摘要:

Background Coronary artery thrombosis plays an important pathophysiological role in unstable angina and non-Q-wave myocardial infarction. To date, heparin and thrombolytic therapy has not provided complete or consistent benefit. We hypothesized that recombinant hirudin, a direct thrombin inhibitor, would prevent accumulation of coronary artery thrombus in a manner superior to heparin.=60% stenosis of a culprit coronary artery or saphenous vein graft with visual appearance of thrombus were randomized to one of two different doses of heparin (either a target activated partial thromboplastin time (aPTT) of 65 to 90 or 90 to 110 seconds) or one of four doses of hirudin (0.05, 0.10, 0.20, or 0.30 mg x kg sup -1 x h sup -1 infusion) in a dose-escalating protocol. After 72 to 120 hours of study drug, a repeat coronary angiogram was obtained, and the paired studies underwent quantitative analysis. The primary end point was change in the average cross-sectional area of the culprit lesion. Other efficacy end points also involved changes in culprit lesion dimensions and TIMI flow grade. Recombinant hirudin led to a dose-dependent elevation of aPTT that appeared to plateau at the 0.2-mg/kg dose. A higher proportion of hirudin-treated patients had their aPTT within a 40-second range (16% heparin versus 71% hirudin, P<.001). Overall, the 116 patients treated with hirudin tended to show more improvement than the 50 patients receiving heparin relative to the primary efficacy variable--the average cross-sectional area (P=.08)--as well as minimal cross-sectional area (P=.028), minimal luminal diameter (P=.029), and percent diameter stenosis (P=.07).Conclusions Recombinant hirudin appears to be a promising antithrombotic intervention compared with heparin for inhibition of coronary artery thrombus. Large-scale comparative trials are warranted. (Circulation. 1994;89:1557-1566.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The success of streptokinase in acute myocardial infarction is hampered by the high failure rate to achieve early reperfusion. This study evaluates the possible benefit of Hirulog (Biogen, Cambridge, Mass), a direct thrombin inhibitor, as adjunct therapy to streptokinase to enhance early patency and prevent rethrombosis. Heparin has been shown to be of very limited benefits in this setting.Methods and Results Forty-five patients were randomized to Hirulog or heparin (2:1 ratio). Coronary angiography documented a TIMI 2 or 3 flow after 90 minutes in 77% of the patients treated with Hirulog and streptokinase and in 47% of patients treated with heparin and streptokinase (P<.05) and after 120 minutes in 87% and 47% of patients, respectively (P<.01). TIMI 3 flow was established in 77% of patients with Hirulog compared with 40% with heparin (P<.02). The clinical outcome and the bleeding rate were also favorable to Hirulog; no reocclusion was observed at late angiography performed 4.7 days later.Conclusions Hirulog in this pilot study significantly improved the early patency rate of the infarct-related artery with a favorable clinical profile. This new direct thrombin inhibitor exhibits promise as adjunctive therapy to thrombolysis. (Circulation. 1994;89:1567-1572.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Plasma endothelin concentrations are increased in the acute phase of myocardial infarction and in chronic heart failure. Since endothelin may contribute to hemodynamic deterioration by potent vasoconstrictory and cardiotoxic actions, increased plasma levels may be associated with an unfavorable prognosis after myocardial infarction.Methods and Results We tested the hypothesis that plasma endothelin determination in the subacute phase of myocardial infarction is related to subsequent survival and assessed whether plasma endothelin measurements provide additional prognostic information to that obtained from clinical and biochemical variables previously known to be associated with high mortality. Plasma endothelin determination was obtained from 142 patients (average age +-SD, 67.8+-10.1 years) on day 3 after documented myocardial infarction and was related to 1-year mortality. Sixteen patients died during the follow-up period. In a univariate Cox proportional-hazards model, day 3 plasma endothelin concentrations were significantly related to mortality (P<.0001). Patient age, previous treatment for systemic hypertension, presence of clinical heart failure, and plasma atrial natriuretic factor levels were all related to mortality in univariate analysis but provided no additional prognostic information to that obtained from endothelin determination in a multivariate model.Conclusions Plasma endothelin concentrations are strongly related to outcome after myocardial infarction and provide prognostic information independent of clinical and biochemical variables previously associated with a poor prognosis. (Circulation. 