Biomedical subjects

L W Gimple

Publications and source records attributed to L W Gimple.

At least 55 records · Page 3Linked to original sources

PubMed1993

Thrombin-induced mitogenesis of vascular SMC is partially mediated by autocrine production of PDGF-AA.

Previous studies have shown that alpha-thrombin (Thr) is a mitogen for cultured smooth muscle cells (SMC), but controversy exists concerning mechanisms of growth stimulation. The purpose of these studies was to determine whether autocrine production of platelet-derived growth factor-AA (PDGF-AA) mediated Thr-induced SMC mitogenesis. SMC derived from aortae of Sprague-Dawley rats were grown to confluence, growth arrested in serum-free medium, and treated. Conditioned medium (CM) was harvested by adding bovine serum albumin as a carrier and hirudin to neutralize residual Thr. Results demonstrated that CM from Thr-treated SMC (Thr CM) had increased mitogenic activity compared with control CM (Cnt CM) and that PDGF-AA levels were increased 12-fold in Thr CM compared with Cnt CM. The excess mitogenic activity in Thr CM was markedly inhibited by PDGF-AA-neutralizing antibodies. Cotreatment with Thr and PDGF-AA-neutralizing antibodies resulted in a 30% decrease in Thr-induced [3H]thymidine incorporation. These results demonstrate that autocrine production of PDGF-AA partially mediated Thr-induced SMC mitogenesis.

Animals↗

PubMed1993

Quantitative planar rest-redistribution 201Tl imaging in detection of myocardial viability and prediction of improvement in left ventricular function after coronary bypass surgery in patients with severely depressed left ventricular function.

BACKGROUND: Although many patients with multivessel coronary artery disease (CAD) and severely depressed left ventricular (LV) function will benefit from coronary artery bypass graft surgery (CABG), surgeons may be reluctant to perform CABG on these patients without evidence of myocardial viability in regions of severe asynergy. We hypothesized that quantitative planar rest-redistribution 201Tl imaging would identify viable myocardium and predict improved regional and global function after revascularization in patients with depressed LV function and CAD. METHODS AND RESULTS: Twenty-one patients (mean LV ejection fraction, 0.27 +/- 0.05) were studied. Regional and global LV functions were evaluated before and 8 weeks after CABG with radionuclide ventriculography. Segments were prospectively classified as showing normal, mildly reduced, or severely reduced viability on the basis of quantitative analysis of defect severity and redistribution on planar resting 201Tl imaging. By 201Tl criteria, 90% of hypokinetic segments were classified with normal or mildly reduced viability. Among akinetic or dyskinetic segments, 20% had normal 201Tl uptake, 53% had mildly reduced viability, and only 27% had severely reduced viability. 201Tl viability criteria identified segments that improved function after CABG. Sixty-two percent of severely asynergic segments with normal viability and 54% with mildly reduced viability improved function after surgery, but only 23% with severely reduced viability improved function (p = 0.002). When only adequately revascularized segments were considered, the predictive value of a positive preoperative viability scan for functional improvement was 73%. The greatest improvement in global LV function after CABG occurred in patients with the greatest number of asynergic segments classified as viable before surgery (p < 0.01). In 10 patients with more than seven viable, asynergic segments, mean LV ejection fraction increased significantly after CABG (0.29 +/- 0.07 to 0.41 +/- 0.11, p = 0.002). In 11 patients with seven or fewer viable, asynergic segments, mean LV ejection fraction remained unchanged after revascularization (0.27 +/- 0.05 to 0.30 +/- 0.08, p = NS). CONCLUSIONS: In patients with CAD and severely depressed LV function, preoperative quantitative planar rest-redistribution. 201Tl imaging identifies viability in many asynergic myocardial segments, and these segments frequently improve function after CABG. The presence of numerous asynergic but viable myocardial segments before surgery correlated significantly with improvement in global LV function after bypass surgery.

Aged↗

PubMed1993

Why do patients with congestive heart failure tolerate the initiation of beta-blocker therapy?

