Diethard Pruefer

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.

Ischemia-Reperfusion Injury

The term ischemia-reperfusion injury describes the experimentally and clinically prevalent finding that tissue ischemia with inadequate oxygen supply followed by successful reperfusion initiates a wide and complex array of inflammatory responses that may both aggravate local injury as well as induce impairment of remote organ function. Conditions under which ischemia-reperfusion injury is encountered include the different forms of acute vascular occlusions (stroke, myocardial infarction, limb ischemia) with the respective reperfusion strategies (thrombolytic therapy, angioplasty, operative revascularization) but also routine surgical procedures (organ transplantation, free-tissue-transfer, cardiopulmonary bypass, vascular surgery) and major trauma/shock. Since the first recognition of ischemia-reperfusion injury during the 1970s, significant knowledge has accumulated and the purpose of this review is to present an overview over the current literature on the molecular and cellular basis of ischemia-reperfusion injury, to outline the clinical manifestations and to compile contemporary treatment and prevention strategies. Although the concept of reperfusion injury is still a matter of debate, it is corroborated by recent and ongoing clinical trials that demonstrated ischemic preconditioning, inhibition of sodium-hydrogen-exchange and administration of adenosine to be effective in attenuating ischemia-reperfusion injury.

Aprotinin inhibits leukocyte–endothelial cell interactions after hemorrhage and reperfusion

BACKGROUND The 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. METHODS The 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. RESULTS Intravenous 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.

Effects of Aprotinin on Gene Expression and Protein Synthesis After Ischemia and Reperfusion in Rats

Background— Reperfusion injury of ischemic myocardium has been attributed to neutrophil infiltration, inflammatory activation and cardiac necrosis/apoptosis. Serine protease inhibition with aprotinin is cardioprotective, but the mechanism is unknown. Methods and Results— We studied aprotinin in a rat model of myocardial ischemia for 20 minutes and reperfusion for 20 minutes, 8 hours or 24 hours. Aprotinin (20 000 IU/kg) given 5 minutes before reperfusion significantly reduced leukocyte accumulation (P<0.01), myocardial injury (determined by CK depletion, P<0.01) and myocyte apoptosis (P<0.05) compared with vehicle treated rats. Differential gene expression analysis showed myocardial ischemia plus reperfusion increased expression of proinflammatory genes like P-selectin, E-selectin, intercellular adhesion molecule, tumor necrosis factor-α, tumor necrosis factor-α receptor, interleukin-6, monocyte chemoattractant protein-1, p53, and Fas (CD59). Aprotinin before reperfusion suppressed expression of these inflammatory genes. Finally, differential protein expression analysis demonstrated increased intercellular adhesion molecule-1, tumor necrosis factor-α, and p53 after myocardial ischemia plus reperfusion, and this effect was diminished by aprotinin. Conclusions— We demonstrated myocardial ischemia plus reperfusion induced leukocyte accumulation, inflammation, gene expression, protein expression and finally tissue injury and showed aprotinin limiting reperfusion injury through each of these stages, even after 24 hours of reperfusion. This effect seems partly attributable to suppression of proinflammatory genes and leukocyte accumulation. This work casts further light on the complex signaling of ischemia and reperfusion.

Sodium/hydrogen exchange inhibition with cariporide reduces leukocyte adhesion via P‐selectin suppression during inflammation

The Na+/H+ exchange (NHE) inhibitor cariporide is known to ameliorate ischaemia/reperfusion (I/R) injury by reduction of cytosolic Ca2+ overload. Leukocyte activation and infiltration also mediates I/R injury but whether cariporide reduces I/R injury by affecting leukocyte activation is unknown. We studied the effect of cariporide on thrombin and I/R induced leukocyte activation and infiltration models and examined P‐selectin expression as a potential mechanism for any identified effects.

Anti-inflammatory actions of aprotinin provide dose-dependent cardioprotection from reperfusion injury

Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen‐derived radicals and proteases causing damage.

Anomalous origin of the left coronary artery from the pulmonary artery: mid-term results after surgical correction

ObjectivesChildren with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) are at risk for myocardial infarction and death. This retrospective study shows the mid-term follow-up after the use of aortic implantation and alternative methods to achieve coronary transfer.MethodsSince 1990 seven consecutive children underwent primary repair of ALCAPA. Age at operation ranged from 2 to 71 months (median 11 months). Operative techniques included ligation (n = 1), intrapulmonary tunnel (n = 1), and aortic implantation (n = 5). One patient with severe mitral valve incompetence underwent additional mitral valve replacement. A 4-month-old patient was successfully treated after the operation with a left heart assist device.ResultsOne death in the series occurred at 2 weeks after intrapulmonary tunneling. The mid-term results were evaluated in the six survivors with a follow-up mean of 98 months (ranged 58–168). In all surviving patients with two-vessel coronary blood supply, left ventricular end-diastolic volume and left ventricular ejection fraction returned to near normal values 2–12 months postoperatively. The mitral valve incompetence decreased in all patients with a native mitral valve. One patient with coronary ligation showed severe mitral valve regurgitation and received additional mitral valve replacement concomitantly. Six years after primary valve replacement of a 21 mm SJM (Saint Jude Medical) a change of the mechanical valve to a 27 mm valve was necessary because of development of severe stenosis due to growth.ConclusionsIt is always preferable to establish an antegrade flow of oxygenated blood through the coronary arteries and to create a two-coronary artery system. Mitral valve annuloplasty or replacement may be necessary for patients with severe mitral valve incompetence.