1994;89:1573-1579.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction.Methods and Results The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts.Conclusions The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF. (Circulation 1994;89:1580-1586)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Previous studies have shown the feasibility of peripheral arterial ultrasound angioplasty.Methods and Results In this report, we describe the use of percutaneous therapeutic ultrasound for coronary angioplasty. In vitro, 11 postmortem, atherosclerotically occluded coronary arteries were obtained to assess catheter-delivered ultrasound for arterial recanalization as well as for assessment of the size of particulate debris. Clinically, coronary ultrasound angioplasty was performed in 19 patients (mean age, 56 years) to assess safety and feasibility for the treatment of obstructive coronary atherosclerosis. Three patients with unstable angina and 16 with exercise-induced myocardial ischemia were treated with a prototype 4.6F coronary catheter ultrasound ablation device with a 1.7-mm diameter ball tip. The ultrasound coronary catheter delivered ultrasound energy at 19.5 kHz, with a power output of 16 to 20 W at the transducer. Energy is delivered in a pulsed mode with a 50% duty cycle of 30 milliseconds. Patients were treated for a mean of 493 seconds (range, 130 to 890) with intracoronary ultrasound ablation. All lesions were treated with adjunctive balloon angioplasty. All 11 postmortem coronary occlusions were recanalized, and 99% of the particulates generated were <10 microns in diameter. We found that after ultrasound, mean (+-SD) coronary arterial stenosis fell from 80+-12% to 60+-18% (P<.001) and to 26+-11% (P<.001) after adjunctive balloon angioplasty. Mean pressures required to achieve full balloon inflation were 2.7 atm (range, 1 to 5.5) with a median of 3.0-mm balloon size (2.5 to 3.5). No ultrasound-related complications were identified.Conclusions Intracoronary ultrasound plaque ablation appears to be safe. Our findings suggest that catheter-delivered high-intensity, low-frequency ultrasound may be useful for lesion debulking and enhancing arterial distensibility, allowing balloon dilation at relatively low pressures. (Circulation. 1994;89:1587-1592.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The purpose of the study was to investigate the relation of lipoprotein(a) and serum lipid parameters to restenosis after percutaneous transluminal coronary angioplasty (PTCA) and to assess the association of these same biochemical markers to coronary artery disease (CAD) in individuals with angiographically defined normal and diseased coronary arteries.Methods and Results Sixty-two patients with successful PTCA had follow-up angiography at 35+-10 weeks. Restenosis occurred in 21 male patients (46%) and 6 female patients (38%). Elevated apolipoprotein B (P<.01) and decreased high-density lipoprotein-2 cholesterol (P<.02) were found to be independently associated with restenosis after angioplasty, whereas lipoprotein(a) was not.Eighty-five patients undergoing PTCA were compared with 46 subjects who had no evidence of CAD on angiography. Elevated lipoprotein(a) (P<.001) and reduced apolipoprotein A1 to B ratio (P<.001) were found to be strong independent risk factors for the presence of CAD when adjustment was made for age (P<.005), male sex (P<.01), smoking (P<.005), and hypertension (P=.06).Conclusions Serum lipoprotein(a) levels are not associated with restenosis after PTCA, but elevated levels are strongly associated with CAD. Low-serum, high-density lipoprotein-2 cholesterol concentration and elevated apolipoprotein B concentration were found to be associated with restenosis after PTCA. (Circulation. 1994;89:1593-1598.