BACKGROUND: Despite its negative inotropic effects, the initiation of beta-adrenergic blockade is tolerated by patients with congestive heart failure (CHF). Accordingly, we examined the acute hemodynamic effects of beta-adrenergic blockade on systolic and diastolic left ventricular (LV) function and ventriculo-arterial coupling. In addition, isolated myocardium from patients with CHF shows selective beta 1-receptor downregulation, implying a greater role for the beta 2-receptor in maintaining in vivo LV contractility. As a secondary aim, we hypothesized that nonselective beta-adrenergic blockade would have greater negative inotropic effect than beta 1-blockade in patients with CHF. METHODS AND RESULTS: Patients with clinical CHF (n = 24) and control patients without CHF (n = 24) were given either the nonselective beta-blocker propranolol or the beta 1-selective blocker metoprolol. LV pressure-volume relations were obtained before and after the administration of intravenous beta-blocker, and measures of LV systolic and diastolic function were examined. Patients with CHF had a deterioration in LV systolic function with a fall in LV systolic pressure (139 +/- 6 to 125 +/- 6 mm Hg), cardiac index (2.56 +/- 0.11 to 2.20 +/- 0.11 mL.min-1 x M-1), dP/dtmax (1173 +/- 63 to 897 +/- 50 mm Hg/s), and end-systolic elastance (0.88 +/- 0.10 to 0.64 +/- 0.10 mm Hg/mL), P < .05 for all. Although there was deterioration of active LV relaxation (isovolumetric relaxation 63 +/- 2 to 73 +/- 3 milliseconds, peak filling rate 543 +/- 33 to 464 +/- 28 mL/s, P < .05 for both), there was no change in passive LV diastolic function (pulmonary capillary wedge, 24 +/- 2 to 24 +/- 1 mm Hg; chamber stiffness, 0.0154 +/- 0.0005 to 0.0163 +/- 0.0005 mL-1, P = NS for both), and a decrease in afterload (arterial elastance 3.85 +/- 0.31 to 3.38 +/- 0.24 mm Hg/mL, P < .05). Control patients had no change in these parameters other than a prolongation of isovolumetric relaxation (48 +/- 1 to 55 +/- 2 milliseconds, P < .05). The effects of propranolol (n = 12) versus metoprolol (n = 12) on these parameters in patients with CHF were similar. CONCLUSIONS: These data do not support a greater in vivo physiological role of the myocardial beta 2-receptor in CHF. The preservation of passive diastolic function and ventriculo-arterial coupling provide possible explanations of why beta-adrenergic blockade is tolerated by patients with CHF.

Adrenergic beta-Antagonists↗

PubMed1993

Platelet activation during coronary angioplasty in humans.

BACKGROUND: Previous studies have indicated that balloon angioplasty is associated with local platelet activation. In addition, different contrast media have different effects on thrombus formation during angioplasty in humans. We hypothesized that coronary angioplasty in humans is associated with activation of platelets to specific platelet agonists and that this activation may be differently modified by different angiographic contrast agents. METHODS AND RESULTS: We studied 25 patients referred for angioplasty of the left anterior descending or circumflex coronary arteries. All patients were pretreated with aspirin and received heparin. Blood samples for assessment of platelet aggregation to serotonin, ADP, epinephrine, and collagen were obtained from the coronary sinus before any contrast injection, after initial diagnostic contrast injections, and after three balloon inflations. Patients were randomized to receive iopamidol, diatrizoate, or ioxaglate. Contrast alone was not associated with altered platelet aggregation. However, balloon angioplasty was consistently associated with increased platelet aggregation to serotonin but not to ADP, epinephrine, or collagen. These effects were similar with the three contrast agents studied except that the use of iopamidol was associated with increased platelet responsiveness to all concentrations of ADP after balloon dilation. CONCLUSIONS: Coronary angioplasty in humans was associated with increased platelet aggregation in blood drawn from the coronary sinus. This effect was primarily seen when serotonin was used as an agonist.

Adenosine Diphosphate↗

PubMed1993

Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor.

