Manfred Dahm

Simvastatin Inhibits Inflammatory Properties of Staphylococcus aureus α-Toxin

Background—Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus &agr;-toxin–induced increase in leukocyte-endothelial interactions during exotoxemia. Methods and Results—The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 &mgr;g/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 &mgr;g/kg S aureus &agr;-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71±10 to 14±4.7 cells/min (P <0.01) and adherence from 14±3.5 to 0.4±0.2 cells (P <0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5±1.2 to 4.2±0.9 (P <0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation. Conclusions—These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.

Mid-term results of pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension

BACKGROUND In patients with chronic thromboembolic pulmonary hypertension, acute and striking decreases of pulmonary artery pressures and vascular resistance can be achieved by pulmonary thromboendarterectomy. In this study, the long-term effects of pulmonary thromboendarterectomy on hemodynamic indices and right ventricular function were investigated. METHODS Sixty-five patients (31 women and 34 men; mean age, 47 +/- 17 years; range, 19 to 69 years; New York Heart Association [NYHA] functional class II, n = 3; class III, n = 38; class IV, n = 24) were reassessed 13 to 48 months (mean, 27 months) after pulmonary thromboendarterectomy. Measurements are reported as mean +/- standard deviation. RESULTS All patients reported a significant improvement of symptoms: 46 patients were in NYHA functional class I, 16 patients in class II, and 3 patients in class III. Mean pulmonary vascular resistance was significantly reduced compared with preoperative and postoperative values (preoperative: 1,015 +/- 454 dynes.s.cm-5; postoperative: 322 +/- 154 dynes.s.cm-5; follow-up: 198 +/- 72 dynes.s.cm-5; p < 0.001 versus preoperative; p < 0.025 versus postoperative). Concomitantly, cardiac index was significantly increased compared with preoperative values (preoperative: 2.0 +/- 0.7 L.min-1.m-2; follow-up: 2.9 +/- 0.5 L.min-1.m-2; p < 0.001). Significant reductions of right ventricular dimensions and recovery of right ventricular function could be demonstrated radiologically and echocardiographically. In 3 patients (preoperative NYHA class IV, NYHA class III at follow-up) with proven coagulation abnormalities, pulmonary vascular resistance was moderately increased at follow-up compared with postoperative measurements. CONCLUSIONS In patients with chronic thromboembolic pulmonary hypertension, a persistent decrease of pulmonary vascular resistance and improvement of right ventricular function and NYHA functional status can be achieved by pulmonary thromboendarterectomy.

Immunogenicity of Glutaraldehyde-Tanned Bovine Pericardium

Glutaraldehyde-tanned bovine pericardium was tested for its ability to induce immunologic responses in vivo. Sections of glutaraldehyde-tanned bovine pericardium were implanted between the abdominal muscles of rats and guinea pigs. Control animals received Dacron implants. Lymphocytes and sera from animals were isolated at 2 and 4 weeks after implantation (four animals per group per time). Tritiated thymidine incorporation and an enzyme-linked immunosorbent assay were used to measure T- and B-lymphocyte responses to glutaraldehyde-tanned bovine pericardium antigens. At the same time points, implants and surrounding tissue from all animals were processed for histologic data. Results show that T-lymphocytes from animals with glutaraldehyde-tanned bovine pericardium implants responded significantly (p less than 0.001) to glutaraldehyde-tanned bovine pericardium antigens in vitro but not to Dacron. In contrast, lymphocytes from animals with Dacron implants failed to respond to glutaraldehyde-tanned bovine pericardium or Dacron preparations. Results of enzyme-linked immunosorbent assay show that animals with glutaraldehyde-tanned bovine pericardium implants produced antibody directed against glutaraldehyde-tanned bovine pericardium antigens. Histologic study revealed a dense mononuclear and multinuclear giant cell infiltrate at the interface between glutaraldehyde-tanned bovine pericardium and surrounding host tissues, with focal degradation of implant collagen. Dacron elicited a nonspecific lymphocytic and foreign body-type reaction. These results indicate that glutaraldehyde-tanned bovine pericardium can induce immunologic responses in vivo consistent with a host-versus-graft reaction.

