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Biomedical subjects

S R Bergmann

Publications and source records attributed to S R Bergmann.

At least 109 records · Page 6Linked to original sources
PubMed1986

Enhancement of salvage of reperfused ischemic myocardium by diltiazem.

Concomitant use of pharmacologic agents may be required for maximal salvage of ischemic myocardium by reperfusion. Accordingly, in dogs with induced thrombotic coronary occlusion, the effects of intravenous diltiazem given 30 minutes before administration of streptokinase on myocardial blood flow and myocardial salvage were evaluated. Two independent types of end points were employed. Positron emission tomography was utilized for noninvasive assessment of myocardial perfusion and infarct extent. Direct measurements included quantification of myocardial infarction by assay of creatine kinase activity in myocardial homogenates. Infarct extent averaged 27.9 +/- 11.4% of left ventricular weight in 10 control dogs in which coronary occlusion was maintained for 24 hours. In eight dogs given streptokinase alone, the infarct extent averaged 16.7 +/- 10.0% of left ventricular mass (p less than 0.05 versus control). In nine other dogs given diltiazem (15 micrograms/kg per min continuously until death was induced) beginning 30 minutes before streptokinase, infarct extent averaged 9.4 +/- 6.7% of left ventricular mass (p less than 0.05 compared with reperfusion alone). At the dose administered, diltiazem did not alter blood flow, heart rate or mean arterial pressure after coronary occlusion or thrombolysis. The region at risk, determined in 16 dogs from perfusion images obtained with positron tomography and oxygen-15-labeled water after coronary occlusion, was similar in the three groups (30.6 +/- 7.3% of the left ventricle in six control dogs, 31.8 +/- 4.5% in five dogs with reperfusion alone and 30.5 +/- 11.6% in five dogs with reperfusion plus diltiazem). Infarct size quantified in terms of the extent of myocardium exhibiting less than 50% of peak carbon-11-labeled palmitate uptake 24 hours after occlusion and expressed as the percent of the region at risk averaged 89.6 +/- 11.4% in control dogs, was significantly reduced to 45.1 +/- 29.8% in dogs with reperfusion alone and was reduced further to 22.3 +/- 16.4% in dogs given diltiazem and reperfusion. Thus, concomitant treatment with diltiazem markedly enhances salvage of reperfused myocardium after coronary thrombolysis.

Animals↗
PubMed1986

Effect of fatty acid on performance and lipid content of hearts from diabetic rabbits.

The relationship of external work to exogenous substrate supply and whole heart lipid content was studied in hearts isolated from 27 normal and 24 alloxan-diabetic rabbits. In addition, we evaluated hearts from seven rabbits after 4 days of untreated diabetes followed by 10 days of insulin therapy. Hearts were retrogradely perfused with erythrocyte-enriched modified Krebs-Henseleit media in which glucose, palmitate, and insulin were present in concentrations simulating diabetic plasma (13 mM, 0.4 mM, and 15 microU/ml, respectively). Diabetes was associated with a greater than 40% reduction in peak left ventricular systolic pressure, dP/dtmax, and left ventricular pressure-time index (P less than 0.01 for each). Perfusion of hearts from six diabetic animals with low concentrations of exogenous fatty acid (0.06 mM) normalized left ventricular (LV) performance. Insulin therapy also completely normalized LV performance. This improvement was associated with lower heart fatty acid and triacylglycerol content. These studies suggest that the myocardial dysfunction in hearts from rabbits with alloxan-induced diabetes of 2-wk duration may be, in part, due to enhanced sensitivity to deleterious effects of high exogenous levels of fatty acid.

Alloxan↗
PubMed1986

Characterization of beta-adrenoreceptors in vivo with iodine-131 pindolol and gamma scintigraphy.