Thrombin has been implicated in the stimulation of smooth muscle cell (SMC) proliferation that contributes to post angioplasty restenosis. The present studies demonstrated that human alpha-thrombin was a potent and efficacious mitogen for cultured rat aortic SMC, stimulating an increase in 3H-thymidine incorporation, as well as an increase in cell number at 1 to 10 nM concentration. gamma-Thrombin, which is enzymatically active but lacks fibrinogen clotting activity, stimulated SMC mitogenesis but was approximately 10-fold less potent than alpha-thrombin. In contrast, D-phenylalanyl-L-propyl-L-arginyl-chloromethyl ketone-alpha-thrombin, which lacked enzymatic activity, had no mitogenic effect. Diisopropylfluorophosphate-alpha-thrombin failed to stimulate mitogenesis except at concentrations having equivalent enzymatic activity as that of alpha-thrombin at its threshold for mitogenesis. Thus, thrombin-induced proliferation was dependent on enzymatic activity. A 14-residue peptide (SFLLRNPNDKYEPF) corresponding to amino acids 42 through 55 of the human thrombin receptor (Vu, T. K., D. T. Hung, V. I. Wheaton, and S. R. Coughlin, 1991. Cell. 64:1057-1068) had full efficacy in stimulating SMC proliferation. Reversing the first two amino acids of this peptide abolished mitogenic activity. Northern analysis demonstrated that SMC expressed a single mRNA species that hybridized to a labeled thrombin receptor cDNA probe. These findings indicate that alpha-thrombin stimulates SMC proliferation via the proteolytic activation of a receptor very similar or identical to that previously identified.

Amino Acid Sequence↗

PubMed1993

Successful preoperative diagnosis and treatment of a saphenous vein coronary artery bypass graft aneurysm.

A 71-year-old man who underwent a coronary artery bypass using a saphenous vein bypass graft (SVG) in 1977 presented with a new mediastinal mass on chest radiography. A variety of imaging techniques were applied and magnetic resonance imaging (MRI) provided excellent anatomic detail of an aneurysm of the previously placed SVG. This condition was successfully treated with repeat operation, aneurysm resection, and placement of new bypass grafts. We recommend that any patient with a history of previous coronary artery grafting who presents with a mediastinal mass be evaluated for the possibility of a graft aneurysm. The best mediastinal imaging technique for this purpose appears to be an MRI scan.

Aged↗

PubMed1992

Myocardial thallium-201 scintigraphy for assessment of viability in patients with severe left ventricular dysfunction.

Many patients with ischemic heart disease and depressed left ventricular (LV) function have asynergic zones with sustained microcirculatory perfusion and myocardial metabolic activity that exhibit improved systolic function after coronary revascularization. The 2 predominant noninvasive techniques used to determine myocardial viability in patients with severely depressed LV function are thallium-201 (201Tl) scintigraphy and positron emission tomography (PET). Myocardial extraction of 201Tl is unaltered under experimental conditions of myocardial stunning or short-term hibernation (characterized by decreased flow and ischemic dysfunction). Akinetic or dyskinetic LV wall segments can exhibit normal or near normal 201Tl uptake as long as some residual flow is present. 201Tl scintigraphy can identify viable asynergic segments when performed on patients with severe coronary artery disease who are in the resting state. Many of these patients have initial resting defects that demonstrate delayed redistribution, or mild persistent defects that show improved perfusion and function after revascularization. There is a direct correlation between the extent of 201Tl uptake in zones of severe regional myocardial asynergy and the magnitude of improvement in resting LV ejection fraction after coronary bypass surgery. Rest 201Tl scintigraphy may help in the selection of patients with coronary artery disease and severely depressed LV function who would benefit the most from revascularization.

Animals↗

PubMed1992

Effect of chronic subcutaneous or intramural administration of heparin on femoral artery restenosis after balloon angioplasty in hypercholesterolemic rabbits. A quantitative angiographic and histopathological study.

BACKGROUND: Heparin is known to have antithrombotic, anticoagulant, and antiproliferative effects. We hypothesized that chronic subcutaneous and/or direct intramural administration of heparin would reduce restenosis and inhibit plaque growth after balloon angioplasty. METHODS AND RESULTS: Focal atherosclerosis was induced bilaterally in the femoral arteries of 59 rabbits by air desiccation intimal injury and a 2% cholesterol diet. After angioplasty, the rabbits were assigned to one of four treatment groups. Control arteries (n = 21) received no additional heparin. A second group of 20 arteries was treated with a porous balloon that delivered heparin (1,500 units) directly into the arterial wall. A third group (n = 29) received subcutaneous heparin (350 units.kg-1.day-1) for 28 days, and a fourth group (n = 23) was treated with subcutaneous and intramural heparin. Quantitative angiography showed a modest reduction in restenosis (defined as the change in minimal luminal diameter from immediately after angioplasty to 28 days) with subcutaneous heparin compared with control arteries (0.32 +/- 0.18 versus 0.58 +/- 0.34 mm, p < 0.01); however, luminal diameter was not improved at 28 days compared with before angioplasty. Intramural delivery of heparin by the porous balloon catheter was confirmed by use of fluoresceinated heparin in one animal. Angiographic restenosis was not reduced in arteries treated with intramural heparin versus controls (0.61 +/- 0.54 versus 0.58 +/- 0.34 mm, p = NS). Blinded planimetric analysis of histological sections showed no differences in luminal cross-sectional area narrowing by atherosclerotic plaque, in plaque area, or in plaque/media ratio at 28 days among the four treatment groups. CONCLUSIONS: Chronic subcutaneous heparin after balloon angioplasty results in a modest reduction in angiographic restenosis in this model; however, the absolute luminal diameter is not improved compared with before angioplasty, and plaque area and percent luminal narrowing by plaque were not different among the four treatment groups. Heparin can be delivered into an atherosclerotic plaque by a porous balloon, but this treatment does not reduce restenosis after angioplasty in this model.