Long-term results after thromboendarterectomy for chronic pulmonary embolism

OBJECTIVE In patients with chronic thromboembolic pulmonary hypertension, pulmonary vascular resistance (PVR) can be reduced by pulmonary thromboendarterectomy (PTE). In this study, long-term symptomatic and hemodynamic effects were investigated. METHODS Twenty-two patients (12 female, 10 male, mean age 40 years, preoperative NYHA functional class II/III/IV: n = 1/12/9) were re-evaluated 48-72 months (mean 60 months) after surgery. In addition to clinical assessment, radiologic, hemodynamic and echocardiographic investigations were performed. RESULTS All patients reported a marked improvement of their clinical condition. At follow-up, 11 patients were identified as NYHA class I, 10 as NYHA class II and one patient was in class III. PVR and mean pulmonary artery pressure (mPAP) were significantly reduced (preoperative PVR 800+/-274 dynes/s per cm(-5), follow-up PVR 180+/-28.3 dynes/s per cm(-5); P < 0.001; preoperative mPAP 48.5+/-7.4 mmHg, follow-up mPAP 27.5+/-4.9 mmHg; P < 0.001). There was also a significant increase in arterial blood oxygen tension (preoperative PaO2 59+/-10 mmHg; follow-up PaO2 84+/-12 mmHg; P < 0.001). Chest roentgenograms and echocardiographic examinations revealed significantly decreased right heart dimensions and a recovery of right heart function. CONCLUSION In patients with severe chronic thromboembolic pulmonary hypertension, persistent symptomatic and hemodynamic improvements can be achieved by PTE.

Clopidogrel and aspirin in the prevention of thromboembolic complications after mechanical aortic valve replacement (CAPTA)

Axel Schlitt*, Ralf S. von Bardeleben, Anne Ehrlich, Antje Eimermacher, Dirk Peetz, Manfred Dahm, Hans J. Rupprecht Department of Medicine II, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Coordination Center for Clinical Studies, Johannes Gutenberg-University Mainz, Mainz, Germany Clinic for Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg-University Mainz, Mainz, Germany Department of Cardiothoracic and Vascular Surgery, Johannes Gutenberg-University Mainz, Mainz, Germany

Subendothelial infiltration of neutrophil granulocytes and liberation of matrix-destabilizing enzymes in an experimental model of human neo-intima

It was the objective of this study to examine the role of human neutrophil granulocytes (PMN) in an in-vitro model of human neo-intima developed for the study of atherosclerosis. Human granulocytes were subjected to a co-culture model of human endothelial and smooth muscle cells. Subendothelial lipid accumulation was achieved by addition of native LDL to the culture medium. Tissue samples were analyzed by immunohistochemistry and scanning/transmission electron microscopy, and culture supernatants were examined for the presence of interleukin-8 (IL-8), MCP-1, GRO-alpha, elastase and matrixmetalloproteinase-8 (MMP-8). Following addition of 2 mg/ml LDL, adherence, transmigration and infiltration depth of PMN was increased significantly when compared to controls. LDL challenging was paralleled by a time- and dose-dependent secretion of IL-8 from intimal smooth muscle cells. PMN infiltration was mediated by the IL-8-signalling pathway and accompanied by release of elastase and MMP-8 into the supernatant and induction of endothelial cell apoptosis. In conclusion, LDL-induced secretion of IL-8 by intimal smooth muscle cells provides a potential mechanism of PMN-recruitment into culprit lesions. The concomitant release of potent matrix-degrading enzymes and the induction of EC apoptosis may have implications for plaque destabilization and cardiovascular events.

