Bolus application of a novel recombinant plasminogen activator in acute myocardial infarction patients: pharmacokinetics and effects on the hemostatic system.
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Adult↗
Biomedical subjects
M M Müller
Publications and source records attributed to M M Müller.
Decreased tissue reaction to bioprosthetic heart valve material after L-glutamic acid treatment. A morphological study.
Degenerative alterations of two different glutaraldehyde (GA)-fixed bioprosthetic heart valve materials were investigated in subcutaneous rat implants: Bovine pericardium, prepared according to clinically used bioprosthetic heart valve material (BHV) was compared to alternatively preserved pericardium (APHV), which was fixed in GA and treated with L-glutamic acid. Following 63 days of subcutaneous implantation, calcification of APHV implants was significantly lower as compared to BHV implants (13 +/- 6 versus 158 +/- 18 micrograms Ca/mg dry weight tissue; p less than 0.05). In BHV implants ultrastructural investigations showed nucleation of plate-shaped hydroxyapatite crystals at the surface of collagen fibrils and in remnants of connective tissue cells; no signs of calcification could be detected in APHV implants. The time-course of the inflammatory reaction was determined by quantification of immunohistochemical stained mononuclear host-cells invading the implants. In both preparation groups inflammatory reaction reached maximum 42 days after implantation. However, infiltration rate of inflammatory cells was markedly decreased in APHVs as compared to BHVs (p less than 0.05).
Animals↗
Neopterin release from human endothelial cells is triggered by interferon-gamma.
Human umbilical vein endothelial cells (HUVEC) were investigated for their ability to produce neopterin, a biochemical marker for an activated immune system. Interferon-gamma (IFN-gamma), IL-1 alpha, IL-2, IL-6, tumour necrosis factor-alpha, granulocyte/macrophage colony stimulating factor, phytohaemagglutinin and concanavalin A were used to stimulate HUVEC. While IFN-gamma induced neopterin release from HUVEC in a time- and dose-dependent manner, all the other cytokines used had no effect on neopterin production. High neopterin levels are found in patients with rejection episodes or infections. Our results suggest that not only monocytes and macrophages, which are known to synthesize neopterin, but also endothelial cells are responsible for these high serum neopterin levels.
Biopterins↗
Improved biocompatibility of bioprosthetic heart valves by L-glutamic acid treatment.
Treatment of glutaraldehyde-fixed pericardium with L-glutamic acid and storage in bacteriostatic preservatives (paraben) stably antagonizes free, reactive aldehyde groups within the fixed bioprosthetic heart valve tissue. In 63-day subcutaneous implants in rats, the calcification rate of this treatment (13.3 +/- 2 mg calcium/g wt tissue) was markedly reduced as compared to conventionally treated tissue (169 +/- 24 mg/g; p less than 0.05). To test the influence of tissue-released toxic aldehydes on spontaneous endothelial cell ingrowth in vivo, vascular grafts (8-cm long, 6-mm diameter) from fixed pericardium treated with L-glutamic acid were interposed into the carotid arteries in ten sheep. They were compared to grafts from conventionally treated pericardium implanted at the contralateral side. Following 3 months of implantation, planimetry revealed 49% +/- 20% of the surface of conventionally preserved pericardium to be covered with red thrombus, but only 12% +/- 5% in L-glutamic acid treated pericardium (p less than 0.05). The ultrastructural findings of a closed endothelial cell layer on the graft surface reveals the new technique to be a promising approach towards increased biocompatibility of aldehyde-fixed bioprosthetic heart valves.
Animals↗
Endothelial cell lining of bioprosthetic heart valve material.
In this in vitro study, the growth properties of cultured endothelial cells on conventionally treated pericardial valve material were measured. These data were compared to endothelial cell proliferation on an alternatively treated valve material. This alternative preservation procedure was developed in order to bind free, residual glutaraldehyde in the valve tissue by reaction with L-glutamic acid. In order to optimize endothelial cell attachment and proliferation, fibronectin and fibrillar collagen type I were tested as surface precoating substances. Cell viability of the seeded cells was evaluated by means of proliferation kinetics, antithrombotic activity, and morphological appearance. Endothelial cell death occurred within the first 2 days after seeding on conventionally treated valve tissue, independent of the type of precoating. On alternatively treated tissue, regular endothelial cell proliferation was observed. Precoating with fibrillar collagen markedly increased endothelial cell attachment and proliferation as compared to fibronectin. Maintenance of antithrombotic activity of the seeded cells was proven by regular release of prostacyclin.