Angioplasty, Balloon↗

PubMed1992

On-line intraoperative quantitation of regional myocardial perfusion during coronary artery bypass graft operations with myocardial contrast two-dimensional echocardiography.

We hypothesized that the success of coronary artery bypass graft operations could be assessed by means of on-line quantitative myocardial contrast echocardiography. Accordingly, myocardial contrast echocardiography was performed at baseline and after each placement of venous graft in 21 patients undergoing coronary artery bypass graft operations. Time-intensity plots were generated on-line with the use of a dedicated computer system, and areas under the curve were assessed for each injection. Successful on-line quantitation of myocardial contrast echocardiography data was performed in 17 patients; this allowed comparison before and after coronary artery bypass graft operations for 21 grafts, with agreement between expert visual analysis and quantitative data in 91% of these cases. Three distinct perfusion patterns were noted on myocardial contrast echocardiography: (1) reduced contrast effect before coronary artery bypass graft operations with improvement after coronary artery bypass graft operations (n = 11); (2) adequate contrast effect before coronary artery bypass graft operations with no change after coronary artery bypass graft operations (n = 9) (for patients in group 2, the mean percentage of coronary stenosis was less than the mean for patients in group 1-67% +/- 25% vs. 88% +/- 20%, p = 0.05); and (3) no contrast effect either before or after coronary artery bypass graft operations in one patient with previous infarction. One third of the time (34 of 95 injections), on-line quantitation was unsuccessful. Failure was related three times more often to problems associated with myocardial contrast echocardiography, such as attenuation and inadequate quality of bubbles, than to computer failure. Despite its limitations, on-line quantitative myocardial contrast echocardiography is feasible in patients undergoing coronary artery bypass graft operations and provides important objective information regarding the success of revascularization.

Aged↗

PubMed1991

Effectiveness of recombinant desulphatohirudin in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.

BACKGROUND: The effectiveness of balloon angioplasty is limited by a restenosis rate of approximately 30%. Recombinant desulphatohirudin (r-hirudin [CGP 39393]) has been found to be highly effective in preventing acute platelet-rich thrombosis after deep arterial injury as compared with heparin. METHODS AND RESULTS: This study evaluated the effect of intravenous r-hirudin, a selective inhibitor of thrombin, on restenosis after balloon angioplasty in 29 rabbits. Focal femoral atherosclerosis was induced by air desiccation endothelial injury followed by a 2% cholesterol diet for 1 month. At angioplasty (2.5-mm balloon with three 60-second, 10-atm inflations 60 seconds apart), the rabbits received heparin (150 units/kg bolus, n = 16) or r-hirudin (1 mg/kg bolus followed by infusions of 1 mg/kg for the first hour and 0.5 mg/kg for the second hour, n = 13). Angiograms performed before and after angioplasty and before death were analyzed quantitatively by a blinded observer. Rabbits were killed 2 hours (n = 14) or 28 days (n = 15) after angioplasty. Femoral arteries were fixed in situ by perfusion of 10% formaldehyde at 100 mm Hg. The mean luminal diameter of the arteries with successful angioplasty (greater than or equal to 20% increase in luminal diameter) in rabbits treated with heparin (n = 8 arteries) increased from 1.18 +/- 0.29 mm before angioplasty to 1.86 +/- 0.24 mm immediately after angioplasty (p less than 0.001) and decreased to 0.94 +/- 0.69 mm (p = 0.0004) at 28 days after angioplasty. In rabbits treated with r-hirudin (n = 11 arteries), the mean luminal diameter increased from 1.14 +/- 0.17 mm before angioplasty to 1.68 +/- 0.20 mm immediately after angioplasty (p less than 0.001) and decreased to 1.37 +/- 0.47 mm (p = 0.01) at 28 days after angioplasty. The mean reduction in luminal diameter by angiography was less in the r-hirudin-treated group than in the heparin-treated group (0.30 +/- 0.33 versus 0.92 +/- 0.61 mm, p = 0.01). Blinded planimetric analysis of stained histological sections of the femoral arteries also showed less cross-sectional area narrowing by plaque in rabbits treated with r-hirudin compared with those treated with heparin (22 +/- 16% verus 48 +/- 29%, p = 0.01). Both groups had similar numbers of arteries with histological evidence of balloon-induced plaque tear (12 of 13 versus 13 of 15). CONCLUSIONS: Rabbits receiving r-hirudin at the time of experimental balloon angioplasty had significantly less restenosis by angiography and by quantitative histopathology than rabbits receiving heparin.

