Mounting evidence suggests that delayed xenograft rejection (DXR) of discordant xenografts has a strong humoral component. To explore the possibility of targeting this humoral response more efficiently, we performed a preliminary study in baboons immunized against pig blood cells using the immunosuppressor mitoxantrone (Mx). The results from this study showed that, in comparison with cyclophosphamide (CyP), Mx induced a long-lasting depletion of circulating B cells within 6 days of its administration and delayed secondary anti-Gal antibody (Ab) responses to pig blood cell immunizations. Given these results, we next evaluated Mx in an in vivo model of pig to baboon renal xenotransplantation. We performed a series of renal xenotransplantations in baboons using human CD55-CD59 transgenic donor pigs. In the first group of baboons (Mx group; n = 4) Mx was administered 6 days prior to the day of transplantation, the objective being to perform the xenotransplantation in a context where the recipient would have few remaining circulating B cells and thus have an impaired capacity to mount an Ab response to the xenograft. We compared this group to a second group of baboons treated with CyP starting 1 day prior to transplantation (CyP group; n = 2). All baboons receiving Mx or CyP received an additional immunosuppression of cyclosporin A, mycophenolate mofetil and steroids. No hyperacute rejection was observed in either group but all xenografts underwent DXR. Mx did not show superiority to CyP in terms of graft survival with a mean survival time of 8 +/- 2 days compared with 9 days for both CyP-treated baboons. Neither CyP nor Mx decreased serum levels of pre-existing anti-Gal Abs but levels of these Abs decreased dramatically within 1 day of transplantation, likely reflecting their immediate trapping within the xenograft. Interestingly however, in contrast to CyP, Mx inhibited the return of anti-Gal immunoglobulin M (IgM) to the circulation, even at the time of rejection. Nevertheless, strong intragraft deposits of IgM, IgG and the activated complement complex C5b-9 were observed in biopsies at rejection. Furthermore, despite the expected profound depletion of circulating B cells by Mx within 6 days of its administration, biopsies from both groups at rejection displayed a mild B cell infiltrate accompanied by a strong macrophage and intermediate T-cell infiltration, the latter tending to be more abundant in Mx-treated animals. Our data show that in this particular model of pig to baboon xenotransplantation and at the dose used, Mx was not superior to CyP in conferring protection against rejection, despite its capacity to profoundly deplete circulating B cells and to inhibit anti-Gal Ab responses to xenografts. DXR was thus possible without the return of anti-Gal Abs and may have been mediated by the early fixation of pre-existing Abs with secondary complement activation. However, although Mx was not more efficient than CyP in controlling DXR, its capacity to deplete B cells and delay Ab recovery may be beneficial in the context of Gal knockout organ transplantation where the induced Ab response is likely to take precedence over the preformed response.

BACKGROUND:Donor-specific tolerance induction remains an attractive objective that generates much research in the field of transplantation. Unfortunately, most of the protocols available involve pregraft conditioning, making these treatments incompatible with clinical applications.METHODS:LEW.1A rats were grafted with histoincompatible LEW.1W hearts. On the day of transplantation, recipients were treated with anti-CD40L combined with donor splenocytes. The hearts were evaluated for graft survival; cellular infiltrate and intragraft cytokines were determined using real-time reverse transcriptase-polymerase chain reaction. Tolerance induction was assessed by skin grafting and adoptive transfers.RESULTS:The combination of a single injection of anti-CD40L and donor splenocytes, given on the day of surgery, allowed 40% of cardiac allografts to survive long-term (mean survival time=66.3 day). The cellular composition or the extent of graft infiltrate was not modified but was associated with a massive decrease of proinflammatory cytokines expression within the graft. Long-term survivors accepted donor-matched skin grafts, and leukocytes harvested from these animals transferred tolerance into irradiated freshly grafted recipients.CONCLUSION:A combination of costimulation blockade and donor cells, given once at the time of transplantation, is sufficient to induce allograft tolerance in rats.