The Fontan-Operation: From Intra- to Extracardiac Procedure

PURPOSE For treatment of univentricular heart, the Fontan operation has been established as the definitive palliation. The current controversy is mainly based on the high incidence of arrhythmias after an intra-atrial lateral tunnel Fontan operation. METHODS From January 1995 until April 2002, 46 children underwent a Fontan-type operation with or without a small fenestration. In 33 patients (group I) an intracardiac tunnel and in 13 patients (group II) an extracardiac conduit procedure was performed. PRINCIPAL FINDINGS There was no perioperative mortality. All patients showed postoperative a significant increase of arterial oxygen saturation, from 76 to 86% after surgery with fenestration, or to 90.5% without fenestration respectively. In patients with fenestration procedure, the saturation rose to 90% after closure of fenestrations 9 to 12 months after operation. CONCLUSIONS Modified Fontan operations can be performed in normothermia on the beating heart with acceptable mortality. The extracardiac conduit Fontan procedure has the benefits of less surgical injury and a higher intraoperative flexibility.

Analyse der chirurgischen Therapie des Vorhofscheidewanddefektes (ASD) bei Adoleszenten und Erwachsenen

ZusammenfassungFragestellungZiel unserer Studie war die Erfassung und Analyse der Langzeitergebnisse bei adoleszenten und adulten Patienten nach operativer Therapie des Atriumseptumdefektes (ASD).MethodikWir analysierten 106 konsekutive Patienten, die wegen eines Atriumseptumdefektes (ASD) im Alter von 16 bis 74 Jahren (Alter: 39,2±16,3 J; w:m/69: 37) in einem Zeitraum von 15 Jahren operiert wurden.Ergebnisse16% der Patienten boten präoperativ Herzrhythmusstörungen. Diese waren bei einem Alter von über 50 Jahren signifikant häufiger (p=0,001). 78 Patienten (74%) zeigten eine Rechtsherzbelastung im EKG oder im TTE/TEE. 36% davon wiesen eine pulmonale Hypertonie auf. Sowohl der systolische als auch der mittlere Pulmonalarteriendruck korrelierten positiv mit dem Alter des Patienten (r=0,3; p=0,007 bzw. r=0,22; p=0,046). 12 Patienten (11,3%) hatten präoperativ embolische Ereignisse: 5 Apoplex, 5 rezidivierende TIA- und 2 periphere Emboliefälle. Die perioperative Mortalität betrug 0%. Ein Follow-up war bei 73 Patienten (69%) nach 5,4 Jahren möglich (Min.: 0,84, Max. 14,1 Jahre). 53% der Patienten mit präoperativen Herzrhythmusstörungen wiesen zum Zeitpunkt des Follow-up einen Sinusrhythmus auf. Im Schnitt hatte sich das Patientenkollektiv um 1,3 NYHA-Klassen verbessert. Die Verbesserung in der NYHA-Klassifikation war unabhängig vom Alter zum Zeitpunkt der Operation (p>0,05). Die 5- bzw. 10-Jahres-Überlebensrate betrug unabhängig vom präoperativen Pulmonalarteriendruck nach Kaplan-Meier 97 bzw. 93%.SchlussfolgerungDie Langzeitergebnisse der chirurgischen Behandlung adoleszenter und adulter Patienten mit ASD zeigen eine deutliche Verbesserung der Rhythmusstörungen sowie des NYHA-Stadiums und damit der Lebensqualität.SummaryBackgroundThe aim of this study was the analysis of the long-term follow-up of young and adult patients with atrial septal defect after surgical therapy.MethodsWe analyzed 106 patients with atrial septal defect (ASD) between 16 and 74 years (mean 39.2±16.3 y; w:m/69 : 37) who underwent a surgical defect closure over a 15 year period.ResultsIn 16% of the patients cardiac arrhythmias were observed in the preoperative period. The incidence of arrhythmias was significant higher in the patient group over 50 years (p=0.001). 78 patients (74%) showed a right heart volume overload in the ECG and echocardiography, while 36% had a pulmonary hypertension. Twelve patients (11.3%) had emobolic events: 5 patients with apoplexy, 5 with transitory ischemic attack and 2 patients with peripheral embolism. The perioperative mortality was 0%. A follow-up was performed with 73 patients (69%) within 5.4 years after operation (min: 0.84, max: 14.1 years). 53% of patients with preoperative arrhythmia showed regular sinus rhythm. The NYHA stadium of the study group was 1.3 NYHA class lower than preoperative irrespective of age and year of operation (p>0.005). The 5 and 10 year survival rate was 97 and 93%, respectively, independent of pulmonary arterial pressure.ConclusionsAdolescent and adult patients with ASD have a benefit of surgical therapy in reduced arrhythmia rate and improvement in their NYHA class and thus in their quality of life.

