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Biomedical subjects

M Schmoeckel

Publications and source records attributed to M Schmoeckel.

At least 37 records · Page 2Linked to original sources
PubMed1997

Transgenic human decay accelerating factor makes normal pigs function as a concordant species.

BACKGROUND: Increasing interest has focused on xenotransplantation as a potential solution to the organ shortage. To overcome hyperacute rejection, pigs have been produced that are transgenic for human decay accelerating factor (DAF). For the evaluation of the effects of human DAF, an ex vivo working heart model was used. METHODS: We compared hemodynamic performance of four transgenic pig hearts (group A) with that of four Landrace pig hearts (group B) and eight rhesus monkey hearts (group C). For perfusion fresh blood had been taken from healthy volunteers. From the coronary sinus effluent, samples were taken for the determination of 6-keto prostaglandin F1 alpha, prostaglandin E2, creatine phosphokinase, and lactate dehydrogenase, respectively. Hemodynamic parameters were measured continuously for 150 minutes after the start. After 15 minutes of reperfusion, the Langendorff-mode was switched to the working heart model. After hearts failed to pump against the afterload column, experiments were terminated, and tissue sections were taken for electron microscopy. RESULTS: Groups A and C showed superior cardiac performance as measured by stroke work index (SWI) that exceeded group B by 2.5 to 3 times (p < 0.05). In all three groups the SWI slowly decreased during perfusion. In group B, SWI decreased to a minimum as early as 90 minutes after the start. In all groups, 6-keto prostaglandin F1 alpha and prostaglandin E2 as indicators of endothelial cell activation increased. In group B, however, the levels exceeded those of groups A and C by six and nine times, respectively (p < 0.05). As markers of myocardial damage, creatine phosphokinase and lactate dehydrogenase increased in all groups. But again levels in group B exceeded those of groups A and C by four to five times (p < 0.05). Electron microscopy revealed single cell necrosis in group B, whereas groups A and C showed interstitial edema only. CONCLUSIONS: Our experiments indicate a crucial role of DAF in preventing rejection in discordant species combinations. Transgenic human DAF seems to inhibit successfully complement-mediated damage to the endothelial cell, thus preventing endothelial activation and consequently myocardial damage. Transgenic human DAF makes a discordant species (pig) function as a concordant species, that is, hyperacute rejection does not occur.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Surgical therapy for coronary artery disease in patients with a left ventricular ejection fraction of 25% or less.

BACKGROUND: In patients with advanced coronary artery disease (CAD) and markedly decreased left ventricular ejection fraction (EF) symptoms of myocardial ischemia and insufficiency may be complicated by ventricular arrhythmias. Appropriate surgical therapy must be tailored to the individual symptoms. The aim of this study was to compare the different current methods. METHODS: From 9/1990 to 9/1994 138 patients with coronary artery disease and a left ventricular EF of < or = 25% were operated. Patients with dominating Angina pectoris and vital myocardium were revascularized (ACB; n = 17); two of these patients were 12 and 37 months p.o. transplanted. Because of dominating dyspnea, diffuse CAD and missing AP heart transplantation seemed indicated (HTX; n = 102). In two of these patients ventricular assist devices were implanted as a bridge to transplantation; both patients survived. Patients with malign tachycardias received either an implantable cardio-defibrillator (ICD; n = 16) or had arrhythmia surgery (ARS; n = 3). Patients of the HTX-Group were younger (54 vs 60 years; p < 0.05), had more often previous surgery (28% vs 20%) and were in worse conditions (NYHA 3.5 vs 3.0; p < 0.05). RESULTS: The main cause of death after transplantation was multi-organ failure (MOF; 14/102; 13.8%). The best long-term survival (87% after 3.2 years, p < 0.01 vs HTX)-with low average functional classes (NYHA 2.9)-had the patients after ICD implantation. The best quality of live (NYHA 1.1; p < 0.01 vs ICD)-associated with a high mortality due to preoperatively impaired organ-systems (62% operative survival, 57% 4-years survival)-was achieved by transplantation. In patients with a history of ventricular arrhythmias, who are waiting for a transplantation, the implantation of an ICD should be considered. Bypass surgery as well as arrhythmia surgery showed good survival (1-year survival 82% and 66% respectively) and functional results (NYHA 1.7 and 1.5 respectively).

Arrhythmias, Cardiac↗
PubMed1996

Prevention of hyperacute rejection by human decay accelerating factor in xenogeneic perfused working hearts.

