Biomedical subjects
Publications and source records attributed to J T Willerson.
The plasminogen-plasmin enzyme system and its therapeutic manipulation provide the substrate for an assessment of the clinical use of thrombolytic agents. Proven effective in acute MI and its complications, such agents have other potential applications--e.g., in stroke or pulmonary embolism--and are being investigated in those contexts.
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The objectives of this study were to test the hypotheses that thrombin inhibitors 1) enhance tissue-type plasminogen activator (t-PA)-induced coronary thrombolysis and 2) prevent or delay coronary artery reocclusion. Seventy-one dogs developed occlusive coronary thrombi after introducing a copper coil into the left anterior descending coronary artery (LAD). Coronary blood flows were monitored by an externally positioned pulsed Doppler flow probe. t-PA was given with or without heparin at different times after LAD occlusions. In some experiments, hirugen, a synthetic hirudin-based peptide and specific thrombin inhibitor, was given as 4 mg/kg i.v. bolus and 3 mg.kg-1.h-1 i.v. infusion at 30 min after LAD occlusion with t-PA and a bolus of heparin. Thrombolysis times were significantly shorter in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Reocclusion times were significantly longer in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Continuous heparin infusions prolonged reocclusion times to greater than 180 min in all treated dogs. The addition of hirugen to t-PA plus one bolus heparin prolonged reocclusion times to 90 +/- 6 min in dogs with 30-min thrombi. Thus heparin enhances t-PA-induced thrombolysis and delays reocclusion. Addition of a specific thrombin inhibitor, such as hirugen, to heparin enhances its effect on delaying reocclusion.
BACKGROUND: Experimental cardiac ischemia in some animal models results in the activation of the enzyme 5-lipoxygenase and the subsequent production of leukotrienes, potent proinflammatory lipid mediators, by the affected myocardium. Furthermore, prototype antileukotriene drugs can show some beneficial effects on infarct size and cardiac function in these models. Accordingly, urinary excretion of leukotriene E4 (LTE4), the major urinary metabolite of peptide leukotrienes in humans, was measured in patients admitted to the hospital with evidence of acute myocardial ischemia to assess in vivo release of 5-lipoxygenase products during and after the ischemic episode. METHODS AND RESULTS: Urinary leukotriene excretion was measured by reversed-phase high-performance liquid chromatography and specific radioimmunoassay on admission with acute chest pain and again on day 3 in the following patient groups: acute myocardial infarction (AMI), AMI and clinical evidence of early reperfusion after treatment with recombinant tissue-type plasminogen activator (rt-PA), diagnosis of unstable angina (UA) based on clinical history and coronary arteriography, controls with nonischemic chest pain who underwent coronary arteriography, and age-matched controls and normal hospital employees. In 16 patients with diagnosis of AMI, LTE4 excretion on admission (331 +/- 99 pg/mg creatinine sulfate; mean +/- SEM) was considerably higher than that measured on day 3 (195 +/- 59 pg/mg creatinine sulfate). In a subgroup of seven subjects treated with rt-PA resulting in early reperfusion, day 1 excretion was similar (215 +/- 50 pg/mg) but had significantly declined by day 3 (65 +/- 16 pg/mg; p less than 0.01). Urinary LTE4 excretion at admission for chest pain was also elevated in 14 patients having unstable angina (UA; 370 +/- 125 pg LTE4/mg creatinine sulfate). This had declined significantly (p less than 0.05) by day 3 (at which time chest pain had resolved) to 94 +/- 31 pg/mg creatinine sulfate, an excretion rate comparable with that measured in eight similarly aged subjects (64 +/- 12 pg/mg creatinine). CONCLUSIONS: This study suggests that peptide leukotrienes are released during episodes of myocardial ischemia and provides clinical evidence for involvement of their biosynthetic enzyme, 5-lipoxygenase, during and after acute myocardial infarction and unstable angina attacks. Thus, potent and specific orally active leukotriene biosynthesis inhibitors may have therapeutic potential in limiting myocardial damage and functional abnormalities after acute ischemia.