Aortenisthmusstenose bei Erwachsenen: operative Korrektur – mittel- und langfristige Ergebnisse

ZusammenfassungFragestellung Ziel dieser retrospektiven Untersuchung war es, die Mittel- und Langzeitergebnisse der operativen Korrektur von Aortenisthmusstenosen (ISTHA) bei Erwachsenen zu erfassen. Patienten und Methodik Zwischen August 1985 und Januar 1999 wurden 20 Patienten (8 Frauen, 12 Männer) wegen ISTHA im Alter 19–60 Jahren (im Mittel 33 Jahre) operiert. Alle Patienten fielen klinisch durch Bluthochdruck der oberen Extremitäten auf (im Mittel 177/92 mmHg). Bei 9 Patienten von 16 (56%) handelte es sich um einen Zufallsbefund (bei 4 konnte dies nicht eruiert werden). Eine eingeschränkte präoperative Belastbarkeit wiesen 13 Patienten (65%) auf. Herzrhythmusstörungen zeigten sich bei 3 Patienten (15%). 14 Patienten (70%) zeigten im Röntgenbild Rippenusuren. Als operative Therapie erfolgte bei 5 Patienten (25%) eine End-zu-End Anastomose, bei 7 (35%) eine Erweiterungsplastik, bei weiteren 3 (15%) eine Rohrprothesenimplantation und bei 5 Patienten (25%) ein extraanatomischer Bypass. Die Operationsdauer betrug zwischen 105 und 240 Minuten, im Durchschnitt 159 Minuten. Ergebnisse Perioperativ trat bei einem Patienten eine Nachblutung wegen Nahtdehiszenz auf, die eine Not-Rethoracotomie erforderlich machte. Die Folgen des hämorrhagischen Schocks führten am nächsten Morgen zum Tod. Die Frühmortalität betrug somit 5% (1/20). Bei 10 Patienten normalisierte sich der Blutdruck direkt postoperativ, bei 5 Patienten blieb er leicht erhöht (RR zwischen 140 und 160 mmHg systolisch). Bei den übrigen 4 Patienten konnte dies nicht mehr eruiert werden. In 14 Fällen (73,7%) war ein postoperatives Follow-up nach durchschnittlich 9,4 Jahren (Minimum 1,2; Maximum 13,8 Jahre) durchführbar. Ein Patient war 12,4 Jahre nach der Operation an Herzversagen verstorben. Somit betrug die Spätmortalität 7,1% (1/14). Im Durchschnitt verbesserten sich die Patienten um 0,85 NYHA-Klassen in ihrer Belastbarkeit. Zum Zeitpunkt des Follow-up hatte nur einer von 13 Patienten einen fortbestehenden Hypertonus. Schlussfolgerung Die chirurgische Behandlung von Aortenisthmusstenosen bei Erwachsenen reduziert die arterielle Hypertonie und verbessert die Belastbarkeit von Patienten. Im dem von uns beobachteten Kollektiv zeigte sich eine geringe Früh- sowie Spätmortalität und Morbidität. Zeitlebens sollten Verlaufsbeobachtungen in spezialisierten Zentren durchgeführt werden.SummaryAims The aim of this retrospective study was to determine the mid- and long-term results after surgical repair of aortic coarctation in adults. Patient and Methods Twenty adults (8 women, 12 men), mean age 33 years (range, 19 to 60 years), underwent aortic coarctation surgical repair between August 1985 and January 1999. In nine from 16 patients (56%), the diagnosis was given as incident finding. All patients suffered from preoperative hypertension. Mean systolic blood pressure was 177/92 mmHg measured at the upper extremities. Thirteen (65%) patients demonstrated reduced load capacity. Rhythm disorders were described in 3 (15%) patients. Fourteen patients (70%) demonstrated rib notching in the chest ray. Operative technique was resection an end-to-end anastomosis for 5 patients (25%), resection and interposition of a Dacron-tube graft for 5 patients (25%), Dacron-patch dilatation was performed in 7 (35%) patients, and in 5 (25%) patient we performed an extraanatomical bypass graft. The mean operation time was 159 minutes (range, 105 to 240 min). Results Early mortality occurred in 1 patient (5%) as a result of surgical problems (suture dehiscence). This patient was directly re-operated, but died the next morning from consequences of hemorrhagic shock. Of the 20 patients with preoperative hypertension, 10 were normotensive; in five patients the blood pressure was slightly elevated (systolic blood pressure between 140 to 160 mmHg) and one patients had prolonged hypertension. In 4 patients, blood pressure could not be retrospectively determined. The mean follow-up period was 9.4 years (range, 1.2 to 13.8 years). One patient died 12.4 years after operation from cardiac failure. Thus, there was one late death 7.1% (1 from 14 patients) during follow-up. On average, the New York Heart Association Class (NYHA) was improved by 0.85 NYHA classes. Conclusion The surgical repair of aortic coarctation in adults reduces hypertension and improves capacity. In our group of patients with surgically repaired coarctation, early and late mortality was commonly low. It would be prudent for all patients to have a long-term follow-up at a cardiac center.