Hellmut Oelert

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

BACKGROUNDnIn 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.nnnMETHODSnSixty-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.nnnRESULTSnAll 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.nnnCONCLUSIONSnIn 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.

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

Low-density lipoprotein (LDL) can be transformed to an atherogenic moiety by nonoxidative, enzymatic degradation. Enzymatically degraded LDL induces macrophage foam cell formation, provokes release of cytokines, and also activates complement. To determine whether complement activation may contribute to atherogenesis, 6 pairs of homozygous C6-deficient rabbits and their non-C6-deficient heterozygous siblings were fed a cholesterol-rich diet for 14 weeks. Cholesterol levels and plasma lipoprotein profiles of the animals in the C6-competent and C6-deficient groups did not significantly differ, and the high density lipoprotein and LDL cholesterol ratios at the end of the experiment were 0.07+/-0.01 and 0.08+/-0.01 (SEM), respectively. However, differences in atherosclerotic plaque formation were discernible macroscopically, with extensive aortic lesions being visible in all C6-competent animals and absent in all C6-deficient animals. Aortas were sectioned from thorax to abdomen, and 10 sections were stained from each aorta. Quantification of atherosclerotic lesions and lumen stenosis with the use of computer-based morphometry documented a dramatic protective effect of C6 deficiency on the development of diet-induced atherosclerosis. We conclude that the terminal complement sequence is centrally involved in atherosclerotic lesion progression.

Detection of Central Pulmonary Artery Thromboemboli by Transesophageal Echocardiography in Patients with Severe Pulmonary Embolism

Transthoracic echocardiography generally provides only indirect signs of pulmonary embolism. In contrast, with transesophageal echocardiography the thromboembolus itself can be visualized in the central parts of the pulmonary artery. The aims of our study were to evaluate, first, the incidence of central pulmonary artery thromboemboli in patients with severe pulmonary embolism, and second, the accuracy of the echocardiographic diagnosis. Our study group comprised 60 patients with proved severe pulmonary embolism. All patients were examined by transthoracic and transesophageal echocardiography. The echocardiographic findings concerning the absence or presence of central pulmonary artery thromboemboli were compared with the results of different reference methods. Central pulmonary thromboemboli were found in 35 patients (58.3%) by echocardiography. Two types of thrombus were differentiated. Type A is a long, highly mobile thrombus, and type B is an immobile wall-adherent thrombus. In comparison with the reference methods, we determined a sensitivity of 96.7% and a specificity of 88% for the echocardiographic detection of central pulmonary artery thromboemboli in patients with severe pulmonary embolism. Transesophageal echocardiography seems to be a useful method for the diagnosis of severe pulmonary embolism. In our series, central pulmonary artery thromboemboli were present in more than half of the patients. In these cases, transesophageal echocardiography can clarify the diagnosis within a few minutes without further invasive diagnostic procedures.

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.

Quantification of mitral valve stenosis by three-dimensional transesophageal echocardiography

The aim of this study was the evaluation of the diagnostic potentials of transesophageal 3D-echocardiography in the determination of mitral valve stenosis. 54 patients were investigated by transthoracic and multiplane transesophageal echocardiography. In 41 patients cardiac catheterization was performed. 3D-echocardiographic data acquisition was performed by automatic transducer rotation at 2° increments over a span of 180°. The transesophageal probe was linked to an ultrasound unit and to a 3D-workstation capable of ECG- and respiration gated data acquisition, postprocessing and 2D/ 3D image reconstruction. The mitral valve was visualized in sequential cross-sectional planes out of the 3D data set. The spatial position of the planes was indicated in a reference image. In the cross-sectional plane with the narrowest part of the leaflets the orifice area was measured by planimetry. For topographic information a 3D view down from the top of the left atrium was reconstructed. Measurements were compared to conventional transthoracic planimetry, to Doppler-echocardiographic pressure half time and to invasive data. The mean difference to transthoracic planimetry, pressure half time and to invasive measurements were 0.3 ± 0.1 cm2, 0.2 ± 0.1 cm2 and 0.1 ± 0.1 cm2, respectively. Remarkable differences between the 3D- echocardiographic and the 2D- or Doppler- echocardiographic methods were observed in patients with severe calcification or aortic regurgitation. In 22% of the patients the 3D data set was not of diagnostic quality. New diagnostic information from a 3D view of the mitral valve could be obtained in 69% of the patients. Thus, although image quality is limited, 3D- echocardiography provides new topographic information in mitral valve stenosis. It allows the use of a new quantitative method, by which image plane positioning errors and flow-dependent calculation is avoided.