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Tissue-type plasminogen activator (TPA) is the principal activator of plasminogen. Since hemostasis in the microcirculation of allografts is a well-recognized complication of transplantation, we asked (1) whether the distribution and amount of cellular TPA in biopsies of transplanted human hearts are associated with fibrin deposits in and around the microcirculation, (2) whether such changes involve the physiological inhibitors of TPA and plasmin, and (3) whether the presence of these activators and inhibitors of fibrinolysis in tissue is correlated with clinical outcome.Methods and Results We immunocytochemically quantified the presence of fibrin, plasmin, TPA, and the TPA inhibitor PAI-1 in 938 biopsies from 68 consecutive cardiac allografts over a 54-month period. The localization, distribution, and quantification of TPA in arteriolar smooth muscle cells revealed that 35 of the 68 allografts maintained vascular TPA reactivity consistent with time-zero biopsies of autologous donor hearts: this was designated as the normal TPA group. In contrast, 33 of the 68 allografts significantly lost vascular TPA reactivity compared with time-zero biopsies of autologous donor hearts: this was designated as the depleted TPA group. Analysis of sequential biopsies from both groups during 54 months revealed that the mean cumulative quantitative TPA value for the normal TPA group was 1.0+-0.01, whereas the depleted TPA group value was 1.9+-0.02 (P=.0001), and the mean cumulative quantitative fibrin value for the normal TPA group was 1.0+-0.01, whereas the depleted TPA group value was 1.5+-0.05 (P=.0001). Biopsies of allografts in the depleted TPA group contained endothelial reactivity for TPA-PAI-1 complexes, whereas biopsies from the normal TPA group did not. Plasmin-associated molecules were rarely identified in biopsies of the normal TPA group but were present in the depleted TPA group, and the fibrin-to-plasmin ratio in the normal TPA group always was less than the fibrin-to-plasmin ratio in biopsies from the depleted TPA group. Analysis of demographic and risk factors revealed no significant differences between patients in the normal and depleted TPA groups, but none of the 35 patients in the normal TPA group died or were retransplanted, and 13 of the 33 patients in the depleted TPA group died or required retransplantation (P=.0001).Conclusions Time-zero hearts (n=68) and 34 of 38 stable allografts contained immunocytochemically detectable TPA only in vascular smooth muscle cells. Twenty-nine of 30 patients with normal TPA in their time-zero biopsies who subsequently developed a poor clinical outcome were found to have depleted TPA in biopsies evaluated during their first postoperative month and remained depleted throughout the study. Of 33 patients with depleted TPA, 39% died or required retransplantation. Depleted arteriolar TPA associated significantly with vascular and interstitial deposits of fibrin, plasmin, and endothelial TPA-PAI-1 complexes. These findings indicate that hemostatic and fibrinolytic pathways are activated in failing allografts, and they reveal evidence of depleted TPA before clinical or histopathological signs of failure. Patients with such allografts were found to be at high risk of death independently of other widely used clinical/laboratory parameters of prediction. (Circulation. 1994;89:1599-1608.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Since organic nitroesters and endothelium-derived nitric oxide mediate vasodilation through a final common pathway, that is, by activation of soluble guanylate cyclase in vascular smooth muscle, nitroglycerin (NTG) could specifically enhance the endothelium-dependent vasodilatory response to acetylcholine (Ach) in patients with congestive heart failure (CHF) and endothelial cell dysfunction. Accordingly, the net effects of an intra-arterial infusion of NTG (10 sup -9 mol/L) on endothelium-dependent and endothelium-independent vasodilation were assessed in the forearm circulation of patients with CHF.Methods and Results The forearm blood flow responses to intra-arterial administration of graded concentrations of Ach (10 sup -7 to 10 sup -5 mol/L) were determined by venous occlusion plethysmography (mL/min per 100 mL) in 18 patients with CHF and 5 age-matched normal subjects before and during intra-arterial infusion of NTG (10 sup -9 mol/L) for 20 minutes. In eight patients, the duration of the infusion of NTG (n=5) or vehicle control solution (n=3) was extended to 12 hours with measurement of the forearm blood flow responses to Ach at 20 minutes, 4 hours, and 12 hours. In five additional patients, forearm blood flow response to intra-arterial administration of two doses of phentolamine (0.05 and 0.5 mg) were determined before and during a 20-minute NTG infusion. Regional administration of NTG 10 sup -9 mol/L did not change resting forearm blood flow in either normal subjects or patients with CHF. Before administration of NTG 10 sup -9 mol/L, intra-arterial infusions of Ach 10 sup -7, 10 sup -6, and 10 sup -5 mol/L increased forearm blood flow to 14.7+-6.2, 20.2+-4.7, and 38.4+-7.9 mL/min per 100 mL in normal subjects and to 4.1+-0.8, 5.0+-1.1, and 10.6+-2.3 mL/min per 100 mL in patients with CHF. After administration of NTG 10 sup -9 mol/L for 20 minutes, the