Besides virological and physiological concerns, the success of xenotransplantation (Xt) is still dependent on the prevention of delayed xenograft rejection (DXR). Although multifactorial, DXR is mainly due to xenonatural antibody (Ab) recognizing their xenogenic antigen (Ag) followed by complement activation. Despite the use of intensive treatments capable of inhibiting the humoral response, DXR can still not be avoided and always occurs within weeks following transplantation. Moreover, these latter treatments currently used in Xt could not be used clinically in humans because of their high risk of over-immunosuppressing the patients. Mitoxantrone (Mx) is a drug well known for its antiproliferative properties and is used clinically in oncology and in the treatment of relapsing multiple sclerosis. In models of arthritis in rats, it has been shown to be 10 to 20 times more powerful than cyclophosphamide (CyP) at blocking both inflammatory and B-cell responses. Because of its B-cell inhibitory capacity and considering the implication of the humoral response in xenograft rejection, we have compared Mx with CyP for its ability to block in vivo anti-pig immunization induced via subcutaneous injections of pig red blood cells into baboons. Neither drug was able to inhibit the anti-pig responses following the first and second immunizations, emphasizing the particularity of preformed Ab responses. However, the rise in Ab in the Mx treated animals was significantly delayed as compared with the non-treated as well as the CyP treated animals and was mainly because of a profound depletion of circulating B-cells. Mx displays an interesting antihumoral effect that we now intend to test in a pig kidney to baboon Xt model, with anticipated administration of the drug allowing an early B-cell depletion.

OBJECTIVES:heritable connective tissue abnormalities and arterial hypertension may predispose to aortic dissection. This study evaluates gene expression profiles in the acutely dissected human aorta.DESIGN, MATERIALS AND METHODS:Atlas Human Broad Arrays I, II, and III (Clontech) were used to compare gene expression in acutely dissected (6 patients) and normal ascending aortas (6 multiorgan donors). The tissues were also compared macroscopically.RESULTS:of 3537 genes analysed, 1250 (35%) were expressed in aortic tissue. For statistical analysis we focused on 627 genes, which had an intensity>0.95 of the mean patients or controls. Dissected and adjacent macroscopically intact aorta displayed similar gene expression patterns. On the contrary, 66 genes were expressed significantly different in dissected aorta, compared with undiseased control aorta of multiorgan donors. Genes, predominantly upregulated in dissection, are involved in inflammation, in extracellular matrix proteolysis, in proliferation, translation and transcription. Predominantly downregulated genes code for extracellular matrix proteins, adhesion proteins and cytoskeleton proteins.CONCLUSION:our results demonstrate for the first time the complexity of the dissecting process on a molecular level. The ultimate dissection seems to be the dramatic endpoint of a long-lasting process of degradation and insufficient remodelling of the aortic wall. Altered patterns of gene expression suggest a pre-existing structural failure of the aortic wall, resulting in dissection.

Background: Former studies on sternal wound infections indicate predisposing factors like diabetes, obesity, use of bilateral internal mammary grafts, impaired renal function and reoperation. We wanted to evaluate whether the time of resternotomy for postoperative bleeding has any influence on the development of a sternal wound infection and other complications. Methods: In our department, 12,315 patients underwent median sternotomy for cardiac surgery between 1987 and 1998. We analyzed the clinical data of all patients which were reoperated on for postoperative bleeding, especially patients with subsequent operations caused by sternal wound infections. All data were compared by T-test respectively X-2-test, and p<0.05 was regarded as significant. Results: 406 of the 12,315 patients were re-explored because of postoperative bleeding (3.3 %). 57 (14%) of these patients died in the postoperative period of non-infectious complications. The remaining patients were divided into two groups: Group A (286 patients) (70.4%) did not suffer from any sternal wound complications, where as group B patients (n = 63) (15.6%) needed subsequent surgery due to sternal infection. There were no significant differences in either concerning age, clinical data and first operation. All patients had an average blood loss of 223 ml/hr. The time before re-operation for bleeding was 5.3 +/- 1.7 hours in group A compared to 11.1 +/- 4.2 hours in group B (p<0.05). A significant delay of reoperation for bleeding could also be found for patients with postoperative septic complications (empty set: 5.2 +/- 1.9 hours, +: 12.9 +/- 5.2 hours), renal failure, mechanical ventilation >48 hours and a stay in hospital >20 days. Conclusions: Early reoperation for postoperative bleeding decreases the number of subsequent complications, e.g. sternal wound infections, septic complications and prolonged mechanical ventilation.