As a potential source of organs for xenotransplantation, pigs that are transgenic for human decay accelerating factor (DAF) have been bred in order to overcome hyperacute rejection. We investigated the protective effect of human DAF in a porcine working heart model perfused by human blood. Hearts of normal landrace pits served as controls. The following parameters were measured: stroke work index, coronary flow and arteriovenous oxygen consumption, 6-keto prostaglandin F1alpha and prostaglandin E2 as markers of endothelial cell activation; creatine phosphokinase and lactate dehydrogenase for evaluation of the extent of myocardial damage; TNFalpha and IL-6 as markers of mononuclear cell activation. Histological and ultrastructural investigations from myocardial tissue sections were done at the end of perfusion. Human (h) DAF appeared to inhibit complement-mediated endothelial cell activation of transgenic pig hearts successfully. This was in contrast to landrace pig hearts, which had a sixfold increase of prostaglandin levels during perfusion with human blood. The cardiac weight increase during perfusion time due to interstitial edema tended to be less in the hDAF group. Myocardial damage was minimal in transgenic hearts, whereas normal pig hearts produced a threefold increase of creatine phosphokinase and lactate dehydrogenase levels. In these hearts, electron microscopy revealed single cell necrosis of myocytes and vacuolization of mitochondria with cristae rupture. According to the results obtained in the working heart model, the breeding of pigs that are transgenic for hDAF represents a promising step to making heart xenotransplantation a clinical reality in the future.

Acute Disease↗
PubMed1995

Postoperative neuropsychological dysfunction and cerebral oxygenation during cardiac surgery.

In 41 patients undergoing cardiac operations with extracorporeal circulation, oxidized cytochrome a,a3(CtO2), deoxygenated hemoglobin (Hb), and oxygenated hemoglobin (HbO2) were measured in brain tissue by near-infrared spectrophotometry (NIRS) intraoperatively. Monitoring also included electroencephalography (EEG) and jugular-bulb venous saturation (SBJO2). All operations were performed using membrane oxygenators, moderate hypothermia (26-28 degrees C) and pH alpha-stat management. During cardiopulmonary bypass (CPB) CtO2 and HbO2) were reduced, reaching minimal values when rewarming was instituted. At the end of the operation CtO2 and HbO2 had regained initial levels. During CPB, arterial PCO2, pH, and temperature were closely related to CtO2 (r = 1000, r = -0.964 and 0.929 respectively; p < 0.001, p < 0.001, and p < 0.003 respectively). Neuropsychological testing by the Mini-Mental-State Test indicated reversible postoperative neuropsychological deficits in four patients. There patients had a lower CtO2 minimum compared to those without these deficits (-4.5 mumol/L v. -0.7 mumol/L; p = 0.036). These findings support the hypothesis that neuropsychological deficits in patients after cardiac surgery can be caused by intraoperative cerebral hypoxia.

Adult↗
PubMed1995

Bidirectional effects of endogenous opioid peptides on endothelin release rates in porcine aortic endothelial cell culture: mediation by delta opioid receptor and opioid receptor antagonist-insensitive mechanisms.

The effects of opioid peptides on immunoreactive endothelin (ir ET) release from cultured porcine aortic endothelial cells over a 1-hr period (4-5 or 23-24 hr) were determined by radioimmunoassay and high-performance liquid chromatography after treatment for either 4 or 23 hr. Endogenous opioids, the synthetic delta opioid [D-Pen2,5]enkephalin and, for comparison, atrial and brain natriuretic peptides were added to the culture medium in concentrations ranging from 10(-12) to 10(-7) M. Thrombin (0.1-10 U/ml) served as a stimulatory reference. 1) Brain natriuretic peptide displayed only insignificant effects on ir ET release at 5 hr, but strongly inhibited ir ET release at 24 hr. 2) Opioids modulated release rates at 5 hr but did not display significant effects at 24 hr: metorphamide with predominant mu/kappa and weak delta opioid receptor activity stimulated release in a dose-dependent manner, whereas [Met5]enkephalin-Arg6-Phe7 with mu/delta activity and the delta agonists [Leu5]enkephalin, sulfated [Leu5]enkephalin and [D-Pen2,5]enkephalin decreased release rates; [Leu5]enkephalin was the most potent of the latter drugs. 3) Coincubation with either the nonselective opioid receptor antagonist naloxone (10(-5) M) or the delta receptor-selective antagonist ICI-174,864 (N,N-bisallyl-Tyr-D-Ala-Aib-Aib-Phe-Leu-OH) (10(-5) M) abolished all opioid-induced inhibitory effects, but rather potentiated or unmasked stimulatory effects of opioid peptides on ir ET release rates at 5 hr and also at 24 hr in the case of the delta agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Increased endothelin plasma concentrations in patients with coronary artery disease or hyperlipoproteinemia without coronary events.