The aim of this study to was to assess the feasibility of using iodopindolol to delineate myocardial beta-adrenoreceptors in vivo. Preliminary biodistribution studies indicated that binding of 131I-d,I-pindolol in the heart was stereospecific, saturable, and displaceable by I-propranolol but not by phenoxybenzamine. However, considerable nonspecific binding was encountered. Subsequently, the stereoisomer, 131I-I-pindolol, was shown to be a high affinity beta-adrenoreceptor antagonist (Kd approximately 0.37 nM) as assessed by Scatchard analysis, and one exhibiting marked specific uptake in lung and heart in rabbits. In contrast, 131I-d-pindolol exhibited no specific binding in rabbit left ventricular membrane preparations nor specific organ uptake. Gamma camera scintigraphy with both isomers demonstrated that the I-isomer accumulated in lung and heart, and that its accumulation was blocked by I-propranolol. In contrast, d-isomer uptake was nonspecific and diffuse. The results indicate that it should be possible to externally visualize receptors by differentiating specific and nonspecific binding components of a ligand in vivo with the use of radiolabeled stereoisomers.

Animals↗
PubMed1985

Salutary effects of moderate hypothermia on the circulatory and myocardial consequences of acute coronary occlusion in dogs.

The efficacy of moderate hypothermia with rewarming in attenuating the myocardial and circulatory consequences of acute coronary ligation was studied in open-chest, anesthetized dogs. Thirty minutes after ligation of the proximal left anterior descending coronary artery, 14 dogs were surface-cooled to 27 degrees C, maintained at this temperature for 2 hr, rewarmed to normothermic levels, and monitored for an additional hour. Fifteen dogs were maintained for a corresponding time period after coronary ligation at normothermic levels. Dogs maintained normothermic demonstrated significant depression (from preligation values) of dP/dt, cardiac output (CO), stroke volume (SV), and left ventricular stroke work and power (LVSW, LVSP) at elevated levels of left ventricular end-diastolic pressure (LVEDP). Dogs subjected to the hypothermic procedure demonstrated decreased inotropic status during hypothermia, but with rewarming, exhibited significantly greater values of left ventricular pressure, dP/dt, CO, SV, LVSW, and LVSP at lower values of LVEDP than observed in dogs maintained normothermic. Increased dysrhythmic activity was not observed during hypothermia. Hearts from dogs subjected to the hypothermic protocol demonstrated qualitatively greater dehydrogenase activity both at the periphery and in the center of the nonperfused region. The results suggest that moderate hypothermia during evolving myocardial infarction may preserve left ventricular cardio- and hemodynamics and thus may be useful in delaying morphological and functional deterioration until definitive treatment can be instituted.

Animals↗
PubMed1985

Assessment of myocardial metabolism with 11C-palmitate. Comparison with 123I-heptadecanoic acid.

Carbon-11 (11C)-palmitate is chemically identical to its physiological counterpart. After intravenous injection the myocardial distribution of 11C-activity can be measured accurately by positron emission tomography. Regions of decreased 11C-palmitate uptake can be readily identified and their size quantified. Results obtained in dogs with experimental coronary thrombosis and in patients with myocardial infarction indicate that positron emission tomography with 11C-palmitate allows non-invasive assessment of the metabolic recovery of the myocardium after lysis of the occluding coronary thrombus. There is experimental evidence that the rate of clearance of 11C-palmitate activity from the myocardium is related to oxidative fatty acid metabolism. In dogs, a restriction of the oxygen supply to the myocardium results in a decrease in the rate of 11C-clearance independently of whether myocardial perfusion is concomitantly reduced or not. Similarities in myocardial uptake and clearance exist between iodine-123 (123I)-heptadecanoic acid and 11C-palmitate. However, interpretation of the kinetics of the radio-iodinated fatty acid analogue has to take into account the different intracellular fate of the iodine label compared with the fatty acid structure.

Animals↗
PubMed1985

Pathophysiology of myocardial reperfusion.

The feasibility of myocardial reperfusion induced by coronary thrombolysis stimulated marked changes in the management of patients with acute myocardial infarction. Despite the demonstrable successful recanalization achieved in many patients, effective tissue reperfusion has not necessarily been achieved. Furthermore, factors defining the risk/benefit relationships of reperfusion, the extent to which salutary effects on jeopardized myocardium can be anticipated, and the ultimate long-term benefit conferred on the patient all require further definition. Widespread implementation of interventions utilized to induce myocardial reperfusion should be based on thorough characterization of the functional and metabolic responses of the heart to reperfusion. This selective review considers reperfusion within the context of an extensive body of information pertinent to the pathophysiological mechanisms underlying ischemic injury and discusses the potential favorable and unfavorable responses to reperfusion.