Angioplasty, Balloon↗

PubMed1990

Pharmacodynamic study of F(ab')2 fragments of murine monoclonal antibody 7E3 directed against human platelet glycoprotein IIb/IIIa in patients with unstable angina pectoris.

The pharmacodynamics of intravenous bolus injections of 0.05, 0.10, 0.15, and 0.20 mg/kg of F(ab')2 fragments of the murine monoclonal antibody 7E3, 7E3-F(ab')2, directed against the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor of human platelets, were studied in groups of four patients with unstable angina pectoris. With 0.20 mg/kg, the template bleeding time prolonged from 6.3 +/- 1.9 (mean +/- SD) to greater than 30 min; it subsequently decreased to 13 +/- 7.8 min after 12 h and to 8.3 +/- 1.5 min after 24 h. The number of unblocked GPIIb/IIIa receptors (preinfusion value, 32,000 +/- 3,000 per platelet) decreased to 13 +/- 7% of the preinfusion value 1 h after infusion, and then increased to 33 +/- 10% at 12 h, 44 +/- 8% at 24 h and 67 +/- 7% at 72 h. The logarithm of the bleeding time was inversely proportional with the residual GPIIb/IIIa receptors (r = 0.73, P less than 0.0001). ADP-induced platelet aggregation (measured by changes in light transmittance in percent) decreased from 60 +/- 5% before infusion to 1.5 +/- 3% 1 h after infusion; it then increased to 29 +/- 3% after 24 h and 39 +/- 6% after 72 h. Platelet counts decreased by 16% at 1 h and returned to control values within 24 h. Proportionally smaller effects were seen at lower doses of 7E3-F(ab')2. Antibody injection did not induce spontaneous bleeding. Angina was not observed during the first 12 h when the bleeding time was significantly prolonged, but occurred in 6 of the 16 patients within the next 3 d. 2 of the 16 patients developed low titers of IgG antibodies specific for 7E3-F(ab')2. Thus 7E3-F(ab')2 induces dose-related inhibition of platelet function; at a dose of 0.20 mg/kg, it causes profound inhibition of platelet aggregation and prolongation of the bleeding time, but no spontaneous bleeding.

Adult↗

PubMed1989

Prognostic utility of predischarge dipyridamole-thallium imaging compared to predischarge submaximal exercise electrocardiography and maximal exercise thallium imaging after uncomplicated acute myocardial infarction.

The prognostic value of predischarge dipyridamole-thallium scanning after uncomplicated myocardial infarction was determined by comparison with submaximal exercise electrocardiography and 6-week maximal exercise thallium imaging and by correlation with clinical events. Two endpoints were defined: cardiac events and severe ischemic potential. Of the 40 patients studied, 8 had cardiac events within 6 months (1 died, 3 had myocardial infarction and 4 had unstable angina requiring hospitalization). The finding of any redistribution on dipyridamole-thallium scanning was common (77%) in these patients and had poor specificity (29%). Redistribution outside of the infarct zone, however, had equivalent sensitivity (63%) and better specificity (75%) for events (p less than 0.05). Both predischarge dipyridamole-thallium and submaximal exercise electrocardiography identified 5 of the 8 events (p = 0.04 and 0.07, respectively). The negative predictive accuracy for events for both dipyridamole-thallium and submaximal exercise electrocardiography was 88%. In addition to the 8 patients with events, 16 other patients had severe ischemic potential (6 had coronary bypass surgery, 1 had inoperable 3-vessel disease and 9 had markedly abnormal 6-week maximal exercise tests). Predischarge dipyridamole-thallium and submaximal exercise testing also identified 8 and 7 of these 16 patients with severe ischemic potential, respectively. Six of the 8 cardiac events occurred before 6-week follow-up. A maximal exercise thallium test at 6 weeks identified 1 of the 2 additional events within 6 months correctly. Thallium redistribution after dipyridamole in coronary territories outside the infarct zone is a sensitive and specific predictor of subsequent cardiac events and identifies patients with severe ischemic potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Dipyridamole↗

PubMed1989

Correlation between template bleeding times and spontaneous bleeding during treatment of acute myocardial infarction with recombinant tissue-type plasminogen activator.

The purpose of this study was to correlate bleeding complications during and after treatment with recombinant tissue-type plasminogen activator (rt-PA) with serial template bleeding time measurements, with ADP-induced platelet aggregation, with clinical characteristics, and with hemostatic parameters. Fifty-two of 55 consecutive patients with acute myocardial infarction and template bleeding times (Ivy method) of less than 9.5 minutes were treated with rt-PA in a total dose of 55-212 mg (mean, 109 mg) over 90 to 360 minutes (median, 240 minutes) combined with heparin. The mean bleeding time was significantly prolonged at 90 minutes (from 5.0 +/- 1.9 to 8.2 +/- 4.3 minutes, p less than 0.0001) but returned toward baseline after 4 hours (from a median of 8.0 to 7.0 minutes, p less than 0.05). Thirteen patients (25%) suffered relatively minor but spontaneous bleeding that did not correlate with age, hypertension, smoking, partial thromboplastin time, platelet count, ADP-induced platelet aggregation, steady-state rt-PA level, or extent of fibrinogen degradation. In multivariate analysis, only the 90-minute bleeding time correlated with spontaneous bleeding (p = 0.01). Prolongation of the 90-minute bleeding time to greater than or equal to 9 minutes, which occurred in 21 patients, correlated with spontaneous bleeding with a sensitivity of 69% (95% confidence interval, 39-90%) and a specificity of 69% (95% confidence interval, 52-83%). Retrospective analysis revealed that in 14 patients taking aspirin, the bleeding time at 90 minutes was significantly more prolonged (p less than 0.05) and spontaneous bleeding significantly more frequent (p less than 0.01) than in patients not taking aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗

PubMed1988

Prevention of coronary artery reocclusion and reduction in late coronary artery stenosis after thrombolytic therapy in patients with acute myocardial infarction. A randomized study of maintenance infusion of recombinant human tissue-type plasminogen activator.

Sixty-eight patients with acute "transmural" myocardial infarction presenting within 6 hours (range, 1.3-5.8 hours) of onset of chest pain were given intravenous recombinant tissue-type plasminogen activator (rt-PA) at a dosage of 1 mg/kg during 90 minutes. Coronary angiography at 90 minutes revealed a patent infarct-related coronary artery in 52 patients (76%). These patients were randomized either to treatment by continuous infusion of heparin alone (27 patients) or to treatment by heparin and a maintenance infusion of rt-PA at a dosage of 0.8 mg/kg during 4 hours (25 patients). Coronary angiography was repeated 60 minutes after the start of the maintenance infusion and again after 8-14 days. Acute symptomatic reocclusion of the infarct-related artery occurred during the 1-hour observation period in five (19%) patients treated with heparin alone but in none of the patients treated with rt-PA (p = 0.05). The measured residual stenosis of the patent infarct-related coronary artery was similar in the heparin-treated and the rt-PA-treated groups at 90 minutes infusion: 66 +/- 14% versus 68 +/- 13% diameter stenosis, respectively (mean +/- SD) and 1.1 +/- 1.1 mm2 versus 0.82 +/- 0.7 mm2 area (p = 0.35). At 8-14 days after infusion, residual stenosis was unchanged in the heparin-treated group, but it improved to 55 +/- 17% (p = 0.001) and 1.6 +/- 1.2 mm2 (p = 0.003) in the rt-PA-treated group. At 90 minutes of infusion, residual intraluminal thrombus was observed in 29 of the 52 patients (56%) with a comparably measured distribution in the two groups (p = 0.43). At 150 minutes, however, the extent of intraluminal thrombus was significantly reduced in the rt-PA-treated group as compared with the heparin-treated group (p = 0.03). In-hospital ischemic events (symptomatic reocclusion, unstable angina, or cardiovascular death) occurred in 12 patients of the heparin-treated group but only in three patients of the rt-PA-treated group (p = 0.03). Fibrinogen levels decreased to 65 +/- 21% of baseline at 90 minutes of rt-PA infusion. During the rt-PA maintenance infusion, fibrinogen fell slightly from 63 +/- 26 to 57 +/- 28% (p = 0.18). This study shows that after successful reperfusion with 1 mg/kg rt-PA during 90 minutes, a maintenance infusion of 0.8 mg/kg rt-PA during 4 hours prevents acute symptomatic coronary artery reocclusion, and it reduces the frequency of ischemic events and the severity of residual coronary artery stenosis at hospital discharge.

Aged↗

PubMedDate not supplied

Assessing prognosis after acute myocardial infarction in the thrombolytic era.

The use of physiologic testing for prognostication continues to be useful and widely applied in the predischarge evaluation of patients recovering from an uncomplicated acute myocardial infarction in the thrombolytic era. Because patients with abnormal exercise test results are now routinely sent for angiography, there are no randomized trials or experimental confirmation that exercise parameters are still associated with the same prognostic value in the thrombolytic era. Nevertheless, the excellent outcomes in patients treated with thrombolytic therapy and risk stratified with exercise testing provide strong empiric support for the continued use of noninvasive testing of patients without complications after thrombolytic therapy. Reviews of patient cohorts enrolled in trials of thrombolytic therapy show that these patients have a lower incidence of multivessel disease and less evidence of ischemia (ST segment depression or thallium 201 redistribution) compared with prethrombolytic cohorts. For this and other reasons, the sensitivity and specificity of exercise variables for prognosis or detection of multivessel disease are not as strong. The addition of perfusion imaging will enhance the sensitivity for detection of ischemia within or remote from the infarct zone and will provide information regarding viability. Patients who are unable to exercise or those with poor exercise tolerance, an abnormal exercise blood pressure response, inducible ischemia, or nonsustained ventricular tachycardia are candidates for further invasive evaluation and consideration for coronary revascularization. With 201Tl imaging, evidence for increased pulmonary uptake of the tracer is indicative of high risk and a high probability of an adverse outcome with medical therapy. Low-risk patients are those who achieve their target heart rate or work load without inducible angina, ST segment depression, reversible perfusion abnormalities, or increased lung 201Tl uptake. Defect size is reflective of infarct size, and patients with extensive areas of nonreversible hypoperfusion are also at high risk for future events even in the absence of ischemia. Finally, pharmacologic stress imaging with dipyridamole, adenosine, or dobutamine has been found to be safe when employed for stress testing soon after uncomplicated infarction.

Coronary Disease↗

PubMedDate not supplied

Local adenovirus-mediated delivery of hirudin in a rabbit arterial injury model.

UNLABELLED: Intravascular delivery of an E1/E3 deleted adenovirus encoding the hirudin protein reduces neointimal formation in the rat arterial injury model. Given the interspecies variability in response to adenoviral vectors, we tested this same construct in the hirudin-sensitive cholesterol-fed rabbit arterial balloon injury model. We hypothesized that local delivery of an E1/E3-deleted adenovirus encoding hirudin (Ad-Hir) in addition to early hirudin infusion would limit neointimal formation compared to early hirudin alone. METHODS AND RESULTS: Local delivery of Ad-Hir, 2.5 x 10(10) PFU/ml, using a double balloon catheter [n = 6 vessels (v)] produced a 79% reduction in vessel wall thrombin activity at 48 h after balloon angioplasty (BA) compared with vehicle (Veh, n = 6v; p = 0. 05). In chronic experiments, hypercholesterolemic rabbits underwent femoral BA, and received either early hirudin alone (n = 9v) or early hirudin plus locally delivered Ad-Hir (early hirudin + Ad-Hir; n = 9v), an E1/E3-deleted adenovirus encoding beta-galactosidase (early hirudin + AdGal; n = 7v), or Veh (early hirudin + Veh; n = 10v). Early hirudin + Ad-Hir did not limit the arterial response to injury versus the other groups at 4 weeks after BA. Plaque area, cross-sectional luminal area narrowing by plaque, and T cell infiltration were significantly increased in the adenovirus- versus non-adenovirus-treated arteries. Plaque area correlated with T cell density. CONCLUSION: Following BA in cholesterol-fed rabbits, local transduction with A-Hir produced a marked reduction in vessel wall-associated thrombin activity. However, this strategy increased rather than decreased the arterial response to BA injury. Our results suggest that the lack of therapeutic effect resulted from adenovirus-stimulated plaque formation, possibly resulting from a T cell-mediated inflammatory response.

Adenoviruses, Human↗

PubMedDate not supplied

Arterial injury increases expression of inflammatory adhesion molecules in the carotid arteries of apolipoprotein-E-deficient mice.

Recent studies demonstrate increased cellular adhesion molecule expression by neointimal endothelium overlying primary and restenotic atherosclerotic plaque. In this study, we developed an atherosclerotic mouse model of arterial injury and characterized adhesion molecule expression after injury. Sixteen apolipoprotein-E-(ApoE)-deficient mice fed a Western-type diet for 4 weeks underwent carotid artery wire denudation at week 2. For each segment, the extent of neointima formation and medial thickening, or adhesion molecule expression, were scored separately on a scale from 0 (no plaque/thickening or expression) to 3 (extensive plaque/thickening or expression) using Movat staining (n = 3) or immunohistochemical analysis (n = 13). Histology revealed significant medial thickening (1.8 +/- 0.9 vs. 0.3 +/- 0.5, p < 0. 001) versus controls and pronounced staining for monocytes/macrophages in the wall of injured vessels. Immunohistochemical analysis showed more robust expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the luminal surface of injured arteries versus controls (2.2 +/- 0.6 vs. 1.4 +/- 0.7, p < 0.01, and 2.5 +/- 0.5 vs. 1.2 +/- 0.6, p < 0.001, respectively). Injury increased adventitial ICAM-1 expression (2.6 +/- 0.5 vs. 1.6 +/- 0.5, p < 0.002) and medial VCAM-1 expression (2.2 +/- 0.6 vs. 1.2 +/- 0. 7, p < 0.004). Thus, carotid injury results in significant medial thickening and increases adhesion molecule expression beyond that induced in ApoE-deficient mice fed a Western diet alone. The observation of macrophage infiltration into the media at sites of increased ICAM-1 and VCAM-1 expression suggests that these molecules may mediate monocyte/macrophage trafficking into the wall of injured arteries.

Animals↗

PubMedDate not supplied

Effectiveness of hirulog in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.

BACKGROUND: Thrombin may play an important role in restenosis after balloon angioplasty (BA). Angiographic and pathologic restenosis have been shown to be reduced after BA in an atherosclerotic rabbit model using recombinant desulfatohirudin, a selective and direct thrombin inhibitor. We hypothesized that potent and specific thrombin inhibition with the synthetic peptide hirulog given intravenously at the time of angioplasty would reduce restenosis in rabbits, confirming a specific role of thrombin in restenosis. METHODS AND RESULTS: Focal femoral atherosclerosis was induced in 27 rabbits by air desiccation endothelial injury followed by a 2% cholesterol diet for 1 month. Rabbits received either heparin (150 units/kg bolus, n = 14) or hirulog (5 mg/kg bolus followed by 5 mg/kg/h for 2 h, n = 13) at the time of BA (2.5-mm balloon with three 60-second, 10-atm inflations 60 s apart). Angiograms performed before and after BA and before sacrifice were analyzed quantitatively. Rabbits were sacrificed 28 days after BA for quantitative histopathologic analysis. Minimum luminal diameter (mm) did not differ between treatment groups before (1.1 +/- 0.2 vs. 1.2 +/- 0.1 mm) or after (1.5 +/- 0.2 vs. 1.6 +/- 0.1) BA in arteries from heparin-versus hirulog-treated rabbits, respectively. At 28 days, however, minimum luminal diameter was significantly less (1.0 +/- 0.4 vs. 1.5 +/- 0.2, p = 0.0001) and percent stenosis was greater (0.46 +/- 0.25 vs. 0.22 +/- 0.08, p = 0.0002) in arteries from heparin- versus hirulog-treated rabbits, respectively. Similarly, quantitative histopathology showed less cross-sectional area narrowing by plaque in the hirulog group (56 +/- 24 vs. 42 +/- 21%, p = 0.04). CONCLUSION: A 2-hour infusion of hirulog at the time of angioplasty improved late angiographic luminal dimensions and reduced cross-sectional area narrowing by plaque in rabbits compared with heparin controls. Together with previous studies, this confirms a specific role for thrombin in restenosis after angioplasty.

Angioplasty, Balloon↗