Animals↗
Endothelial cell lining of bioprosthetic heart valve materials.
To investigate the conditions for endothelial cell lining of glutaraldehyde-treated bioprosthetic heart valves, we examined in vitro the growth properties of endothelial cells on clinically used pericardial valve material and on glutaraldehyde-fixed pericardium treated with L-glutamic acid. To improve endothelial cell attachment to the valvular surface, we precoated both materials either with fibronectin or with fibrillar collagen (95% type I, 5% type III). Toxicity of glutaraldehyde, released from clinically used valve material, caused endothelial cell death, independent of the type of precoating. Treatment of the valve material with L-glutamic acid resulted in regular endothelial cell proliferation. We found that collagenous precoating, compared with fibronectin precoating, markedly enhanced endothelial cell proliferation and attachment (p less than 0.05). Maintenance of antithrombogenic potency of the seeded cells on L-glutamic acid-treated valve material was proved by regular release of prostacyclin. We conclude that bioprosthetic heart valve materials can be lined with endothelial cells if toxic glutaraldehyde released from the bioprostheses is eliminated.
Animals↗
Aprotinin decreases release of 6-keto-prostaglandin F1 alpha and increases release of thromboxane B2 in cultured human umbilical vein endothelial cells.
Use of the proteinase inhibitor aprotinin significantly improves hemostasis and reduces bleeding after operations in which extracorporeal circulation is used. The mechanism of action, however, has been only partially clarified. In this work we investigated whether aprotinin influenced the production and release of the eicosanoids prostacyclin, measured as the stable metabolite 6-keto-prostaglandin F1 alpha, and thromboxane A2, measured as the stable metabolite thromboxane B2, from endothelial cells. Human umbilical vein endothelial cells were incubated with different concentrations of aprotinin (5.5, 20, 55, and 100 mumol/L). The levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 were measured at baseline and after thrombin stimulation. A concentration-dependent effect of aprotinin on 6-keto-prostaglandin F1 alpha synthesis was demonstrated. After incubation with 100 mumol/L of aprotinin, a 90% reduction in 6-keto-prostaglandin F1 alpha production was seen (31.69 versus 307.44 picograms per million cells; p less than 0.001). Conversely, thromboxane B2 production showed a 345% increase after incubation with aprotinin (287.80 versus 83.82 picograms per million cells; p less than 0.0001). Since 6-keto-prostaglandin F1 alpha inhibits and thromboxane B2 strongly enhances platelet aggregation, it appears that one mechanism of the clinically observed effectiveness of aprotinin lies in the altered ratio of 6-keto-prostaglandin F1 alpha: thromboxane B2 in endothelial cells, which leads to enhanced platelet aggregation and improved vessel sealing.
6-Ketoprostaglandin F1 alpha↗
Serum lipid peroxide levels in the course of coronary by-pass surgery.
Reperfusion of the ischemic myocardium is associated with the extension of already existing injury. Investigation of the reperfused myocardium under different conditions revealed ultrastructural changes as well as functional disturbances which were identified as free radical-mediated damage. Free radical scavengers and antioxidant agents have been shown to reduce the size of the infarct, in which a temporary regional ischemia was followed by reperfusion. Elaborately designed in vitro and animal models strongly suggest that reperfusion injury might be of clinical significance in operations involving extracorporeal circulation, as in coronary by-pass surgery. However, there is limited information on the relationship between reperfusion injury and subsequent clinical conditions. In our study, we determined lipid peroxide concentrations in timed serum samples of patients who had undergone coronary by-pass surgery. Preoperative lipid peroxide concentrations were 2.50 +/- 0.50 mumol/l. This value increased to 3.30 +/- 1.00 mumol/l after six hours and showed a second increase to 4.20 +/- 0.80 mumol/l 48 hours after the onset of reperfusion. These results suggest that postoperative increases in lipid peroxide concentrations can be of multifactorial origin and may be an indication of reperfusion injury to the myocardium. Further studies are under way to elucidate the relevance of this increase in different groups and clinical conditions.