Risk factors influencing the outcome after surgical treatment of complicated deep sternal wound complications.

Abstract Background : Median sternotomy is the most frequently used incision for cardiac procedures but carries a substantial risk for deep sternal wound infections and/or sternal dehiscence. In contrast to previous studies that examined risk factors for sternal infections this study evaluates factors that lead to poor outcome after surgical revision of the non healing sternum. Methods : Between 1985 and 1999, 193 adults (mean age 64 ± 9 years, m/f = 3/1) necessitated sternal revisions (incidence 1.93%). Pre-, intra- and post-operative risk factors were evaluated for their influence on the outcome after sternal revision. Results : 65 of the 193 patients had a complicated course: ten (5.2%) died due to sepsis/multi organ failure ( n = 6) or cardiac causes ( n = 4). 32 patients (16.6%) needed several revisions, 17 (9%) were discharged with sternal instability, 5 (3%) with chronic fistula and one with persistent osteomyelitis. Univariate and multivariate analysis identified cardiopulmonary resuscitation (odds ratio ( OR ) = 11.188, p = 0.010), corticoid treatment ( OR = 7.043, p = 0.0055), diabetes ( OR = 4.130, p = 0.0128), smoking history ( OR = 2.996, p = 0.0041), renal insufficiency (hazard ratio ( HR ) = 1.884), old age ( OR = 1.108, p = 0.0266), high body mass ( HR = 1.06), ECC time ( p = 0.023), cross clamp time ( p = 0.028), systemic hypothermia ( p = 0.016), non-use of IMA ( p = 0.042) or prolonged ventilation as risk factors for mortality or poor outcome. No correlation between sternal closure technique, mediastinal irrigation or antibiotic therapy and outcome after mediastinal revision could be found. Conclusions : To avoid disappointing results after sternal revision one should aim to preoperatively identify high-risk patients and aggressively address risk factors. This rather than modifications of the surgical and medical approach might improve the outcome of patients with mediastinal complications.

Troponin T: a reliable marker of perioperative myocardial infarction?

Following cardiac surgery, electrocardiography and creatine kinase isoenzyme MB (CK-MB) activities are of limited value in diagnosing a non-transmural infarction. With the recent availability of an assay to detect serial levels of the specific cardiocyte contractile protein troponin T the possibility has been increased of closing a diagnostic gap among cardiosurgical patients. Ninety patients with severe diffuse three-vessel disease undergoing myocardial revascularization were grouped by their postoperative electrocardiographic (ECG) findings (group I--unchanged ECG; group II--new Q-waves representing perioperative myocardial infarction (PMI)). Serial levels of troponin T and the activity of CK-MB were measured 6, 12, 24 and 48 h after aortic unclamping. The course of CK-MB activity was compared to a profile and values derived from patients with unchanged (n = 1312) or new Q-wave ECGS (n = 89). In 72 patients (80.0%) with unchanged postoperative ECG (group I) serial troponin T levels remained constantly low and reached a median peak value of 0.37 microgram/l (quartile 0.13-0.50 microgram/l) after 24 h. Serial CK-MB activities demonstrated the typical non-ischemic course with a monoexponential decline from an initial median peak value of 15.5 U/l (quartile 12.0-21.0 U/l) to 7.0 U/l (quartile 6.0-9.0 U/l). In seven patients (7.8%) with new Q-waves and a pathologic CK-MB profile (group II) troponin T reached median levels of 10.47 micrograms/l (quartile 6.34-12.50 micrograms/l) (P < 0.001 I vs II). Four of five patients with a new right bundle branch block demonstrated low troponin T levels below 1 microgram/l and a normal CK-MB profile. Among six patients with unchanged QRS-configuration and elevated troponin T levels between 0.84 and 4.99 micrograms/l CK-MB activity showed a characteristic PMI pattern in two patients. Troponin T is characterized by a very narrow margin of normal values represented by a maximum third quartile of 0.50 microgram/l. A singular value of troponin after 6 h or 24 h may be sufficient evidence to confirm the diagnosis of a PMI.