Endothelins are made by endothelial cells, macrophages, and vascular smooth muscle cells, among others, and are the most potent endogenous vasoconstrictors yet discovered, with additional growth-promoting properties. A locally increased endothelin production in coronary artery disease or other atherosclerotic diseases may increase circulating endothelin plasma concentrations before symptoms of disease are manifest. We determined endothelin plasma concentrations (1) in 43 patients suffering from coronary artery disease (CAD); (2) in 43 patients with hyperlipoproteinemia without coronary artery disease (HLP); (3) in 29 healthy control subjects (C), by means of a novel extraction procedure and radioimmunoassay followed by chromatographic separation. Plasma concentrations in HLP and C overlapped, but were still significantly different (29 +/- 10 vs 21 +/- 8 fmol/ml, ANOVA and Duncan's test). Significantly increased plasma concentrations were also found in patients with CAD, with the highest levels in a subgroup of 8 patients presenting with unstable angina (43 +/- 12 vs 53 +/- 15 fmol/ml). There were no statistically significant differences between CAD groups with (n = 28) or without hyperlipoproteinemia (n = 15) (42 +/- 14 vs 41 +/- 16 fmol/ml; n.s.). Likewise there was no relationship between endothelin plasma concentration in any of the patients studied and lipid fractions in serum. Increased endothelin plasma concentrations in HLP patients without evidence of coronary artery disease are thus not related to the hyperlipidemic state per se, but may rather indicate presence of an increased vasoconstrictor tonus, pre-clinical or silent atherosclerotic disease.

Chromatography, Gel↗
PubMed1993

Effects of recombinant human erythropoietin on autologous blood donation before open heart surgery.

We studied the effects of four different doses of recombinant human erythropoietin (rhEPO) on the amount of preoperative autologous blood donation. 43 patients prior to open heart surgery were randomized into 5 groups (100, 200, 400, 800 U/kg rhEPO i.v. or placebo) and treated twice weekly over a period of 4 weeks. Autologous blood was taken at a hemoglobin of 13 g/dl and a hematocrit of 34% respectively. Application of low-dose rhEPO (100 and 200 U/kg) did not increase the amount of autologous blood donated, only 400 and 800 U/kg produced a significant increase by 27% and 39% respectively (p < 0.01) In addition RBC showed a reduced decline of hemoglobin level (p < 0.01). Reticulocytes increased by 2.5 times the baseline in the placebo and treatment groups up to 200 U/kg. Again, only 400 and 800 U/kg produced a significantly higher increase of 3.2 and 3.6 times respectively (p < 0.05 and p < 0.01). Although iron was supplied orally, ferritin levels declined in all groups whereas serum iron and transferrin levels remained unchanged. No influence could be detected on WBC, thrombocyte count, or arterial blood pressure. Mild and reversible side effects were observed in 8 patients (19%). Perioperatively 34 patients (81%) received exclusively autologous blood, only 8 patients (19%) needed additional homologous blood transfusions. Administration of high-dosed rhEPO (400-800 U/kg) seems to be an effective treatment with only slight side effects for increasing erythropoiesis during autologous blood donation.

Adolescent↗
PubMed1993

Heart transplantation after Senning operation for transposition of the great arteries.

In a 17.5-year-old boy and a 21-month-old girl orthotopic heart transplantation was performed after intractable right-heart failure had developed 14.5 years and 15 months respectively after Senning operation for TGA. Before the atrial repair, combined with closure of the VSD in each case, initial operation had involved a banding of the pulmonary artery in the boy and a modified Blalock-Taussig shunt in the girl. A coarctation of the first patient remained untreated. After resection of the diseased organ a new intraatrial septum of glutaraldehyde-fixed bovine pericardium was created. 15 and 3 months respectively after orthotopic heart transplantation both patients belong to NYHA classification I.

Adolescent↗
PubMed1993

Long-term results of pacemaker therapy after orthotopic heart transplantation.