BACKGROUND: This study was designed to test the hypothesis that endogenously produced nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries of mongrel dogs. METHODS AND RESULTS: NG-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide formation, was administered at 5 mg/kg to 15 dogs after the left anterior descending coronary artery was mechanically injured and narrowed by external constrictors and to nine dogs before endothelial injury of the femoral artery and after injury and moderate arterial constriction. Treatment with L-NMMA resulted in cyclic flow variations (as detected by external Doppler flow probes) in the left anterior descending artery of seven of 15 dogs and in the femoral artery of four of nine dogs after endothelial injury. L-Arginine, the precursor for nitric oxide synthesis, was administered at 60 mg/kg and abolished cyclic flow variations in each of the 11 dogs. D-Arginine did not change the L-NMMA-induced cyclic flow variations. Saline infusion did not induce or change cyclic flow variations in any of the animals. Acetylcholine (1, 10, and 100 micrograms/min; n = 9) was administered in the femoral artery of nine additional dogs before and after endothelial injury in moderately stenosed femoral arteries. Acetylcholine did not induce cyclic flow variations in any animal; however, it did increase the severity of cyclic flow variations that developed in severely stenosed arteries. The diameter of the femoral artery was measured by intravascular ultrasound imaging. L-NMMA caused vasoconstriction of normal arteries, but no change was detected in endothelium-injured arteries. In contrast, L-arginine caused vasodilation of normal arteries, but, again, no change was noted in endothelium-injured arteries. Acetylcholine dilated normal femoral arteries but constricted arteries with endothelial injury. In both in vitro and ex vivo platelet studies, L-NMMA enhanced platelet aggregation, whereas L-arginine significantly reduced platelet aggregation. D-Arginine and acetylcholine showed no effect on platelet aggregation. CONCLUSIONS: Promotion of nitric oxide production decreases platelet aggregation and may eliminate cyclic flow variations, whereas a reduction in nitric oxide formation enhances platelet aggregation and may induce cyclic flow variations. Acetylcholine causes vasoconstriction at the femoral arterial site of endothelial injury and may increase the severity of cyclic flow variations.
BACKGROUND: The efficacy of thrombolytic therapy in treating patients with acute myocardial infarction is limited by failure to achieve reperfusion in some patients, by the prolonged time required to achieve reperfusion, and by reocclusion of some coronary arteries. We designed this study to examine the effect of combined inhibition of thrombin and thromboxane synthesis and blockade of thromboxane A2 receptors in addition to tissue-type plasminogen activator (t-PA) on thrombolysis and reocclusion in an experimental canine model with coronary thrombosis. METHODS AND RESULTS: Blood flow velocity in the left anterior descending coronary artery (LAD) of 32 anesthetized mongrel dogs was monitored by a pulsed Doppler flow probe. Coronary thrombosis was induced by applying electrical stimulation to the LAD at the site where an external constrictor was used to narrow the artery. Three hours after the formation of occlusive thrombus, animals were randomly assigned to receive one of the following: 1) t-PA (80 micrograms/kg + 8 micrograms.kg-1.min-1 i.v.) and saline; 2) t-PA and hirulog, a hirudin-based synthetic peptide and specific thrombin inhibitor (2 mg/kg + 2 mg.kg-1.hr-1 i.v.); 3) t-PA and ridogrel, a combined thromboxane A2 synthetase inhibitor and receptor antagonist (5 mg/kg + 2.5 mg.kg-1.hr-1 i.v.); or 4) t-PA, hirulog, and ridogrel. Reperfusion developed in 14% (one of seven) of dogs treated with t-PA alone at an average of 86 +/- 4 minutes after treatment, in 78% (seven of nine) of dogs treated with t-PA plus hirulog at 53 +/- 11 minutes, in 13% (one of eight) of dogs treated with t-PA plus ridogrel at 85 +/- 5 minutes, and in 88% (seven of eight) of dogs treated with t-PA, hirulog, and ridogrel at 37 +/- 10 minutes (comparison of the frequency of and the time to reperfusion, both p < 0.01). Among the dogs with reestablished coronary blood flow, reocclusion developed in the one treated with t-PA alone at 36 minutes after reperfusion, in seven of the seven treated with t-PA plus hirulog at 66 +/- 15 minutes, and in two of the seven treated with t-PA, hirulog, and ridogrel at 151 +/- 21 minutes (comparison of the frequency of and time to reocclusion, both p < 0.05). Reocclusion was not detected in the one dog treated with t-PA and ridogrel or in the other five dogs treated with t-PA, hirulog, and ridogrel within 180 minutes after reperfusion. Hirulog prolonged and maintained activated clotting times at a level twice that of baseline values. Hirulog inhibited ex vivo platelet aggregation induced by thrombin, and ridogrel inhibited platelet aggregation induced by U46619, a thromboxane mimetic. CONCLUSIONS: Inhibition of thrombin in addition to treatment with t-PA enhances thrombolysis. A combination of inhibition of thrombin and thromboxane synthetase and blockade of thromboxane A2 receptor enhances thrombolysis and delays or may prevent reocclusion of the recanalized coronary arteries.