Reevaluation of Direct True Lumen Cannulation in Surgery for Acute Type A Aortic Dissection

BACKGROUND The optimal mode of arterial cannulation in acute type A aortic dissection is controversial. We retrospectively investigated our experience with direct true lumen cannulation as an alternative to standard cannulation procedures. METHODS From April 2004 to August 2007, 29 patients (20 men, 9 women; mean age of 63.2 +/- 12.6 years) underwent emergency operation for acute type A aortic dissection with direct true lumen cannulation. After venous drainage into the venous reservoir, the ascending aorta was completely transected in the region between the sinotubular junction and innominate artery. After visual and digital identification of the true lumen, the arterial cannula was directly inserted into the true lumen and secured with a ligature. RESULTS Mean aortic cross-clamp time was 77.4 +/- 28.3 minutes, and hypothermic circulatory arrest for the distal anastomosis was 10.4 +/- 11.0 minutes. All patients survived the surgical procedure. No surgical problems were observed by applying this strategy. Mean intensive care unit stay was 4.0 +/- 3.5 days. Postoperative mean ventilation time was 43.3 +/- 41.3 hours. One patient had a prolonged postoperative course and required permanent ventilation. Two patients required temporary hemofiltration. Neurologic disorders occurred in 6 patients: 2 had severe cerebral hypoxia, and 4 had temporary hemiplegia under good regression. All patients were alive at discharge. CONCLUSIONS Direct true lumen cannulation is a promising surgical strategy for emergency operations in type A aortic dissection. It is a simple, quick, and safe method to provide antegrade flow through the true aortic lumen.

Comparison of cardiac troponin I versus T and creatine kinase MB after coronary artery bypass grafting in patients with and without perioperative myocardial infarction.