Aprotinin inhibits leukocyte–endothelial cell interactions after hemorrhage and reperfusion

BACKGROUNDnThe serine protease inhibitor aprotinin has been successfully used to reduce blood loss in patients undergoing cardiac operations. We studied aprotinin for its ability to modulate leukocyte-endothelial cell interactions after ischemia and reperfusion.nnnMETHODSnThe effects of aprotinin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and immunohistochemical analysis. The inflammatory cascade (leukocyte rolling, firm adherence, and transmigration) was studied after thrombin stimulation and after hemorrhage and reperfusion.nnnRESULTSnIntravenous bolus administration of aprotinin treatment (20,000 U/kg) significantly reduced leukocyte rolling from 55 +/- 8 to 17 +/- 3 cells/min (p < 0.01) and adherent cells from 12 +/- 2 to 7 +/- 1.4 cells (p < 0.05) along the venous endothelium of the rat mesentery after thrombin activation. In addition, aprotinin pretreatment significantly inhibited transmigration of leukocytes from 11.3 +/- 1.2 to 6.0 +/- 1.1 cells (p < 0.05) through the microvascular endothelial wall. Similarly, aprotinin decreased leukocyte-endothelium interaction after hemorrhagic shock. Moreover, immunohistochemistry demonstrated that aprotinin significantly attenuated P-selectin expression by the intestinal vascular endothelium. CONCLUSIONS. Our data demonstrate that aprotinin potently inhibits recruitment of leukocytes in the microvasculature by interfering with endothelial cell-polymorphonuclear neutrophil interaction, and is a potent endothelial protective agent in clinically relevant doses. Thus, aprotinin pretreatment may be useful for primary prevention of inflammatory tissue injury mediated by ischemia-reperfusion injury such as shock, trauma, open heart operation, or other extensive vascular surgical procedures.

Assessment of cardiac performance using Tei indices in patients undergoing pulmonary thromboendarterectomy

BACKGROUNDnThis study was designed to evaluate left and right ventricular performance using Tei indices in patients with severe chronic thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy (PTE). The Doppler-derived indices are easily measurable indicators of ventricular function based on nongeometric assessment, which helps overcome some of the difficulties entailed in the geometric assessment of left ventricular (LV) and right ventricular (RV) function in pulmonary hypertension.nnnMETHODSnThe indices were derived for 24 patients (aged 54+/-14 years) before and after PTE. Calculation of these indices was based on the duration of two time intervals using the formula (A - B)/B, where A is the interval between cessation and onset of mitral inflow (or tricuspid inflow) and B is LV or RV ejection time. In addition, LV and RV end-diastolic and end-systolic chamber areas were determined using two-dimensional echocardiography, and systolic function was calculated. Mean pulmonary artery pressure was determined invasively.nnnRESULTSnPTE led to a significant reduction of mean pulmonary artery pressure (46+/-10 versus 25+/-6 mm Hg; p < 0.05). LV and RV indices were abnormally high before surgery, declined significantly afterwards, and then almost matched normal values (0.61+/-0.26 versus 0.37+/-0.18; p < 0.05 and 0.55+/-0.22 versus 0.37+/-0.13; p < 0.05). Geometric assessment of the left and right ventricle also showed impaired systolic function before PTE, with significant improvement after surgery.nnnCONCLUSIONSnLV and RV Tei indices allow a quantitative assessment of ventricular function in patients undergoing PTE. Lower indices after surgery reflect an improvement of the previously impaired cardiac function. Our results emphasize the value of PTE in the treatment of chronic thromboembolic pulmonary hypertension.

Value and Limitations of Transesophageal Echocardiography in the Evaluation of Aortic Prostheses

Results of 34 transesophageal (TEE) studies in patients with suspected aortic prosthetic dysfunction were compared with transthoracic echocardiographic (TTE) results and to anatomic findings. Mass lesions noted at surgery (autopsy) were correctly described in 93% by TEE versus 43% by TTE. Abscesses were detected in 88% by TEE versus 18% by TTE. Bioprosthetic degeneration was visualized in 88% versus 38% and prosthetic obstruction correctly identified in 75% versus 50% by TEE and TTE, respectively. Anatomic aortic regurgitant lesions were identified in 96% by TEE versus 77% by TTE, whereas the correct origin was detected in 88% of cases by TEE versus 54% of cases by TTE. TEE provides valuable additional information on morphologic conditions and flow pathology in aortic valve prostheses.

The ineffectiveness of the NO‐cyclic GMP signaling pathway in the atrial myocardium

1 This study was performed to determine whether nitric oxide (NO) has direct effects on force of contraction (Fc) in atrial myocardium from rats, rabbits, guinea‐pigs, frogs, and man. 2 Glyceryl trinitrate, isosorbide dinitrate, 3‐morpholino‐sydnonimine hydrochloride (SIN‐1), and S‐nitroso‐N‐acetylpenicillamine (SNAP) did not signficantly reduce Fc in the various preparations investigated, either given alone or after stimulation of α‐ or β‐adrenoceptors. 3 SNAP did not change the time course of contractions in rat, guinea‐pig and human preparations. 4 8‐Bromo‐guanosine‐3′:5′‐cyclic monophosphate (8‐Br‐cyclic GMP) produced a negative inotropic effect in rat, guinea‐pig and human atrial preparations and shortened time to peak tension and relaxation time in human preparations. 5 High K+ (85 mmol 1−1‐induced contracture in rat heart muscle was reduced by 8‐Br‐cyclic GMP but not by SIN‐1. 6 N‐monomethyl‐L‐arginine (l‐NMMA), an inhibitor of NO synthase, failed to influence muscarinic effects on Fc or frequency from rat and guinea‐pig hearts. 7 We conclude that NO, under the experimental conditions described here, has no direct effects on the heart, although cyclic GMP may be involved in the regulation of myocardial contraction.