This study characterizes the sequential alterations of, and relations between, multiple electrolytes in cytoplasm, mitochondria, and whole cells during hypoxia and on reoxygenation in isolated neonatal rat ventricular myocytes. Subcellular electrolyte content and distribution were measured by electron probe x-ray microanalysis, membrane phospholipid degradation by tritiated arachidonic acid release, and cell morphology by electron microscopy. At 1-2 hours of hypoxia, the myocyte population showed a loss of cytoplasmic potassium, magnesium, and chlorine without alteration of cytoplasmic sodium or calcium. Mitochondria showed increased potassium with unchanged magnesium content. There was no morphological evidence of cell injury or tritiated arachidonic acid release. At 3-5 hours of hypoxia, the myocyte population showed a further loss of cytoplasmic potassium and magnesium and an increase in cytoplasmic sodium, chlorine, and calcium. At a single-cell level, the increase in cytoplasmic sodium preceded the increase in cytoplasmic calcium. Mitochondria showed increased sodium and chlorine and decreased magnesium before increased calcium content; potassium loss was manifest only at 5 hours of hypoxia. At 3-5 hours of hypoxia, there was also tritiated arachidonic acid release and morphological evidence of cell injury. Reoxygenation for 1 hour after 5 hours of hypoxia partially reversed the mean alterations of all electrolytes, except calcium, in the cytoplasm of the myocyte population, whereas analysis was required at a single-cell level to show a partial reversal in calcium levels in cytoplasm of reoxygenated cells. Reoxygenation for 1 hour after 5 hours of hypoxia partially reversed the mean alterations of all electrolytes, including calcium, in the mitochondria of the myocyte population. Recovery of potassium in the cytoplasm correlated with reduction of mitochondrial calcium content on reoxygenation and best predicted recovery of cellular homeostasis of sodium, chlorine, magnesium, and calcium. This study demonstrates that in this experimental model of hypoxia 1) initial losses of cytoplasmic potassium and magnesium occur in the absence of cell injury; 2) increases of sodium, chlorine, and calcium occur in association with cell injury, with sodium increasing before calcium; 3) membrane phospholipid degradation and electrolyte derangement, including increased calcium, may contribute to reversible and irreversible phases of cell injury; 4) analysis of calcium at a subcompartmental level and at a single-cell level is required to correlate reduction of calcium on reoxygenation with recovery of cell homeostasis; 5) reduction of calcium content in mitochondria may predict recovery of cell homeostasis; and 6) recovery of potassium on reoxygenation best predicts recovery of cell membrane function and cell homeostasis.
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The Carpentier-Edwards bioprosthesis is a glutaraldehyde-fixed porcine xenograft with a fully flexible thin-walled stent. Cardiac catheterization studies were performed in 17 patients to evaluate use of this valve in the aortic position. Hemodynamic studies established a mean peak gradient across the prosthesis of 19 mm Hg (range 5 to 65). The mean effective orifice area was calculated to be 1.6 cm2 (range 0.8 to 3.3). All patients demonstrated an improvement in functional class after operation. Mean left ventricular ejection fraction increased from 51 +/- 16 to 68 +/- 9 percent (P less than 0.004) in eight patients operated on for aortic stenosis, but was not significantly changed in patients operated on for aortic insufficiency. Hemodynamic comparison of the Carpentier-Edwards bioprosthesis with the standard Hancock xenograft showed similar effective orifice areas for the 23 and 25 mm diameter valves. In two patients studied the 21 mm Carpentier valve demonstrated a greater effective orifice area than that previously reported for the standard Hancock xenograft. The Carpentier-Edwards bioprosthesis affords both clinical and hemodynamic improvement when used in the aortic position and may allow improved effective orifice area when used in the smaller aortic root.