Background and Purpose:Cardiac troponins have shown to be specific markers of myocardial injury. The aim of this prospective study was to compare patterns and kinetics of troponin I and T after coronary artery bypass grafting (CABG) with or without perioperative myocardial infarction (PMI).Patients and Methods:119 patients (male/female: 96/23, age 64 ± 10 years) underwent first time elective CABG. Preoperative mean ejection fraction was 55.8% ± 15.6%. The mean number of grafts was 3.1 ± 1.1/patient, in 85.7% the internal mammary artery was used. Cardiac troponin I (cTnI) and T (cTnT) levels, total serum activities of creatine kinase (CK) and creatine kinase isoenzyme MB (CK-MB) were measured before operation, at arrival on the intensive care unit (ICU), and 6, 12, 24, 48, and 120 h after unclamping of the aorta. Twelve lead electrocardiograms (ECGs) were recorded preoperatively and at days 1, 2, and 5. Perioperative data and postoperative cTnI and cTnT levels were correlated statistically.Results:Two patients died due to refractory myocardial failure in the early postoperative period. For further evaluation, patients were divided in two groups according to postoperative ECG changes (group I: patients without PMI, n = 107; group II: patients with PMI, n = 10: six of them with Q-wave and four of them with non-Q-wave PMI). Calculated best cutoff values for cTnI and cTnT were 8.35 µg/l and 0.768 µg/l in ROC (receiver-operator characteristic) analysis. Serum concentrations of cTnI, and cTnT were in the normal range preoperatively and increased significantly after surgery in both groups. In both groups, cTnI reached its medium peak level after 24 h (group I: 2.7 µg/l, 95% confidence interval [CI]: [2.1,3.2]); group II: 70.5 µg/l). CTnT reached its medium peak level in group I without PMI after 48 h (0.298 µg/l, 95% CI: [0.254,0.354]), in group II with PMI not until 120 h (3.0 µg/l) postoperatively. In group II serum level of both troponins remained considerably high at 120 h (cTnI median = 10.75 µg/l, cTnT median = 3 µg/l).Conclusion:Release patterns of cTnI and cTnT after CABG are different: cTnI reaches its postoperative peak value earlier and declines more quickly than cTnT. After uncomplicated CABG, serum levels of both cardiac troponins remain continuously low. Elevated concentrations reflect perioperative myocardial ischemia or infarction. CTnT shows a different release pattern in patients with or without myocardial infarction.Hintergrund und Ziel:Kardiale Troponine sind derzeit die am besten geeigneten myokardialen Ischämiemarker. Ziel dieser prospektiven Studie waren die Ermittlung und der Vergleich der Kinetik und Verlaufsmuster von Troponin I und T nach elektiven koronarchirurgischen Eingriffen mit Herz-Lungen-Maschine (ACB) mit oder ohne perioperativen Myokardinfarkt (PMI).Patienten und Methodik:Untersucht wurden 119 Patienten (männlich/weiblich: 96/23, Alter: 64 ± 10 Jahre, Ejektionsfraktion: 55,8% ± 15,6%) mit operationsbedüftiger koronarer Herzerkrankung, die sich einer elektiven ACB-Operation unterzogen. Die durchschnittliche Bypasszahl betrug 3,1 ± 1,1/Patient. In 85,7% wurde die LIMA (linke Arteria mammaria interna) als Bypass verwendet. Bei allen Patienten wurden die Kreatinkinase (CK), Kreatinkinase MB (CK-MB), kardiales Troponin I (cTnI) und T (cTnT) präoperativ, bei Ankunft auf der Intensivstation sowie 6, 12, 24, 48 und 120 h nach Eröffnung der Aortenklemme bestimmt. Die Dokumentation eines Zwölf-Kanal-Elektrokardiogramms (EKG) erfolgte präoperativ, am Operationstag sowie am 1., 2. und 5. postoperativen Tag. Zusätzlich wurden prä-, intra- sowie postoperative Einflussgrößen für die postoperative Konzentration der Enzyme erfasst und mit der Höhe des postoperativen Enzymspiegels korreliert.Ergebnisse:In der frühen postoperativen Phase starben zwei Patienten aufgrund eines therapierefraktären Myokardversagens. Anhand des postoperativen EKG-Befunds wurden die Patienten in zwei Gruppen eingeteilt (Gruppe I: Patienten ohne PMI, n = 107; Gruppe II: Patienten mit PMI, n = 10, davon sechs Patienten mit Q-Wave-Infarkt und vier Patienten mit Non-Q-Wave-Infarkt) Anhand der ROC-Analyse wurden als beste Grenzwerte für cTnI 8,35 mg/l und für cTnT 0,768 µg/l ermittelt. Die Konzentration von cTnI und cTnT im Serum lag präoperativ im Normbereich und stieg in beiden Gruppen postoperativ signifikant an. CTnI erreichte seinen medianen Gipfel in beiden Gruppen nach 24 h (2,7 µg/l, 95%-Konfidenzintervall [CI]: [2,1,3,2] in Gruppe I; 70,5 µg/l in Gruppe II), CTnT hingegen in Gruppe I ohne PMI nach 48 h (0,298 µg/l, 95%-CI: [0,254,0,354]), in Gruppe II mit PMI erst nach 120 h (3,0 µg/ l). In der Gruppe mit PMI (II) waren die Serumspiegel beider Troponine nach 120 h noch signifikant erhöht (cTnI Median = 10,75 µg/l, cTnT Median = 3 µg/l).Schlussfolgerung:Nach elektiven koronarchirurgischen Eingriffen zeigen cTnI und cTnT unterschiedliche Kinetik und Verlaufsmuster. CTnI erreicht seinen postoperativen medianen Gipfel früher und fällt schneller ab als cTnT. Bei den Patienten mit PMI ist die Konzentration beider Troponine auch 5 Tage postoperativ noch pathologisch.