The objectives of this study were to identify: (1) the indications for pacemaker implantation; (2) the long-term survival; (3) the percentage of bradyarrhythmias below 50 beats/min persisting for more than 3 months; and (4) the variables predicting persistent bradyarrhythmias following orthotopic heart transplantations. During the recent decade (August 1, 1981 through December 31, 1991), 237 patients underwent orthotopic heart transplantation at our institution. Twenty-six recipients (11%) showed evidence of a symptomatic bradyarrhythmia due to sinus node dysfunction (n = 25) or complete heart block (n = 1), which required insertion of a permanent pacing device. During a mean follow-up period of 17.2 months (range 3 to 57 months), five patients (19%) died and one was lost to follow-up. Actuarial survival at 1 and 4 years were 81% and 65%, respectively, as compared to 79% and 69%, respectively, in patients without permanent pacemakers. Holter monitoring after 3 months (n = 25) and 1 year (n = 14) showed a spontaneous heart rate below 50 beats/min in six (24%) and three patients (18%), respectively. None of the tested variables predicted the necessity of initial pacemaker implantation. However, in patients requiring permanent pacing for a period longer than 3 months, ischemic time of the donor heart was found to be significantly longer as compared to the other patients (221 +/- 76 min vs 137 +/- 91 min, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Acute and chronic effects of nitrendipine on hemodynamics and myocardial ischemia in patients with combined angina pectoris and hypertension.

To examine the antianginal and antihypertensive efficacy of nitrendipine, a new calcium channel blocking agent, 25 patients with chronic stable angina pectoris (NYHA I-III) and systemic hypertension underwent cardiac catheterization and treadmill exercise tests. Acute hemodynamic results were obtained before and 2 h after oral administration of 20 mg nitrendipine. They showed a significant decrease in aortic pressure (162.1 +/- 27.4/80.0 +/- 12.1 vs. 134.9 +/- 23.5/74.2 +/- 13.1 mm Hg), pulmonary arterial pressure (25.4 +/- 5.4/11.3 +/- 3.7 vs. 21.9 +/- 5.4/9.9 +/- 3.7 mm Hg), and pulmonary wedge pressure (10.0 +/- 4.4 vs. 6.6 +/- 3.8 mm Hg). Cardiac index (+31%) and stroke volume (+33%) increased markedly, whereas heart rate remained unchanged (66.9 +/- 11.4 vs. 66.8 +/- 10.8 beats/min). Chronic hemodynamic results and exercise tolerance tests were obtained before and 8 weeks after oral nitrendipine therapy. A significant decrease in arterial blood pressure was observed (167 +/- 22/86 +/- 10 vs. 126 +/- 32/76 +/- 19 mm Hg). Exercise tolerance improved concerning test duration (+22%) and total exercise capacity (+37%). Maximal ST-segment depression decreased by 30% (0.2 +/- 0.03 vs. 0.14 +/- 0.02 mV) and subsequently the anginal frequency was reduced from 7.8 +/- 2.1 to 3.8 +/- 1.7 attacks/week (-50%). The maximal rate-pressure product during exercise remained unchanged. Plasma levels of cholesterol, triglycerides, and LDL- and HDL-cholesterol did not show any significant alterations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Combining the hDAF transgene with the GP IIb/IIIa inhibitor tirofiban improves heart performance and reduces myocardial damage following hyperacute rejection in an ex vivo perfusion model.

Xenograft rejection is associated with vascular injury resulting at least in part from platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis. Assuming that complement activation is a major determinant of humoral immune reactions bringing about platelet-endothelial cell interactions, we tested the effects of the specific platelet glycoprotein IIb/IIIa inhibitor tirofiban in combination with the human decay accelerating factor (hDAF) transgene on hyperacute rejection of pig hearts. Four groups were studied in a working heart-perfusion model. Pig hearts transgenic for hDAF and nontransgenic pig hearts were perfused with human blood containing tirofiban or with unmodified human blood. Cardiac output, stroke work index, and creatine phosphokinases were measured for the evaluation of the extent of myocardial damage. Consumption of complement components was determined. Endothelial deposition of fibrin and intravascular thrombosis were evaluated. Tirofiban improved cardiac output and stroke work index of nontransgenic pig hearts and was able to further increase hemodynamic function of hDAF transgenic pig hearts. Low levels of creatine phosphokinases also revealed a cardioprotective effect of tirofiban. However, a further extension of the survival of hDAF transgenic pig hearts could not be achieved, although tirofiban prolonged beating time of nontransgenic pig hearts. Tirofiban was able to reduce the consumption of complement components independently of hDAF. Intravascular evidence of fibrin and thrombosis tended to be particularly reduced by the combination of tirofiban and hDAF. Thus, the application of tirofiban together with hDAF improves the performance of pig hearts by reducing myocardial damage and intravascular thrombosis.