Acute Disease↗
PubMed1985

Characterization of the functional significance of subcritical coronary stenoses with H(2)15O and positron-emission tomography.

We have previously developed a method employing cardiac positron-emission tomography (PET) with 15O (half-life 2.1 min)-labeled water (H2(15)O) and blood pool subtraction with C15O for assessment of myocardial perfusion. This study was performed to determine whether the method developed permits detection of the differences in blood flow, induced by vasodilator stress, indicative of functionally significant subcritical coronary stenosis despite normal perfusion at rest. Coronary stenoses were induced with a small Teflon cylinder placed in the left anterior descending coronary artery of the closed-chest dog. Regional myocardial blood flow was assessed tomographically with H(2)15O given intravenously and C15O given inhalation. Blood flow distal to the stenoses was normal under conditions of rest. However, significant reductions in the hyperemic response to dipyridamole were detected consistently in regions distal to 50% to 70% diameter stenoses. Flow distal to stenoses more than doubled in absolute terms in response to dipyridamole but was only 43 +/- 9% of the increased flow in normal regions in the same dogs or in corresponding anterior regions in normal dogs. Relative myocardial blood flow measured noninvasively with PET correlated closely with the distribution of radiolabeled microspheres measured in vitro (r = .88). Thus, assessment of myocardial blood flow with H(2)15O and PET in dogs at rest and during vasodilator-induced stress permits detection of physiologically significant coronary stenoses. The procedure should therefore prove useful diagnostically for the detection of coronary insufficiency in patients as well as for the assessment of clinical interventions designed to augment regional perfusion.

Animals↗
PubMed1985

Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator.

To determine whether tissue-type plasminogen activator (t-PA) may prevent coronary thrombosis or accelerate the lysis of clot formed under conditions in which increased concentration of the activator is present before thrombosis, clot lysis studies were undertaken in vitro and in vivo. In vitro, exogenous t-PA (6 to 100,000 ng/ml) accelerated the lysis of clot in a dose-dependent fashion when the clot was formed either from whole plasma or from euglobulin fractions (n = 316 determinations). Adding t-PA before clot formation shortened the time to lysis by at least threefold with euglobulin fractions and by at least 10-fold with whole plasma clots, which is consistent with the presence of inhibitors of fibrinolysis in whole plasma and with the binding of t-PA to nascent fibrin. In an intact dog preparation of coronary thrombosis (n = 25), occlusive thrombus formation was prevented when t-PA was present in subthrombolytic concentrations (430 to 1200 ng/ml, n = 5). Occlusive thrombus formation occurred after only discontinuation of the t-PA infusion and clearance of t-PA. Lower concentrations of t-PA (147 to 427 ng/ml, n = 6) significantly delayed occlusion (26 +/- 6.5 vs 7.8 +/- 2.8 min for controls). In animals with t-PA concentrations of less than 140 ng/ml (n = 4), the time to occlusion was unaltered (7.7 +/- 4.5 min). The present study demonstrates that t-PA present before clot formation inhibits thrombosis or accelerates thrombolysis depending on concentration, and that subthrombolytic doses of t-PA can prevent thrombus formation in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Efflux of metabolized and nonmetabolized fatty acid from canine myocardium. Implications for quantifying myocardial metabolism tomographically.