Aged↗
Glutaraldehyde affects biocompatibility of bioprosthetic heart valves.
A marked release of glutaraldehyde from commercially available pericardial bioprosthetic heart valve (BHV) material in washing solutions was found by high performance liquid chromatography (up to 1.8 ppm of glutaraldehyde per gram of dry tissue). In vitro endothelial cell proliferation rate was impaired dose-dependently in the presence of increasing glutaraldehyde concentrations of the cultivation medium (r = 0.9; p less than 0.05). Cultivation of endothelial cells was impossible on the surface of commercially available BHV material, but successful and uninhibited when toxic glutaraldehyde ligands of the BHV material were antagonized by treatment with L-glutamic acid.
Animals↗
Neopterin in clinical practice.
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Biopterins↗
Regulation of eicosanoid release in human umbilical endothelial cells.
The concentration dependent influence of adenine nucleotides, thrombin and ionophore A 23187 on eicosanoid-production of human endothelial cells was investigated. The prostaglandin I2 (PGI2)-and thromboxane A2 (TXA2)-release were highest at concentrations of 1 mmol/l and 4 mmol/l adenine nucleotides, respectively. TXA2-release decreased at higher concentrations. Ionophore-induced eicosanoid-formation reached its maximum at 15 mumol/l for both PGI2 and TXA2. Thrombin stimulation resulted in a bell shaped concentration dependency, whereby most TXA2 was released at a concentration of 1 U/ml and most PGI2 at 5 U/ml. Intracellular cAMP showed significant (p less than 0.01) increases stimulating cells with ADP- and ATP-concentrations higher than 500 mumol/l, whereas ionophore and thrombin did hardly affect cAMP levels.
6-Ketoprostaglandin F1 alpha↗
Effects of H2O2 and CHPO on ATP-, CP-content and 14C-HX-uptake by HUVECS.
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Adenosine Triphosphate↗
Biocompatibility of aldehyde-fixed bovine pericardium. An in vitro and in vivo approach toward improvement of bioprosthetic heart valves.
Aldehyde-induced side effects limit the clinical usefulness of bioprosthetic heart valves. Treatment of aldehyde-fixed pericardium with L-glutamic acid at pH 3.5 and storage in a nontoxic, bacteriostatic solution resulted in a lower degree of calcification in 63-day subcutaneous implants in rats (13.3 +/- 2 mg calcium per gram dry weight of tissue), as compared with commercially available tissue (169 +/- 24 mg/gm, p less than 0.05). Endothelial cells died within 1 day after seeding on the commercial tissue; however, considerable endothelial cell proliferation was measured, even 14 days after seeding on L-glutamic acid-treated pericardium. Improved biocompatibility of this alternative treatment may be due to stable chemical binding of free, reactive aldehyde groups.
Animals↗
[The value of fructosamine in hemodialysis patients].
Fructosamine is thought to be an alternative diabetic long term parameter to HbAlc. A possible advantage of fructosamine is the shorter half life of this parameter. Therefore changes in the metabolic control of diabetes can be evaluated faster. However, daily variations of protein concentrations limit the clinical usefulness of fructosamine, especially in patients on hemodialysis, where we see variations in total protein- and albumin concentration during dialysis. Due to these limitations we studied the clinical usefulness of a new fructosamine assay in 38 patients with chronic renal failure. Fructosamine values, total protein, albumin, blood glucose and creatinine were measured before and after three hours hemodialysis treatment as well as glycosylated hemoglobin. Before dialysis HbA1c correlated with HbA1c after dialysis (r = 0.99), which documents the usefulness of glycosylated hemoglobin in patients on hemodialysis. Fructosamine before dialysis shows a correlation with fructosamine values after dialysis of r = 0.77. After correction with total protein the correlation was r = 0.95, also after correction with albumin. Fructosamine values before and after dialysis correlated excellently (r = 0.95). Fructosamine values before and after dialysis can only be compared after correction with total protein or with albumin.