Acute Disease↗
PubMedDate not supplied

Mean xenograft survival of 14.6 days in a small group of hDAF-transgenic pig hearts transplanted orthotopically into baboons.

INTRODUCTION: In a discordant orthotopic xenotransplantation model (pig-to-baboon) donor pigs expressing human decay accelerating factor (hDAF) as a regulator of complement activity were used to prevent hyperacute xenograft rejection (HXR). We investigated a modified immunosuppressive therapy consisting of ERL080 (Novartis Pharma AG, Base, Switzerland), cyclosporin A (Neoral), steroids, and a cyclophosphamide (CyP) induction protocol with several reduced doses to prevent acute vascular rejection (AVR). METHODS: Donor hearts were harvested from hDAF-transgenic pigs (18.8 +/- 2.6 kg, Imutran Ltd., a Novartis Pharma AG Company). Four adult baboons (25.6 +/- 2.7 kg) with high titers of xenoreactive antibodies (XAb) served as recipients. Serological and hemodynamic parameters were measured. Finally, myocardial tissue was sampled for histological and immunohistochemical examinations. RESULTS: In the first baboon, an acute graft failure occurred after 1 hour due to preservation injury. The second succumbed after 11.1 day due to an acute renal failure. The third died after 13.1 days of an ileus. The fourth baboon had continuously excellent cardiac function (mean echocardiographic ejection fraction, 69.2%), but succumbed on day 20 due to anemia. Corrected mean xenograft survival (excluding the first baboon because of a technical failure) was 14.6 +/- 2.6 days. XAb decreased after day 3 to constantly low levels (<1:64 titer) after CyP induction. White blood cell count decreased from 10.3 +/- 0.8 to 0.9 +/- 0.3 G/L after day 3. Macroscopically and histologically no typical signs of HXR or severe AVR could be detected. CONCLUSIONS: These results confirm that hDAF transgen blocks HXR in this life-supporting model. AVR was prevented by using a modified quadruple immunosuppressive drug combination (Neoral, ERL080, steroids, and several small single doses of CyP). An optimum "fine-tuning" of immunosuppression is required to achieve the best risk-benefit ratio.

Animals↗
PubMedDate not supplied

Combination of hDAF-transgenic pig hearts and immunoadsorption in heterotopic xenotransplantation of immunosuppressed baboons.

INTRODUCTION: Hyperacute xenograft rejection (HXR) and acute vascular rejection (AVR) after xenotransplantation are triggered by xenoreactive antibodies (XAb) and an activated complement cascade. In a heterotopic (abdominal) xenotransplantation model we combined immunoadsorption (IA, Ig-Therasorb column) and a quadruple immunosuppressive drug therapy in recipient baboons with donor pig hearts transgenic for human decay accelerating factor (hDAF). METHODS: According to XAb titers between 6 and 14 cycles of IA were performed preoperatively in 4 recipient baboons (18.6 +/- 2.5 kg). Hearts of hDAF-transgenic donor pigs (6.1 +/- 1.1 kg, Imutran Ltd., a Novartis Pharma AG Company, Basel, Switzerland) were heterotopically transplanted using the abdominal technique in baboons. Immunosuppression consisted of cyclophosphamide (CyP) induction therapy, ERL080 (Novartis Pharma AG), cyclosporin A (CyA, Neoral), and steroids. Blood levels of mycophenolate, CyA, immunoglobulins (Ig), anti-pig-antibodies, complement factors, and cardiac enzymes were determined. Abdominal electrocardiography (ECG), echocardiography, and palpation were used for monitoring of the pig hearts. Myocardial tissue specimens were examined using immunohistochemistry, light microscope (LM), and electron microscope (EM). RESULTS: Ten cycles of IA alone removed 78% of XAb and accordingly IgM, IgG, IgA, complement C3, and C4. None of the xenografts was hyperacutely rejected, but xenograft failure occurred after 5.0 +/- 1.3 days (range, 2.4-8.0 days) because of an AVR associated with a rapid XAb increase within 24 hours. White blood cell count (10.3 +/- 2.2 G/L) showed a maximum of 13.1 +/- 2.1 (day 1) and constant levels (1.4 +/- 0.3-2.1 +/- 1.3 G/L) between day 3 and 6. Histology (LM/EM) showed massive hemorrhage, necrosis, and vascular thrombi as signs of AVR. CONCLUSION: Although HXR was prevented by using IA and hDAF-transgenic donor hearts, AVR was not avoided due to insufficient immunosuppressive regimen used and a missed postoperative IA treatment as a result of an inefficient control of XAb production.

Adrenal Cortex Hormones↗