressive decline in the extent of myocardium salvaged as the duration of symptoms before therapy increases. These results support efforts to minimize the time delay between symptom onset and initiation of reperfusion therapy in all eligible patients. (Circulation. 1996;93:48-53.)Key Wordsmyocardial infarction, thrombolysis, reperfusion.

ISSN:0009-7322    

出版商:OVID    

年代:1996

数据来源: OVID