It has generally been assumed, from assessment of myocardial metabolism with [1(-11)C]palmitate and positron emission tomography, that clearance of the radiolabel from the myocardium is attributable solely to efflux of the products of oxidative metabolism. However, interpretations would differ if this assumption were unfulfilled. Furthermore, efflux of metabolized and nonmetabolized tracer has not been quantified. Accordingly, in this study, myocardium was perfused extracorporeally in 21 open-chest anesthetized dogs, and the extraction and clearance of [1(-11)C]palmitate were characterized under baseline conditions (normoxia, n = 21), and, again, with ischemia (n = 6), with hypoxia (n = 9), or under control conditions (n = 6). After intracoronary bolus injection of [1(-11)C]palmitate, myocardial time activity curves were measured with a beta-probe, and the products of oxidative metabolism (11CO2) and efflux of extracted but nonmetabolized fatty acid ("back-diffusion" of [1(-11)C]palmitate) were measured directly from analysis of arterial and regional coronary venous blood. Under control conditions, 45.2 +/- 3.8% (mean +/- SD) of initially extracted [1(-11)C]palmitate was metabolized to 11CO2, whereas 6.2 +/- 2.6% back-diffused in unaltered form in 1-10 minutes. In contrast, with ischemia (perfusion of 26% of baseline), only 16.9 +/- 9.8% of administered tracer evolved as 11CO2 (P less than 0.001 compared with control) but 15.6 +/- 8.9% (i.e., almost half of the total amount cleared) evolved unaltered as [1(-11)C]palmitate (P less than 0.05). Similarly, with hypoxia, 15.1 +/- 8.4% evolved as 11CO2 (P less than 0.0001) and 18.8 +/- 11.7% back-diffused (P less than 0.001). Overall, from 1-40 minutes after intracoronary injection of tracer, back-diffusion of [1(-11)C]palmitate contributed 40.6% of total radioactivity in the effluent with ischemia, 48.7% with hypoxia, but only 8.9% under control conditions. Despite the increased back-diffusion of [1(-11)C]palmitate seen with ischemia and hypoxia, the overall residue of 11C activity in myocardium increased, consistent with the diminished clearance observed in the myocardial time-activity curves and the increase in the tissue content of triglyceride and nonesterified fatty acid. Our results indicate that estimates of oxidative metabolism based upon clearance of radiolabeled fatty acid must take into account the efflux of initially extracted but nonmetabolized fatty acid. The findings apply to external determination of oxidative metabolism of the heart with any imaging modality that delineates retention and clearance of labeled fatty acids or their analogs.

Animals↗
PubMed1984

Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction.

Tissue-type plasminogen activator is a naturally occurring, clot-selective activator of fibrinolysis. We recently reported that human tissue-type plasminogen activator isolated from a Bowes-melanoma-tissue-culture supernate lysed coronary thrombi in dogs without depleting circulating fibrinogen or alpha 2-antiplasmin, in contrast to the case with streptokinase and urokinase. In the present study coronary thrombolysis, confirmed angiographically, was induced within 19 to 50 minutes with intravenous or intracoronary tissue-type plasminogen activator in six of seven patients with evolving myocardial infarction. Circulating fibrinogen, plasminogen, and alpha 2-antiplasmin were not depleted by this agent, in contrast to the case in the two patients subsequently given streptokinase. In the one patient in whom lysis was not inducible with tissue-type plasminogen activator, it was also not inducible with streptokinase. These observations indicate that clot-selective coronary thrombolysis can be induced in patients with evolving myocardial infarction by means of tissue-type plasminogen activator, without concomitant induction of a systemic lytic state. Definition of its therapeutic benefit must await greater availability of the agent and the performance of appropriate clinical trials.

Aged↗
PubMed1984

Scintigraphic detection of coronary artery thrombi in patients with acute myocardial infarction.

To determine whether coronary thrombi can be detected scintigraphically after acute myocardial infarction, 24 patients were studied with a new method employing indium-111-labeled platelets and technetium-99m-labeled red blood cells. Nine patients with suspected infarction were evaluated initially within 9 hours of the onset of symptoms and again 18 to 24 hours after onset. Eight patients with neurologic symptoms but without overt cardiac disease and seven patients with angina but without infarction served as unmatched control subjects. Foci of net indium accumulation were detected after image processing that incorporated subtraction of blood pool activity. Carotid and pulmonary artery reference regions, in which blood pool activity is high and active platelet deposition unlikely, were used to correct digitized cardiac scintigrams for indium-111 platelet activity in the blood pool. In patients with infarction, distinct foci of net indium accumulation were present in regions corresponding to the coronary artery supplying ischemic zones. This occurred in seven of eight patients at the time of the earliest evaluation (5.6 +/- 3.3 hours [mean +/- SD] after the onset of symptoms) and in eight of nine patients at the time of subsequent imaging (23.6 +/- 1.9 hours after onset). Only 1 of the 15 control patients exhibited a cardiac focus of net indium accumulation. The percent of indium excess (100 [total indium-111 activity-blood pool indium-111 activity]/blood pool indium-111 activity) within the cardiac region measured (+/- SD) 16.8 +/- 11.6% in all patients with myocardial infarction (19.1 +/- 11.2% in those with visually identified foci) compared with 0.4 +/- 4.3% in control patients (p less than 0.001). This method permits early detection and sequential assessment of coronary artery thrombi. It should permit improved characterization of the role of platelets in the pathogenesis of acute manifestations of coronary vascular disease and improved evaluation of interventions designed to prevent or lyse coronary thrombi.

Blood Platelets↗
PubMed1984

Coronary thrombolysis with intravenously administered human tissue-type plasminogen activator produced by recombinant DNA technology.

Coronary thrombolysis was induced by intravenous infusion of human tissue-type plasminogen activator (recombinant human t-PA or rt-PA) obtained by expression of the cloned gene in a mammalian cell system. Thrombolysis was detected by the appearance of reperfusion arrhythmia and confirmed by repeat angiography in anesthetized dogs with 1-hr-old thrombi of the left anterior descending coronary artery that were induced with a copper coil. Infusion of 1000 IU (10 micrograms)/kg/min intravenous rt-PA (n = 9) elicited reperfusion within 13.7 +/- 1.9 min (mean +/- SE) without producing systemic fibrinolysis or distal coronary embolization. Infusion of urokinase at the same rate elicited thrombolysis in seven of 10 dogs within an average of 19.3 +/- 2.2 min. However, distal coronary embolization occurred in two dogs and systemic fibrinolysis was observed in all. In three dogs treated with urokinase thrombolysis was obtained only with subsequent intracoronary infusion. Restoration of myocardial perfusion and metabolism assessed with positron-emission tomography was consistently noted in dogs treated with rt-PA. Thus, rt-PA, a clot-selective thrombolytic agent that does not activate the fibrinolytic system systemically and that is potentially available in large quantities, in view of its synthesis by recombinant DNA technology, offers a promising practical approach for coronary thrombolysis in patients with acute myocardial infarction.

Angiography↗
PubMed1984

Quantification of regional myocardial blood flow in vivo with H215O.

Using H215O (half-life = 2.1 min) we demonstrated that a modification of the tissue autoradiographic approach permitted quantitation of myocardial blood flow in open-chest dogs by direct assay of myocardial tissue and that noninvasive estimation with positron-emission tomography (PET) delineated relative myocardial blood flow in intact dogs. In open-chest anesthetized dogs, the single-pass extraction fraction of H215O averaged 96 +/- 5% at flows of 80 to 100 ml/100 g/min. This high extraction fraction did not differ significantly over the range of 12 to 238 ml/100 g/min. Myocardial blood flow calculated after a 60 sec intravenous infusion of H215O and direct analysis of tissue correlated well with results obtained with microspheres (r = .94, n = 9 dogs). Subsequently the approach was adapted for preliminary use with PET. Estimation of myocardial content of radiolabeled H2O after intravenous infusion of 20 to 30 mCi of H215O was corrected for vascular pool radioactivity with the use of tomographic data obtained after administration of C15O by inhalation to label red blood cells. Tomograms obtained in vivo in six dogs with either normal or reduced regional blood flow correlated closely with the tomographically detectable distribution of 68Ga-labeled microspheres (r = .93) and with postmortem microsphere distribution (r = .95). The technique accurately reflects myocardial blood flow. With the use of PET, rapid sequential noninvasive estimation of relative regional myocardial blood flow has been demonstrated that should ultimately permit improved objective assessment of nutritional blood flow in patients in response to medical and surgical interventions designed to augment perfusion.

Animals↗
PubMed1984

Effects of acetyl glyceryl ether of phosphorylcholine (platelet activating factor) on ventricular preload, afterload, and contractility in dogs.

Acetyl glyceryl ether of phosphorylcholine (AGEPC), platelet activating factor, is a potent hypotensive agent that may mediate changes in blood pressure during anaphylaxis and may be involved in blood pressure variations of renal origin. This study was designed to characterize the hemodynamic mechanisms responsible for hypotension induced by this recently identified phospholipid. Intravenous administration of AGEPC to anesthetized open-chest dogs (n = 5) produced hemodynamic alterations which, for the purpose of analysis, were divided into three phases based on changes in the mean systemic blood pressure. During phase I (5-30 s) mean systemic blood pressure decreased to levels 5 to 10% below baseline values in association with a rise in cardiac output and a decrease in systemic vascular resistance. Phase II (30-90 s) consisted of a substantial reduction in systemic blood pressure to its nadir, 50% of baseline values, together with a decrease of similar magnitude in cardiac output and a rise in systemic vascular resistance. Phase III (90 s-60 min) exhibited a gradual recovery of mean systemic blood pressure toward normal with a several-fold rise in systemic vascular resistance and a continued low cardiac output. On the right side of the circulation, the predominant effect of AGEPC was a marked transient increase in pulmonary artery pressure in phase I, associated with an elevation of pulmonary resistance during phase II. Diethylcarbamazine blocked virtually all of these hemodynamic changes induced by AGEPC; FPL 55712 substantially blocked the rise in systemic vascular resistance in phase III. These results suggest that leukotrienes may mediate at least some of the hemodynamic effects induced by AGEPC, but further studies will be required when more specific leukotriene blocking agents become available. As assessed during phase III with the end-systolic pressure-dimension relation, myocardial performance itself was diminished. The occurrence of an AGEPC-induced negative inotropic effect was further confirmed in isolated Krebs-perfused guinea pig hearts and isolated blood-perfused rabbit hearts. The results indicate that the mechanism of AGEPC-induced hypotension is complex, affecting both vascular tone and the inotropic state of the myocardium.

Animals↗
PubMed1983

Clot-selective coronary thrombolysis with tissue-type plasminogen activator.

Coronary thrombolysis, an intervention that can abort the sequelae of acute myocardial infarction, was accomplished within 10 minutes in dogs by intravenous administration of clot-selective, tissue-type plasminogen activator. In addition to inducing clot lysis, this promising fibrinolytic agent restored intermediary metabolism and nutritional myocardial blood flow, detectable noninvasively with positron tomography, without inducing a systemic fibrinolytic state.

Animals↗
PubMed1983

Consistent substrate utilization despite reduced flow in hearts with maintained work.

Assessments of myocardial metabolism based on external detection of accumulation of radiolabeled substrates may be influenced, as a result of alterations in flow, by altered substrate delivery as well as altered work (with concomitant changes in metabolic requirements). To determine whether reduced delivery limits substrate utilization under defined conditions of reduced perfusion, an isolated rabbit heart preparation was employed in which flow was reduced but myocardial oxygen consumption (MVo2) and work were kept constant by adjustment of left ventricular end-diastolic pressure and heart rate. Flow was reduced from 1.5 to 0.5 ml . g-1 . min-1, while work was maintained constant in hearts functioning at either low or high levels of MVo2. Consumption of palmitate remained constant (48.8 +/- 11.6 and 68.8 +/- 23.3 nmol . g-1 . min-1), because the proportion of palmitate extracted increased (8.8 +/- 4 to 29.1 +/- 7.2% and 10.3 +/- 3.4 to 21.0 +/- 6.1%). The results indicate that, despite reduction of flow, hearts at constant work loads can extract increasing proportions of delivered substrates such that net utilization remains constant until flow is reduced below the level required to maintain cellular function. They suggest that, under conditions of low flow, impaired extraction of substrates reflects either primarily or secondarily depressed myocardial metabolism rather than simply decreased delivery of substrate.

Adenosine Triphosphate↗