ST amplitude distributions were studied in 41 patients with acute myocardial infarction by deriving isopotential maps from a 5 x 7 electrode precordial matrix. Independent data on infarct size and localization were obtained utilizing the technetium 99m stannous pyrophosphate scintigraphic method. The locus of maximal ST elevation was stable for at least two days in 86% of 27 patients with anterior infarction. A single maximum or maximum-minimum was found in 88% but 22% of the patients had multiple maxima and/or minima in at least two maps. Areas of significant ST elevation were often excluded from the precordial matrix. The site of maximal ST elevation correlated with scintigraphic infarct site but was displaced medially in lateral infarction. The relation between infarct size and sigmaST elevation was significant and curvilinear. sigmaST underestimated size in large anterior infarction. The correlation of the size and the number of sites with ST elevation greater than or equal to 1.5 mm was weak (r = 0.56). The degree of ST abnormality in 14 patients with inferior infarction decreased significantly during the initial 24 hours. The isopotential maps were similar to those obtained in anterior infarction but the polarity was reversed. The results provide limited support for the continued exploration of ST analysis as a clinical method but suggest that sizing methods should be based on total body surface mapping, taking into account the geometry and electrical properties of the torso.
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Oxidative phosphorylation of isolated canine myocardial mitochondria has been evaluated after exposure to different concentrations of phosphate (5--50 mM), lactate ion in excess (5--40 mM, pH 7.4), calcium (50--270 nmol/mg protein), to lactic acidosis (pH 6.3), and to mitochondrial protein dilution (in vitro volume expansion) for 10 min to 8 h. The influence of phosphate and lactate ion addition, lactic acidosis, and in vitro volume expansion on mitochondrial function were studied in the isolation medium (0.18 M KCl, 0.5% BSA (bovine serum albumin), with or without Tris-EDTA, pH 7.4) prior to evaluation of mitochondrial function in the assay medium (0.25 M sucrose, 10 mM Tris-HCl, and 10 mM inorganic phosphate, pH 7.4). The effect of calcium addition was assessed in the assay medium. The results of these studies demonstrate that each of these interventions detrimentally alters mitochondrial oxidative phosphorylative ability. The most severe mitochondrial functional impairment resulted from phosphate or calcium addition. The detrimental effect of phosphate and in vitro volume expansion was partially corrected by the addition of cytochrome c.
Scintigraphic, clinical and pathological findings were correlated in 52 patients studied by technetium-99m stannous pyrophosphate (99mTc-PYP) myocardial scintigraphy before death or surgical resection of myocardium. Fifty-nine clinical events were studied with scintigraphy in the 52 patients; 41 of the 59 were associated with one or more abnormal 99mTc-PYP studies and 18 with normal 99mTc-PYP scintigrams. Myocardial scintigrams were positive in 29 of 31 cases with clinicopathological evidence of a corresponding discrete, grossly obvious acute myocardial infarct, including 16 of 16 transmural myocardial infarcts and 13 of 15 subendocardial infarcts. In 16 of 18 cases, negative myocardial scintigrams correlated with the absence of acute myocardial infarction determined by clinicopathological evidence. In two cases small subendocardial infarcts (less than 3 g) were not detected by 99mTc-PYP myocardial scintigraphy. Of the 12 additional instances of positive 99mTc-PYP myocardial scintigrams, five were associated with clinical unstable angina pectoris and seven were in the category of persistently positive scintigrams, since the scans were obtained 2.5 months or longer after proven or suspected acute myocardial infarcts. In all 12 instances, the positive 99mTc-PYP scintigrams were associated with evidence of multifocal irreversible myocardial damage consisting of myocytolysis, coagulation necrosis and/or fibrosis, and the histological age of the lesions was compatible with acute injury corresponding to the time of scintigraphy. The findings indicate that a positive 99mTc-PYP myocardial scintigram is a sensitive indicator of significant myocardial injury which may occur as confluent coagulation necrosis corresponding to clinical acute myocardial infarction, or as multifocal coagulation necrosis or myocytolysis associated with unstable angina pectoris or recurrent ischemic heart disease, especially after previous infarctions.