vasodilatory response to Ach significantly increased to 5.6+-1.0, 6.9+-1.6, and 17.7+-3.4 mL/min per 100 mL in patients with CHF but did not change in normal subjects. The enhanced forearm blood flow responses to administration of Ach observed after 20 minutes of NTG administration in patients with CHF were sustained throughout a 12-hour NTG infusion. In contrast, regional administration of NTG did not change the vasodilatory responses to phentolamine.Conclusions NTG, when administered intra-arterially for 20 minutes at a dose that does not affect resting forearm blood flow, specifically increased the vasodilatory response to intra-arterial administration of Ach in patients with CHF but not in normal subjects. The vasodilatory response to Ach was consistently enhanced by low-dose NTG throughout a 12-hour period. The vasodilating effects of organic nitroesters on the peripheral vasculature of patients with CHF may result in part from an interaction with the vascular endothelium. (Circulation. 1994;89:1609-1614.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of l-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis.Methods and Results Acetylcholine (10 sup -6, 10 sup -5, 10 sup -4 mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of l-arginine (10 mg x kg sup -1 x min sup -1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n=14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of l-arginine (10 sup -4 mol/L, -6.8% versus -2.8%; P<.01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with l-arginine (at a dose of 10 sup -4 mol/L, +121% versus 176%; before versus after l-arginine, P<.002).Conclusions The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. l-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by l-arginine is more likely in vessels with normal wall morphology. (Circulation. 1994;89: 1615-1623.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Patients with advanced heart failure have bioenergetic abnormalities of skeletal muscle metabolism during exercise. Using Phosphorus-31 magnetic resonance spectroscopy, we sought to determine whether skeletal metabolic responses to exercise are normalized by orthotopic cardiac transplantation.6 months (mean, 15 months) after transplant (n=8). None of the posttransplant patients had biopsy evidence of rejection at the time of study. There were no significant differences in age, preoperative functional class, or symptom duration among the three patient groups. Metabolic responses were monitored in the dominant arm during incremental weight pull exercise and 10 minutes of recovery by Phosphorus-31 magnetic resonance spectroscopy, with measurement of pH and the phosphocreatine (PCr)/(PCr+inorganic phosphate (Pi)) ratio, an index of PCr concentration. In addition, based on recovery data, the rate of PCr resynthesis was calculated as a measure of oxidative metabolism that is independent of work level, recruitment, or muscle mass, and the effective maximal rate of mitochondrial ATP synthesis (Vmax) was determined. Analysis was by ANOVA. There were no differences between groups in pH or PCr/(PCr+Pi) at rest. Compared with the normal control group, the pretransplant group had a decreased exercise duration (11.3+-2.5 versus 15.0+-1.3 minutes, P=.02), a lower submaximal exercise PCr/(PCr+Pi) ratio (0.58+-0.11 versus 0.76+-0.08, P<.05), a reduced PCr resynthesis rate (13+-6 versus 22+-9 mmol/L per minute, P<.05), and a lower calculated Vmax(26+-14 versus 53+-26 mmol/L per minute, P<.05). In the group studied early after transplantation, all the changes noted in the pretransplant group persisted and were if anything somewhat worse. In the group studied late after transplantation, there was a significant improvement in the PCr resynthesis rate compared with the early-posttransplant group (27+-6 late versus 15+-6 mmol/L per minute early, P<.05) and statistically nonsignificant trends toward improvements in submaximal exercise pH (6.86+-0.24 late versus 6.72+-0.24 early) and submaximal PCr/(PCr+Pi) ratio (0.56+-0.14 late versus 0.44+-0.15 early) and Vmax(45+-21 late versus 33+-15 mmol/L per minute early). However, compared with normal subjects, exercise duration and submaximal PCr/(PCr+Pi) were still reduced in the late-posttransplant group.Conclusions Despite successful heart transplantation, skeletal muscle abnormalities of advanced heart failure persist for indefinite periods, although partial improvement occurred at late times. The persistent abnormalities may contribute to the reduced exercise capacity that is present in most patients after transplantation. (Circulation. 1994;89:1624-1631.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID