ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundCurrently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus, we have identified a systemically active peptide analogue (DMP 728) of the arginine- glycine-aspartic acid (RGD) recognition sequence that mediates the binding of ligands such as fibrinogen to the platelet glycoprotein (GP) IIb/I11a receptors. The goals of the present study were to determine the antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models.Methods and ResultsDMP 728 demonstrated antiplatelet efficacy in vitro in inhibiting ADP-induced human platelet aggregation (IC50, 46±2 nmol/L) and fibrinogen binding to human platelets (IC50, 2.3±0.8 nmol/L) or purified human GPIIb/IIIa receptors (IC50, 0.6±0.1 nmol/L). DMP 728 demonstrated high affinity and specificity for human platelet GPIb/IIIa over other adhesion molecules. In anesthetized mongrel dogs, DMP 728 at 0.001 to 1.0 mg/kg IV produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and in prolonging template bleeding time. DMP 728 effects on bleeding time prolongation were more rapidly reversible than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 0.01 mg/kg IV bolus. The antithrombotic efficacy of DMP 728 was examined in vitro and in vivo after IV administration at different doses in various models of arterial thrombosis. In the coronary artery Folts model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV bolus with an ED50of 0.005 mg/kg IV bolus in inhibiting cyclic flow reductions. Additionally, DMP 728 demonstrated 100% prevention of primary thrombosis and rethrombosis (P< .01) after treatment with different thrombolytics, including tissue plasminogen activator and streptokinase, in an electrolytically induced femoral artery thrombosis model in dogs.ConclhsionsAcute intravenous DMP 728 administration (0.001 to 1.0 mg/kg) has dose-dependent antiplatelet and antithrombotic effects in different arterial thrombosis models. These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an effective antithrombotic agent in coronary and peripheral artery thromboembolic disorders.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundComplexing recombinant DNA with cationic liposomes is a convenient means of introducing foreign genes into cells (lipofection) and could potentially form the basis for genetically modifying diseased blood vessels in patients. The mechanism of lipofection is incompletely understood, but it is recognized that the degree of successful gene transfer is highly dependent on cell type. To date, there has been no reported experience with lipofection of human vascular smooth muscle cells.Methods and ResultsPrimary cultures of human vascular smooth muscle cells were transfected under optimized conditions with a plasmid expressing either firefly luciferase (Luc) or nuclear-localized β-galactosidase (NL-,βgal). Cells were derived from either normal human internal mammary arteries n=6), fragments of primary atherosclerotic plaque (n=4), or fragments of restenotic lesions (n=5). Concurrent lipofection of rabbit vascular smooth muscle cells and NIH 3T3 cells was performed as well. Cultures derived from 15 patients all demonstrated positive expression of the reporter gene. Compared with NIH 3T3 cells, however, expression in human vascular smooth muscle cells was markedly reduced: in cells derived from internal mammary artery, Luc expression, normalized for protein content, was 123-fold lower than in NIH 3T3 cells, whereas the proportion of cells expressing NL-β-gal was 30-fold lower. Luc expression in cells derived from restenotic tissue was significantly greater than from cells derived from primary plaque (P< .03). Within a given population of cells, the mitotic index of cells expressing the recombinant gene was significantly higher than the mitotic index for the total population of cells (P< .05). Finally, cotransfection experiments, in which lipofection of smooth muscle cells was performed using genes for NL-β-gal and for human growth hormone, showed that among positive transfectants, a high proportion of cells (23% to 36%) coexpressed both genes.ConclusionsThe efficiency of successful lipofection in human vascular smooth muscle cells in vitro is low. Transfection appears to be preferentially facilitated in cells derived from restenotic tissue, and specific properties of smooth muscle cells, including growth rates, appear to be critical for successful transfection. Further elucidation of cell properties that promote transfection is required to augment the efficiency of liposome-mediated gene transfer in human vascular cells.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundWe have previously described two distinct mutations in the β-myosin heavy chain gene with markedly different clinical presentations and outcome: The 908Ieu→valmutation was associated with a low disease penetrance and a benign prognosis. In contrast, the 403Arg→Glnmutation in a Caucasian kindred was associated with a 100% disease penetrance and high incidence of sudden cardiac death. Recently, another mutation, 606val→Met, has been reported to be associated with “near normal survival” and offered as evidence for the benign nature of neutral charge substitutions.Methods and ResultsWe report (1) a large kindred (245 family members at risk of inheriting the disease gene) with a 256Gly→Glumutation characterized by a similar disease penetrance in adults and in children (56% and 60%, respectively) and a cumulative sudden cardiac death rate of only 2% at 50 years of age, (2) a kindred with the 606Val→Metmutation with four sudden cardiac deaths in eight affected individuals, and (3) a Korean kindred with the 403Arg→Ginmutation. Although the disease occurred early and was associated with a high prevalence of myocardial ischemia in both of our kindreds with the 403Arg→Ginmutation, no sudden cardiac death or syncope has occurred in the Korean kindred. Furthermore, in the Caucasian kindred, all patients had nonobstructive hypertrophic cardiomyopathy, but most of the patients in the Korean kindred had left ventricular outflow obstruction.ConclusionsThe conclusions are as follows: (1) Although several sudden cardiac deaths are sufflicient to establish that a mutation is malignant, study of a large kindred is necessary to be certain that a mutation is benign. To date, only the 908Leu→Valand the 256Gly→Glumutations satisfy this requirement. (2) The 256Gly→Glumutation demonstrates that not all mutations that result in a charge change are malignant. (3) Conversely, the 606Val→Metmutation is malignant in some kindreds; hence, despite the absence of a charge change, minor substitutions in critical regions of 3-myosin heavy chain protein may also have serious consequences. (4) The diverse ethnic origins of the two 403Arg→Ginkindreds provide evidence suggesting that the identical mutation occurred independently and was associated with different genetic backgrounds. Their distinct phenotypes underline the importance of modifying genes and nongenetic factors.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundRibonuclease (RNase) protection has been used to identify β-cardiac myosin heavy chain (MHC) gene mutations that cause familial hypertrophic cardiomyopathy (FHC). Since more than 10 different mutations within this gene have been demonstrated to cause FHC in unrelated individuals, the genetic diagnosis of this condition will involve screening the β-MHC gene. The accuracy with which RNase protection identifies such mutations is critical to defining the utility of this methodology in detecting mutations that cause FHC.Methods and ResultsTwelve unrelated individuals with FHC were selected for further study because their β-MHC genes had been screened for mutations by use of RNase protection, and no mutation was found. We performed linkage analysis of the families of these 12 probands using polymorphic short tandem repeats within the β-MHC gene to determine whether FHC was genetically linked to the MHC locus on chromosome 14. FHC was not genetically linked to the MHC locus in 11 families whose β-cardiac MHC gene did not contain mutations detectable by RNase protection.ConclusionsWe conclude that RNase protection is a sensitive method for screening for mutations within the α-cardiac MHC gene. Further, mutations in the noncoding regions of the β-MHC gene and mutations in the α-cardiac MHC gene are not a common cause of FHC. Negative RNase protection assays of affected individuals suggest that their FHC is due to mutations at other loci.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundThe study was designed to verify the concept of plaques “at risk” and whether inflammation could play a role in plaque rupture and thrombosis. Methods and Results In 20 patients who had died of acute myocardial infarction, the thrombosed arteryMethods and ResultsIn 20 patients who had died of acute myocardial infarction, the thrombosed coronary artery was identified and the site of plaque rupture was traced in serial sections. The cellular characteristics of the fibrous cap at the immediate site of rupture were analyzed and compared with the adjacent cap tissue by use of monoclonal antibodies reactive with macrophages, T lymphocytes, and smooth muscle cells. A deep intimal rupture, extending into the lipid core, was encountered in 12 plaques, whereas 8 had superficial erosions only. Ten atherosclerotic plaques had a distinctly attenuated fibrous cap covering a large atheroma, 7 showed a thick fibrocellular cap overlying a lipid pool, and 3 showed a fibrocellular lesion without a clear lipid core. Macrophages, and to a lesser extent T lymphocytes, were the dominant cells at the immediate site of either rupture or superficial erosion in each instance. These sites, moreover, were always characterized by abundant expression of HLA-DR antigens on both inflammatory cells and adjacent smooth muscle cells, suggesting an active inflammatory reaction. In terms of overall cellular composition of the ruptured plaques, the dominant cell types were macrophages and T cells in 11, smooth muscle cells in 3, and mixtures of both in 6.ConclusionsThe underlying atherosclerotic plaque morphology in complicated coronary artery lesions causing acute myocardial infarction is heterogeneous with respect to both plaque architecture and cellular composition. However, the immediate site of plaque rupture or erosion is always marked by an inflammatory process. This suggests that inflammation plays a role in destabilizing the fibrous cap tissue and, thus, in enhancing the risk of coronary thrombosis.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundIn patients with angiographically detectable atherosclerosis or in those with risk factors for coronary artery disease, intracoronary acetylcholine causes coronary constriction instead of endothelium-derived relaxing factor-mediated dilation. Therefore, it has been hypothesized that diffuse endothelial dysfunction precedes development of coronary atherosclerosis. We tested this hypothesis in a systematic investigation of the effects of ascending doses of acetylcholine on the diameters of nonstenotic segments of the left coronary artery in patients with advanced atherosclerosis and coronary risk factors.Methods and ResultsEffects of intracoronary infusion of acetylcholine (10−6to 10−4mol/L) on diameters of proximal, middle, and distal nonstenotic segments of the left coronary artery were studied in 28 consecutive patients with chronic stable angina, positive exercise tests, and angiographic evidence of obstructive atherosclerosis (≥50% reduction in lumen diameter in at least one vessel). Two patterns of response to the maximal acetylcholine dose (10−4mol/L) were observed. In 21 patients (group 1), only constriction was observed in all left anterior descending and circumflex artery segments studied (16±3%, 19±4%, and 23±4%, respectively;P< .01 compared with control). In 7 other patients (group 2), both constriction and dilation were observed in adjacent segments of the same vessel; maximal acetylcholine dose caused constriction in 14 left anterior descending artery segments from a control diameter of 1.94±0.19 to 1.33±0.26 mm (37% reduction,P< .01) and dilation in 16 other segments from 1.63±0.22 to 1.93±0.21 mm (25% increase,P< .01). In the circumflex artery, this dose caused constriction in 16 segments from a control diameter of 1.88±0.14 to 1.33±0.17 mm (31% reduction,P< .01) and dilation in 12 segments from 1.37±0.12 to 1.71±0.09 mm (34% increase,P< .01).ConclusionsIn 25% of patients studied with advanced angiographic coronary atherosclerosis and coronary risk factors, coronary segments with acetylcholine-inducible dilatation are present. In these patients, the endothelium is not diffusely dysfunctional as currently believed but rather shows marked segmental heterogeneity in the response to acetylcholine reflecting degrees of endothelial dysfunction.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundEstrogen administration in postmenopausal women is associated with a 50% reduction in the clinical manifestations of coronary artery disease. The mechanisms are not known, although one potential explanation is estrogen-induced modulation of coronary vasoreactivity. Acetylcholine is an endo-thelium dependent vasodilator that may be used to assess coronary vasoreactivity and elicits coronary responses that parallel those found with common daily vasomotor stimuli. Therefore, we tested whether estrogen attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.Methods and ResultsAcetylcholine-induced changes in coronary flow, resistance, and cross-sectional area were determined before and 15 minutes after intravenous administration of ethinyl estradiol (EE, 35, ug) in 15 postmenopausal women. The influence of estrogen on basal coronary flow, resistance, and epicardial cross-sectional area was also assessed by measuring these parameters before and after EE or placebo administration in 33 women. Estrogen altered basal coronary vasomotor tone in 22 women as manifested by an EE-induced 23.3 ± 4.5% (mean ± SEM) increase (P < .01) in coronary flow, a 15.0 ± 3.2% decrease (P < .01) in resistance, and a 20.0 ± 6.5% increase (P = .02) in epicardial cross-sectional area. Placebo administration in 11 women did not change these parameters. Estrogen also attenuated abnormal coronary vasomotor responses to acetylcholine. Seven women who exhibited a paradoxical acetylcholine-induced decrease in coronary flow (− 33.5 ± 12.3%, P < .01) and increase in resistance (38.9 ± 14.1%, P = .05) and seven who had an abnormal acetylcholine-induced decrease in epicardial cross-sectional area (− 14.2 ± 4.4%; P = .04) did not have acetylcholine-induced changes in these parameters after EE administration. Acetylcholine induced flow, resistance, and cross-sec-tional area responses before and after EE were significantly different (P < .01, P = .02, and P = .02, respectively). Normal coronary responses to acetylcholine were not affected by EE administration.ConclusionsEE attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. EE also decreases basal coronary vasomotor tone as manifested by increased coronary flow, decreased resistance, and in-creased epicardial cross-sectional area. These acute effects of estrogen on coronary vasoreactivity may explain, in part, the cardioprotective effects of estrogen in postmenopausal women.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundAfter thrombolytic therapy, long-term patency of the infarct-related artery may reduce arrhythmias, limit ventricular dilatation, and provide collaterals to another in-farct zone if further infarction occurs. However, independent long-term prognostic value of infarct artery patency has not been shown.Methods and ResultsWe followed 312 patients with first myocardial infarction treated < 4 hours after pain onset with thrombolysis (streptokinase [n=188] or recombinant tissue-type plasminogen activator [n=124]). At 28±11 days, cardiac catheterization was performed. Flow of the infarct-related artery was assessed by the TIMI scoring system, and a scoring system relating coronary stenoses and flow to the amount of myocardium supplied was also used. Follow-up was for 39 + 13 months. Cardiac death occurred in 5.8% of patients, and there were two noncardiac deaths. Revascularization was performed in 11.5% of patients. On univariate and multivariate analysis, ventricular function (ejection fraction,P= .006 and .02, or end-systolic volume index,P= .01 and .06) was the most important prognostic factor. Patency of the infarct-related artery measured as TIMI 3 flow was marginally significant on univariate analysis (P= .08) but not on multivariate analysis (P= .2). Patency was an independent prognostic factor in univariate and multivariate analysis when measured as an occlusion score (amount of myocardium supplied by an oc-cluded artery,P= .01 and < .05). When the ejection fraction was .50%, only occluded arteries supplying > 25% of the left ventricle affected prognosis adversely. If the ejection fraction was < 50%, occluded arteries supplying < 25% of myocardium also adversely affected prognosis. Treadmill exercise duration 4 weeks after infarction was the only other prognostic factor identified.ConclusionsVentricular function and infarct-related artery patency are independent prognostic factors after thrombolytic therapy for acute myocardial infarction.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundLeft ventricular enlargement after myocardial infarction increases the likelihood of an adverse outcome. In an echocardiographic substudy of the Survival and Ventricular Enlargement (SAVE) Trial, we assessed whether captopril would attenuate progressive left ventricular enlargement in patients with left ventricular dysfunction after acute myocardial infarction and, if so, whether this would be associated with improved clinical outcome.Methods and ResultsTwo-dimensional transthoracic echocardiograms were obtained in 512 patients at a mean of 11.1±3.2 days after infarction and were repeated at 1 year in 420 survivors. Left ventricular size was assessed as left ventricular cavity areas at end diastole and end systole and left ventricular function as percent change in cavity area from end diastole to end systole. Patients were randomly assigned to placebo or captopril, and the incidence of adverse cardiovascular events consisting of cardiovascular death, heart failure requiring either hospitalization or open-label angiotensinconverting enzyme inhibitor therapy, and recurrent infarction were determined over a follow-up period averaging 3.0±0.6 years. Irrespective of treatment assignment, baseline left ventricular systolic area and percent change in area were strong predictors of cardiovascular mortality and adverse cardiovascular events. At 1 year, left ventricular end-diastolic and end-systolic areas were larger in the placebo than in the captopril group (P= .038,P= .015, respectively), and percent change in cavity area was greater in the captopril group (P= .005). One hundred eleven of the 420 1-year survivors with l-year echo measurements (26.4%) experienced a major adverse cardiovascular event, and these patients had more than a threefold greater increase in left ventricular cavity areas than those with an uncomplicated course. Sixty-nine patients with adverse cardiovascular events were in the placebo group compared with 42 patients in the captopril-treated group (a risk reduction of 35%,P= .010).ConclusionsTwo-dimensional echocardiography provides important and independent prognostic information in patients after infarction. Left ventricular enlargement and function after infarction are associated with the development of adverse cardiac events. Attenuation of ventricular enlargement with captopril in these patients was associated with a reduction in adverse events. This study demonstrates the linkage between attenuation of left ventricular enlargement by captopril after infarction and improved clinical outcome.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID