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Biomedical subjects

S R Bergmann

Publications and source records attributed to S R Bergmann.

At least 55 records · Page 3Linked to original sources
PubMed1994

Use and limitations of metabolic tracers labeled with positron-emitting radionuclides in the identification of viable myocardium.

Identification of viable myocardium is crucial in identifying patients who could benefit from interventional therapy such as coronary artery balloon angioplasty or bypass surgery. PET can be used to prospectively identify viable from nonviable myocardium based on the pattern of substrate use in comparison with perfusion. Viable myocardium can be identified with such diverse tracers as 1-11C-palmitate (for assessment of fatty acid metabolism) and 18F-fluorodeoxyglucose (for assessment of the uptake of glucose). Recent studies have suggested that assessment of oxidative metabolism with tracers such as 1-11C-acetate may predict with the greatest accuracy segments of myocardial tissue that will recover after recanalization. Further studies will be necessary to determine whether PET represents a superior technology compared with other more widely available (and less expensive) approaches for identification of jeopardized myocardium. Nonetheless, PET should provide a better understanding of the pathophysiology of myocardial ischemia (since it enables delineation of the biochemical alterations that underlie contractile dysfunction) and of therapeutic strategies likely to be beneficial. It will also be useful for the identification of viable from nonviable myocardium when results of other diagnostic techniques are equivocal, and in patients who are at high risk.

Acetates↗
PubMed1993

Comparison of carbon-11-acetate with fluorine-18-fluorodeoxyglucose for delineating viable myocardium by positron emission tomography.

OBJECTIVES: This study was designed to determine in patients with advanced coronary disease whether prediction of recovery of mechanical function after coronary revascularization could be accomplished more effectively by positron emission tomography (PET) with carbon-11 (11C)-acetate than by PET with fluorine-18 (18F)-fluorodeoxyglucose. BACKGROUND: Results of previous studies have demonstrated that preservation of myocardial oxidative metabolism (measured by PET with 11C-acetate) is necessary for recovery of systolic function after coronary revascularization. METHODS: Myocardial oxidative metabolism was quantified before revascularization in 34 patients by the analysis of the rate of myocardial clearance of 11C-acetate. Metabolism of glucose was assessed by analysis of uptake of 18F-fluorodeoxyglucose. Receiver operating characteristic curves for predicting functional recovery were derived for the measurements of oxidative metabolism and glucose metabolism. In addition, criteria for prediction of recovery of function based on measurements of oxidative metabolism and glucose metabolism were developed and compared. RESULTS: Analysis of receiver operating characteristic curves indicated that estimates of oxidative metabolism were more robust in predicting functional recovery than were estimates of glucose metabolism (p < 0.02). Moreover, threshold criteria with 11C-acetate exhibited superior positive and negative predictive values (67% and 89%, respectively) than did the criteria with 18F-fluorodeoxyglucose (52% and 81%, respectively), p < 0.01. In segments with initially severe dysfunction, estimates of oxidative metabolism tended to be more robust than estimates of glucose metabolism in predicting functional recovery. Moreover, in such segments, the threshold criteria with 11C-acetate tended to exhibit superior positive and negative predictive values (85% and 87%, respectively) than did the criteria with 18F-fluorodeoxyglucose (72% and 82%, respectively), although statistical significance was not achieved. CONCLUSIONS: In patients with advanced coronary artery disease, the extent to which functional recovery can be anticipated after coronary revascularization can be delineated accurately by quantification of regional oxidative metabolism by PET with 11C-acetate.

Acetates↗
PubMed1993

Detection and assessment by positron emission tomography of a genetically determined defect in myocardial fatty acid utilization (long-chain acyl-CoA dehydrogenase deficiency).

Genetic defects in fatty acid oxidation are important, inherited causes of cardiomyopathy, skeletal myopathies, and childhood sudden death. The clinical manifestations and their severity vary widely among affected subjects and different age groups. Although measurement of serum and urinary fatty acid intermediary metabolites and enzymatic assays establish the diagnosis of a defect in fatty acid oxidation, they do not predict the specific clinical manifestations nor their severity in a given subject. To determine whether impaired myocardial fatty acid utilization, indicative of cardiac phenotypic expression of a specific genetic abnormality in fatty acid oxidation, can be detected, cardiac positron emission tomography with the metabolic tracers carbon-11-labeled palmitate and acetate was performed in 6 patients with long-chain acyl-CoA dehydrogenase (ACD) deficiency and in 9 control subjects. The myocardial extraction of both tracers was similar in patients and controls. The rate of clearance of palmitate from myocardium was significantly prolonged in patients compared with that in control subjects (0.022 +/- 0.012 vs 0.061 +/- 0.033 min-1; p < 0.025), indicative of a decreased rate of oxidation of long-chain fatty acids. Furthermore, the extent of diminution of clearance of palmitate, quantified in terms of the rate of clearance for palmitate divided by that for acetate (to correct for individual differences in overall mitochondrial oxidative metabolic flux), correlated with the clinical severity of the long-chain ACD deficiency. Accordingly, noninvasive evaluation with positron emission tomography may not only facilitate diagnosis, but also enable assessment of the pathogenetic impact and effects of therapeutic interventions in the hearts of subjects with specific, inherited defects in fatty acid oxidative metabolism.

Acetates↗
PubMed1993

Persistence of coronary vasodilator responsivity after cardiac transplantation.

Accelerated graft atherosclerosis is a major cause of death after cardiac transplantation. Although its detection currently requires surveillance angiography, loss of vasodilator responsivity may precede obstructive lesions and be detectable by noninvasive assessment of myocardial perfusion. Thirty-five allograft recipients were studied an average of 31 +/- 19 (mean +/- SD) months after transplantation. All were free from angiographically definable macrovascular obstructive coronary artery lesions. Nutritive myocardial perfusion at rest, estimated in absolute terms by positron emission tomography with oxygen-15 water averaged 1.63 +/- 0.51 ml/g/min in patients and was greater than that in 26 healthy volunteers (1.17 +/- 0.33 ml/g/min, p < 0.001). The increase correlated with increased cardiac work at rest in transplant recipients with arterial hypertension and tachycardia. Peak myocardial perfusion induced by intravenous administration of dipyridamole was normal in the transplant recipients (3.49 +/- 1.70 ml/g/min compared with 3.60 +/- 1.41 ml/g/min in volunteers). Because of the high flow at rest, myocardial perfusion reserve (the ratio of hyperemic flow to flow at rest) was diminished (2.3 +/- 1.2 compared with 3.3 +/- 1.5 in volunteers, p < 0.005). These results indicate that the responsivity to vasodilator stimulation is well preserved in transplant recipients devoid of macroscopic coronary arterial lesions obviating detection of early vascular dysfunction in individual subjects. Positron emission tomography may be useful, however, in quantifying the magnitude of the increase in flow at rest secondary to increased cardiac work--a potentially remedial cause of accelerated coronary vascular disease induced by high shear force activation of platelets in the coronary bed, and in detecting impaired perfusion once macrovascular vascular disease is extant.

Adult↗
PubMed1993

Functional recovery after reperfusion is predicated on recovery of myocardial oxidative metabolism.

To test the hypothesis that recovery of myocardial oxidative metabolism (MVO2) is a necessary prerequisite for recovery of contractile function following reperfusion and to evaluate its dependency on the interval of antecedent ischemia before reflow, we evaluated 11 dogs serially for 4 weeks. Six dogs were subjected to prompt reperfusion (after 1 hour of coronary artery occlusion) and five were subjected to delayed reperfusion (after 4 hours of ischemia). Despite equivalent levels of myocardial blood flow with reperfusion, hearts subjected to prompt reperfusion had faster and more complete recovery of MVO2 (assessed by sequential positron emission tomography with [11C]acetate) and function (assessed by echocardiography) compared with dogs subjected to delayed reperfusion. Infarct size was diminished in dogs with prompt reperfusion. In all dogs, recovery of function with reperfusion was predicted and correlated with early recovery of MVO2 (r = 0.61, p < 0.04). The results demonstrate that prompt reperfusion is associated with more rapid and complete recovery of oxidative metabolism and function and support the hypothesis that the ability to metabolize substrate oxidatively is a necessary prerequisite for recovery of function.

Animals↗
PubMed1993

Development and validation of a solvent extraction technique for determination of Cu-PTSM in blood.

The partitioning of [67Cu]Cu-PTSM between plasma and red blood cells (RBC) was investigated in vitro with human, rat, pig and dog blood. Significant inter-species variability is observed in the plasma/RBC partitioning of tracer, ranging from c. 75% association with plasma in human blood to only c. 35% association with plasma in dog blood. This inter-species difference results from selective association of the [67Cu]Cu-PTSM tracer with human albumin. When [67Cu]Cu-PTSM is mixed with human blood in vitro at 37 degrees C the fraction of 67Cu-radioactivity that remains plasma-associated decreases with time, apparently due to the expected intracellular decomposition of the Cu-PTSM complex by RBC; however, this process is sufficiently slow that it should have limited influence on [62Cu]CU-PTSM biodistribution following intravenous injection. Octanol extraction of blood was found to be an effective technique for quantitating the amount of intact [67Cu]Cu-PTSM complex in blood samples. When imaging with [62Cu]Cu-PTSM, octanol extraction may be useful for determining the [62Cu]Cu-PTSM content of arterial blood samples to establish a true radiotracer input function.

Animals↗
PubMed1993

Adenosine protects ischemic and reperfused myocardium by receptor-mediated mechanisms.

To evaluate the role of adenosine receptors in the mediation of adenosine-induced protection of the heart during ischemia and reperfusion, isolated rabbit hearts were perfused at constant flow with 1 microM adenosine started before low-flow ischemia followed by reperfusion. Adenosine delayed the time of onset of ischemic contracture [to 28 +/- 19 (SD) min compared with 10 +/- 10 min in control hearts] and decreased the amplitude of ischemic contracture (29 +/- 16 vs. 48 +/- 14 mmHg; P < 0.05 for each compared with controls). This protection was accompanied by an increase in tissue ATP content (1.72 +/- 0.78 vs. 0.96 +/- 0.23 mumol/g; P < 0.05) and stimulation of anaerobic glycolysis (lactate production of 0.78 +/- 0.28 mumol.g-1 x min-1 compared with 0.53 +/- 0.23 mumol.g-1 x min-1; P < 0.05). Functional recovery during reperfusion was enhanced by adenosine (developed pressure 88 +/- 16% compared with 57 +/- 23% of baseline; P < 0.05), and tissue necrosis, assessed by creatine kinase release, was decreased. The potent, nonselective adenosine receptor blocker 8-phenyltheophylline (10 microM) blocked all of the salutary effects of adenosine. Adenosine given only at reperfusion modestly attenuated reperfusion-induced contracture. The results suggest that exogenous adenosine attenuates ischemic injury by receptor-mediated stimulation of anaerobic glycolysis. During reperfusion its protective action is related to vasodilation.

Adenosine↗
PubMed1993

Quantification of regional myocardial perfusion with generator-produced 62Cu-PTSM and positron emission tomography.

BACKGROUND: Noninvasive assessment of regional myocardial perfusion at rest and after stress is important for the objective evaluation of the effects of coronary artery disease and its response to therapy. Centers that do not have cyclotrons rely on generator-produced radioisotopes for assessment of regional myocardial perfusion with positron emission tomography (PET). The aim of the present study was to develop and implement an approach to quantify regional myocardial perfusion using copper(II) pyruvaldehyde bis-(N4-thiosemicarbazone) (PTSM) labeled with the generator-produced, positron-emitting radionuclide 62Cu (t1/2 = 9.7 minutes). METHODS AND RESULTS: Regional perfusion was estimated from dynamic PET scans after intravenous administration of 62Cu-PTSM in 21 studies in 13 intact dogs evaluated over a wide range of myocardial flow values. In 15 interventions in nine dogs, regional perfusion was also estimated with H2(15)O. Regional perfusion with 62Cu-PTSM was estimated from dynamic blood and tissue time-activity curves, along with the model parameter k1 (forward rate of transport) and the PET parameter FBM (fraction of blood pool activity observed in tissue), using a two-compartment kinetic model. Arterial blood activity was corrected for red blood cell-associated 62Cu. In 44 comparisons, estimates of regional perfusion with 62Cu-PTSM correlated well with estimates obtained with concomitantly administered radiolabeled microspheres (y = 0.90x +/- 0.15, r = 0.95, p < 0.05) over a flow range from 0.23 to 6.14 ml/g per minute. In five healthy human volunteers evaluated at rest with H2(15)O and 62Cu-PTSM, regional perfusion estimated with 62Cu-PTSM was not significantly different from that obtained with H2(15)O (1.05 +/- 0.36 versus 0.96 +/- 0.28 ml/g per minute). 62Cu-PTSM provided high-quality images of the heart. CONCLUSIONS: The results of this study demonstrate that quantification of regional myocardial perfusion is feasible using generator-produced 62Cu-PTSM. Since 62Cu-PTSM can be used to estimate perfusion in the brain, kidney, and tumors as well as in the heart, it is an attractive tracer for centers that rely on generator-produced tracers for the evaluation of perfusion with PET.

Animals↗
PubMed1993

Concordance of nutritive myocardial perfusion reserve and flow velocity reserve in conductance vessels in patients with chest pain with angiographically normal coronary arteries.

We have previously shown that myocardial perfusion can be quantified by positron emission tomography (PET) with 15O-labeled water (H2(15)O), as experimentally validated with radiolabeled microspheres in animal hearts. The purpose of our study was to determine whether myocardial nutritive perfusion reserve assessed with PET in human subjects was parallel to flow velocity reserve assessed in conductance vessels measured with intracoronary Doppler probes. We studied nine patients with chest pain and angiographically normal coronary arteries with intracoronary Doppler flow velocity assessments before and after administration of 16 micrograms of intracoronary adenosine. We also assessed myocardial nutritive perfusion with PET and H2(15)O before and after intravenous administration of dipyridamole (0.56 mg/kg). Perfusion reserve (the ratio of absolute values of myocardial perfusion after dipyridamole administration to perfusion at rest) estimated with PET (3.5 +/- 0.9 s.d.) correlated closely with flow velocity reserve (the ratio of hyperemic intracoronary flow velocity to flow velocity at rest) (3.5 +/- 1.2, r = 0.80, p < 0.01). Absolute values of perfusion assessed tomographically averaged 1.22 +/- 0.19 ml/g/min in patients at rest and 4.16 +/- 0.93 after dipyridamole administration. Our data indicate that noninvasive assessment of myocardial perfusion with PET provides results that parallel intracoronary Doppler flow velocity measurements. Because PET delineates nutritive perfusion throughout the heart in absolute terms, its use may facilitate detection of impaired coronary arterial function and enhance delineation of the efficacy of potentially therapeutic interventions in patients with chest pain and angiographically normal coronary arteries.

Adult↗
PubMed1992

Functional recovery after coronary revascularization for chronic coronary artery disease is dependent on maintenance of oxidative metabolism.

OBJECTIVES: This study was performed to define the importance of maintenance of oxidative metabolism as a descriptor and determinant of functional recovery after revascularization in patients with left ventricular dysfunction attributable to chronic coronary artery disease. BACKGROUND: Although myocardial accumulation of 18F-fluorodeoxyglucose indicates the presence of tissue that is metabolically active, it may not identify those metabolic processes required for restoration of myocardial contractility. Experimental studies suggest that, under conditions of ischemia and reperfusion, maintenance of myocardial oxidative metabolism is an important metabolic determinant of the capacity for functional recovery. METHODS: In 16 patients positron emission tomography was performed to characterize myocardial perfusion (with H(2)15O), oxidative metabolism (with 11C-acetate) and utilization of glucose (with 18F-fluorodeoxyglucose). Dysfunctional but viable myocardium was differentiated from nonviable myocardium on the basis of assessments of regional function before and after coronary revascularization. To define the importance of coronary revascularization on myocardial perfusion and metabolism, tomography was repeated in 11 patients after revascularization. RESULTS: Before revascularization, perfusion in 24 dysfunctional but viable myocardial segments and 29 nonviable segments averaged 79% and 74%, respectively, of that in 42 normal myocardial segments (both p less than 0.01). Dysfunctional but viable myocardium exhibited oxidative metabolism comparable to that in normal myocardium. In contrast, in nonviable myocardium, oxidative metabolism was only 66% of that in normal (p less than 0.01) and 69% of that in reversibly dysfunctional myocardium (p less than 0.003). Regional utilization of glucose normalized to regional perfusion in dysfunctional but viable myocardium was greater than that in normal myocardium (p less than 0.01). However, in both reversibly and persistently dysfunctional myocardium, utilization of glucose normalized to relative perfusion was markedly variable. CONCLUSIONS: The results indicate that preservation of oxidative metabolism is a necessary condition for recovery of function after coronary recanalization in patients with chronic coronary artery disease. Consequently, approaches that measure myocardial oxygen consumption, such as dynamic positron emission tomography with 11C-acetate, should facilitate the identification of those patients most likely to benefit from coronary revascularization.

Adult↗
PubMed1992

Dependence of recovery of contractile function on maintenance of oxidative metabolism after myocardial infarction.

This study was performed to define the importance of maintenance of oxidative metabolism as a descriptor and determinant of the potential for functional recovery after revascularization in patients with recent myocardial infarction. In 11 patients (mean interval after infarction 6 days; 5 patients given thrombolytic therapy), positron emission tomography (PET) was performed to characterize myocardial perfusion (with oxygen-15-labeled water), glucose utilization (with fluorine-18-fluorodeoxyglucose) and oxidative metabolism (with carbon-11-acetate). Dysfunctional but viable myocardium was differentiated from nonviable myocardium by assessments of regional function before and after coronary revascularization. The impact of coronary revascularization on regional myocardial perfusion and metabolism was assessed in nine patients in whom tomography was repeated after revascularization. Before revascularization, dysfunctional but viable myocardium (19 segments) and nonviable myocardium (10 segments) exhibited relative perfusion equivalent to 74% and 63% of that of normal myocardium (33 segments), respectively (p less than 0.02). Dysfunctional but viable myocardium exhibited oxidative metabolism equivalent to 74% of that of normal myocardium (p less than 0.02). In contrast, in nonviable myocardium, oxidative metabolism was only 45% of that seen in normal (p less than 0.02) and 60% of that in reversibly dysfunctional myocardium (p less than 0.003). Regional glucose utilization (normalized to regional perfusion) in dysfunctional but viable myocardium was higher than that in normal myocardium (p less than 0.02). Nonviable myocardium exhibited lower levels of glucose utilization than did normal tissue (p less than 0.02). However, in both reversibly and persistently dysfunctional myocardium utilization of glucose normalized to relative perfusion was markedly variable.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Pretreatment with buflomedil enhances ventricular function by reducing the dysfunctional area after transient coronary artery occlusion.

OBJECTIVE: The aim was to evaluate whether buflomedil (a drug used to treat peripheral vascular disease and which has a number of pharmacological actions potentially beneficial to dysfunctional myocardium) would preserve myocardial function after transient coronary artery occlusion followed by reperfusion. METHODS: The physiological response to a 15 min balloon occlusion of the left anterior descending coronary artery followed by 1 h of reperfusion was monitored in 17 placebo treated dogs and compared with that of 15 dogs which received 10 mg.kg-1 of buflomedil. Buflomedil or its vehicle were given intravenously. Myocardial blood flow was assessed with radiolabelled microspheres and cardiac function was evaluated with quantitative contrast left ventriculography. RESULTS: Buflomedil did not affect baseline haemodynamic variables or contractile function. At the end of occlusion, there was no difference between dogs receiving vehicle compared with those receiving drug with respect to ejection fraction [33(SD 11)% v 34(11)%] or transmural blood flow [0.23(0.11) v 0.28(0.14) ml.g-1 x min-1]. However, at 30 min after reperfusion, ejection fraction was 89% of normal in the buflomedil group compared with 69% of normal in the placebo group (p < 0.03). This difference was sustained 60 min after reperfusion, and was due in part to slightly enhanced flow during reperfusion and a decrease in the dysfunctional area (16 compared with 28 chords lower than -2 SD from the mean, p < 0.04) in the hearts of dogs receiving buflomedil. Areas at risk were equivalent (15.9% and 15.8% of the left ventricle, respectively). CONCLUSIONS: The results suggest that buflomedil and agents with similar modes of action may be beneficial in preserving ventricular function after transient ischaemia followed by reperfusion.

Animals↗
PubMed1992

Imaging of thrombi with tissue-type plasminogen activator rendered enzymatically inactive and conjugated to a residualizing label.

BACKGROUND: Contemporary cardiovascular practice relies increasingly on thrombolysis as a therapeutic modality. Its optimal use requires prompt, noninvasive delineation of thrombotic occlusion in arterial beds and rapid detection of reocclusion after initially successful thrombolysis. METHODS AND RESULTS: We have been developing an approach to noninvasively image thrombi in which plasminogen-activating properties of tissue-type plasminogen activator (t-PA) are attenuated by treatment with D-Phe-L-Pro-L-Arg-chloromethyl ketone (PPACK) and have shown that the inactive t-PA avidly and promptly binds to clots in vitro. In the present study, we conjugated this material to a residualizing label, radioiodinated dilactitol tyramine (*I-DLT), and characterized the potential use of the inactivated, conjugated t-PA as a radiopharmaceutical for imaging thrombi in vivo. The approach developed requires not only avid binding of the tracer to thrombi but also rapid clearance from plasma and a lack of prompt release of radiolabeled degradation products from the liver. The rapid clearance of unaltered or PPACK-treated t-PA was not influenced by conjugation to *I-DLT, but the release of radioiodinated degradation products into plasma after injection of *I-DLT-conjugated t-PA was markedly less than release of degradation products of directly radioiodinated t-PA. When 131I-DLT-PPACK-t-PA was infused for 15 minutes intravenously after a bolus injection of 20% in dogs with coronary, pulmonary, or carotid artery thrombi, clearance was rapid. Mean +/- SEM thrombus-to-blood ratios of radioactivity were high, ranging from 37 +/- 9:1 and 2.8 +/- 0.6:1 with carotid thrombi formed concomitantly or approximately 30 minutes before infusion of tracer, respectively, to 35:1 for concomitantly formed coronary thrombi, 42 +/- 7:1 and 8.1 +/- 0.8:1 for concomitantly formed and preformed pulmonary thrombi, respectively, and 18:1 for a preformed femoral artery thrombus. Thrombi were detectable by planar gamma scintigraphy even though image quality was affected adversely by low concentrations of radioactivity that in aggregate composed a relatively large amount of radioactivity in underlying and overlying tissues. This limitation was overcome by tomographic imaging, which was used to detect both femoral and pulmonary thrombi. CONCLUSIONS: Use of enzymatically inactivated t-PA coupled to a residualizing label permits rapid detection and localization of thrombi in vivo.

Amino Acid Chloromethyl Ketones↗
PubMed1992

Implementation and evaluation of a two-compartment model for quantification of myocardial perfusion with rubidium-82 and positron emission tomography.

Positron emission tomography offers the ability to noninvasively assess regional myocardial perfusion in absolute terms (i.e., milliliters per gram per minute). Accurate estimates have been difficult to achieve with generator-produced 82Rb because of the complex behavior of this tracer in the myocardium. The aim of the present study was to determine whether regional myocardial blood flow could be assessed quantitatively with 82Rb and positron emission tomography by using a two-compartment kinetic model. Regional perfusion in milliliters per gram per minute was estimated from dynamic tomographic scans after intravenous administration of 82Rb in 18 studies in 13 intact dogs studied without intervention, after 2 and 24 hours of induced ischemia, during reperfusion after transient occlusion, or at rest and after pharmacological hyperemia after induced coronary artery stenosis. Regional flow was estimated along with the forward and backward rates of transport (k1 and k2 [minutes-1]) after the relative volume of distribution of the first compartment was fixed to 0.53 ml/ml and the tomographic parameters, the recovery and spillover fractions, were fixed to averaged values obtained in previous studies. In 36 comparisons, estimates of regional flow with 82Rb correlated well with flow measured with concomitantly administered radiolabeled microspheres (r = 0.91, p less than 0.05) over the flow range from 0.14 to 4.25 ml/g/min. A putative index of viability, k2, increased significantly in regions with severe ischemia. The results suggest that quantification of regional myocardial perfusion is possible in centers using 82Rb for estimates of myocardial perfusion when a physiologically appropriate, two-compartment model is used.

Animals↗
PubMed1991

Inhibition of cyclic flow variations and reocclusion after thrombolysis in dogs by a novel antagonist of platelet-activating factor.

To determine whether platelet-activating factor is a specific mediator of cyclic flow variations in damaged stenotic arteries and whether it contributes to reocclusion after thrombolysis, femoral arteries in anesthetized dogs were subjected to mural injury and high grade stenosis to induce cyclic flow variations (28 +/- 4/h) or methods selected to elicit platelet-rich and fibrin-rich thrombosis. Oral administration of a novel triazolobenzodiazepine (U46,195 [10 mg/kg]) that selectively inhibits platelet-activating factor abolished cyclic flow variations within 120 min and for greater than or equal to 2 h thereafter compared with persistent flow variations in dogs given saline solution. Platelet aggregation induced ex vivo with platelet-activating factor was inhibited in parallel with in vivo inhibition of cyclic flow variations after administration of U46,195. However, buccal mucosa bleeding time was not affected. After thrombosis, administration of U46,195 before thrombolysis was induced with human recombinant tissue-type plasminogen activator (1.7 mg/kg intravenously over 60 min) prevented reocclusion within 120 min in six of eight and six of seven arteries by platelet-rich and fibrin-rich thrombosis, respectively. In contrast, in dogs given saline solution, reocclusion occurred in eight of eight (p = 0.007 compared with U46,195) and five of eight arteries by platelet-rich and fibrin-rich thrombosis, respectively. Thus, both cyclic flow variations and reocclusion after thrombolysis appear to be mediated in part by platelet-activating factor. The results suggest that inhibition of platelet-activating factor with specific antagonists may be useful in reducing platelet-mediated occlusion of coronary arteries without eliciting bleeding.

Administration, Oral↗
PubMed1991

Induction of sustained patency after clot-selective coronary thrombolysis with Hybrid-B, a genetically engineered plasminogen activator with a prolonged biological half-life.

BACKGROUND: Despite the utility of tissue-type plasminogen activator (t-PA) in eliciting coronary thrombolysis clinically, early reocclusion remains a problem, occurring despite anticoagulation in 5-30% of patients with initially successful recanalization. This study evaluated the utility of Hybrid-B, a molecular variant of t-PA with a prolonged half-life in the circulation, in eliciting coronary thrombolysis and maintaining patency in the presence of a continuing thrombogenic stimulus. METHODS AND RESULTS: In intact, anesthetized dogs, either 18 mg Hybrid-B over 30 minutes (n = 15) or 50 mg t-PA (Activase) over 60 minutes (n = 8) was administered starting 60 minutes after left anterior descending coronary artery occlusion was induced with a thrombogenic copper coil. Time to lysis averaged 54 +/- 26 (means +/- SD) minutes and 64 +/- 34 minutes with Hybrid-B and t-PA, respectively (p = NS). When Hybrid-B was administered as a bolus (20 mg over 1 minute) to induce a high initial concentration in blood, time to lysis was shortened markedly and averaged 15 +/- 5 minutes. Dogs given Hybrid-B by either infusion or bolus exhibited prolonged time to reocclusion (337 +/- 192 minutes compared with 192 +/- 125 minutes in dogs given t-PA, p less than 0.03), reflecting maintenance of a subthrombolytic but persistently active concentration of activator in blood. Despite the persistence of Hybrid-B in blood, concentrations of fibrinogen and alpha 2-antiplasmin were not depleted markedly and remained at 77 +/- 25 and 56 +/- 24%, respectively, of control values. CONCLUSIONS: Thus, Hybrid-B, a novel variant of t-PA with unique pharmacokinetic properties, elicits prompt, sustained, and clot-selective coronary thrombolysis.

Animals↗
PubMed1991

Noninvasive delineation of the effects of moderate aging on myocardial perfusion.

Aging is accompanied by a decline in many aspects of cardiovascular function but little is known regarding its influence on myocardial perfusion. Eleven young adults (mean age 25 +/- 4 (s.d.) yr) and 15 older adults (mean age 55 +/- 9 yr) without history or symptoms of cardiovascular disease were studied using H2 15O and positron emission tomography under resting conditions and following administration of intravenous dipyridamole. Myocardial perfusion at rest was similar in the older and younger subjects, averaging 1.17 +/- 0.35 and 1.16 +/- 0.32 ml/g/min, respectively (p = ns). Following dipyridamole, peak myocardial perfusion was blunted in the older subjects, averaging 3.12 +/- 1.09 ml/g/min compared with 4.25 +/- 1.54 ml/g/min in the young adults (p = 0.044). Accordingly, present standards for normal perfusion responses to intravenous dipyridamole may require adjustment for age.

Adult↗