Blood Glucose↗
[Diurnal variations of fructosamine in patients with type II diabetes mellitus].
During the last years fructosamine has been presented as a measurement of diabetic long term control, particularly a shorter half life of fructosamine was seen as an advantage over HbAlc (half life of fructosamine: 16 days, half life of HbAlc: 28 days). Due to diurnal variations of fructosamine levels especially in dependence of variations of the albumin-and protein concentrations the interpretation of this parameter was somewhat limited. Recently a new colorimetric fructosamine-assay was developed. We investigated the diurnal variations of fructosamine in 28 patients with type II diabetes. Fructosamine, glucose, albumin, total protein and creatinine were measured at the times towards 3, 6, 9, 12 a.m. and 3, 6, 9, and 12 p.m. In relation to the 6 a.m. fructosamine value (= 100%) the fructosamine levels showed a daily variation from -4% at 3 a.m. to +11% at 9 a.m. Correcting fructosamine levels with total protein or with albumin reduced the variations to -1% to +6% or -3% to +9%. Daily profiles of the new fructosamine assay show a daily variation which can be minimized by correcting with protein-or with albumin concentrations. For clinical routine the daily variations especially of the corrected fructosamine levels are neglectible.
Adult↗
Diagnosis of perioperative myocardial infarction by considering relationship of postoperative electrocardiogram changes and enzyme increases after coronary bypass operation.
We report the results of enzyme determinations in sera from 88 patients, 65 of whom showed inconspicuous reconvalescence, 14 who had myocardial infarction within 24 h (MI 1) after bypass surgery, and nine with myocardial infarction between 24 and 48 h postoperatively (MI 2). We wanted to determine whether the consequent measurement of activities of total creatine kinase (CK), CK isoenzyme MB (CK-MB), lactate dehydrogenase, alpha-hydroxybutyrate dehydrogenase, and aspartate aminotransferase, conducted as a part of routine laboratory diagnostics, provided meaningful information for diagnosing infarcts besides that obtained from the electrocardiogram. The postoperative mean values of the enzyme activities in blood were significantly different among the three groups; however, only a combined evaluation of CK and CK-MB by means of a discriminant analysis allowed the prediction of MI (sensitivity: MI 1 = 98.5%, MI 2 = 95.4%; specificity: MI 1 = 71.4%, MI 2 = 81.8%). CK greater than 600 U/L or CK-MB greater than 45 U/L supports the diagnosis of acute MI.
Adult↗
[Purine metabolism in endothelial cells].
In human umbilical endothelial cells purine metabolism was studied: activities of some key-enzymes, concentrations of ATP, ADP, and creatine phosphate (CP), and the incorporation of labeled purine bases, purine nucleosides and glycine were measured. The results obtained show that endothelial cells are capable of degradation and synthesis of purine nucleotides. The rate of purine nucleotide synthesis via salvage pathways predominates that of de novo synthesis. Preincubation with phosphate resulted in increased nucleotide pools and incorporation of performed purines, whereas ribose showed the opposite effect. An explanation of these effects might be the limited availability of intracellular phosphoribosylpyrophosphate.
Cells, Cultured↗
Thromboxane A2 generation by human umbilical endothelial cells.
Human umbilical endothelial cells were examined for their ability to release thromboxane A2 (TXA2) and prostacyclin (PGI2). We could show that the basal, unstimulated release of the two eicosanoids was inversely related to the cell density. At a density of 100,000 cells/cm2 TXA2 release was 0.062 +/- 0.28 fg/cell/h and PGI2 release was 0.184 +/- 0.051 fg/cell/h, whereas at a cell density of 20,000 cells/cm2 the cells released 1.075 +/- 0.055 fg TXA2/cell/h and 1.653 +/- 0.09 fg PGI2/cell/h. In stimulation experiments ATP and ADP significantly (p less than 0.001) increased the TXA2 and the PGI2 release. ANF caused a slow but still significant (p less than 0.001) enhancement of TXA2 release. Thrombin and ionophore A23187 caused the strongest stimulatory response, resulting in a significantly (p less than 0.001) increased release of both eicosanoids.
Data Interpretation, Statistical↗