Objectives: heart-type fatty acid binding protein (hFABP) is an intracellular molecule engaged in the transport of fatty acids through myocardial cytoplasm and has been used as a rapid marl;er of myocardial infarction. However, its value in the evaluation of perioperative myocardial injury has not yet been assessed. Methods: 32 consecutive patients undergoing coronary artery bypass grafting were included in a prospective, randomized study using standardized operative procedures and myocardial protection. Three patients with perioperative myocardial infarction were added. Serial blood samples were taken preoperatively, before ischemia, 5 and 60 min after declamping, 1 and 6 h postoperatively and on postoperative days 1, 2 and 10 and were tested for hFABP, creatin kinase isoenzyme MB (CKMB) and troponin I (TnI). Results: Hospital mortality was zero. The kinetics of the biochemical parameters revealed a typical pattern fur each marker. In routine patients, hFABP levels peaked as early as 1 h after declamping, whereas CKMB and TnI peaked only 1 h after arrival in the intensive care unit. Patients with perioperative infarction displayed peak levels some hours later in all marker proteins. Peak serum levels of hFABP correlated significantly with peak levels of CKMB (r = 0.436, P = 0.011) and TnI(r = 0.5-18, P = 0.001), indicating the degree of myocardial damage. Conclusions: hFABP is a rapid marker of perioperative myocardial damage and peaks earlier than CKMB or TnI. The kinetics of marker proteins in serial samples immediately after reperfusion is more suitable Fur the detection of perioperative myocardial infarction than a fixed cut-off level. (C) 2001 Elsevier Science B.V. All rights reserved.

Fragestellung: Mögliche Interaktionen zwischen Mittelohrdruck und Gleichgewichtsstörungen werden seit vielen Jahren diskutiert. Der Rolle der druckausgelösten Trommelfellbewegungen, die bei degenerativ fixierten Ossikelgelenken aufgrund des Hydraulikfaktors eine viel grössere Kraft ausüben als der direkte Druck an den Innenohrfenstern, wurde dabei nur geringe Aufmerksamkeit gewidmet. Patienten und Methodik: Wir untersuchten bei 19 Patienten mit einseitigem Morbus Ménière die durch wechselnde Drucke im äusseren Gehörgang (analog zur Tympanometrie) ausgelösten Interaktionen zwischen Trommelfellauslenkungen und vestibulären Reaktionen in der Elektronystagmographie und in der Posturographie. Ergebnisse und Schlussfolgerungen: Bei schnellen und langsamen Druckwechseln konnten zwischen –600 und +400 daPa weder auf dem gesunden noch auf dem erkrankten Ohr im Elektronystagmogramm Nystagmen nachgewiesen werden. Die posturographische Aufzeichnung der vestibulospinalen Reaktionen auf einer Luzerner Messplatte erwies sich dagegen als sensibler. Die Längenzunahme der Schwankungslinie zeigte bei beiden durchgeführten Druckwechseln auf dem kranken Ohr signifikante Unterschiede gegenüber der Messung bei Reizung des gesunden Ohres. Diese Methode ist somit der klassischen Prüfung des Hennebertschen Fistelsymptoms überlegen. Das vestibulospinale System reagiert möglicherweise empfindlicher als das vestibulookuläre auf Druckschwankungen der Perilymphe. Darüber hinaus könnte der nachgewiesene Zusammenhang der druckausgelösten Trommelfellbewegungen mit cochleovestibulären Symptomen bei einigen Patienten mit M. Ménière den Erfolg einer Paukenröhrcheneinlage erklären, da hiermit aussendruckinduzierte Trommelfellbewegungen und damit verbundene Perilymphschwankungen von vornherein unterbunden werden.

PURPOSE:Since it is of great importance to distinguish between a systemic inflammatory response syndrome (SIRS) and an infection caused by microbes especially after heart transplantation (HTX), we examined patients following heart surgery by determining procalcitonin (PCT), because PCT is said to be secreted only in patients with microbial infections. METHODS:Sixty patients undergoing coronary artery bypass grafting (CABG) and 14 patients after heart transplantation were included in this prospective study. In the CABG group we had 30 patients without any postoperative complications (group A). Furthermore we took samples of 30 patients who suffered postoperatively from a sepsis (group B, n=15) or a systemic inflammatory response syndrome (C, n=15). In addition we measured the PCT-levels in 65 blood samples of 14 patients after heart transplantation (Group I: rejection > IIa, II: viral infection (CMV), III: bacterial/fungal infection, IV: controls). RESULTS:In all patients of group A the pre- and intraoperative PCT-values and the measurement at arrival on intensive care unit (ICU) were less than 0.2 ng/ml. On the second postoperative day the PCT-value was 0.33+/-0.15 ng/ml in the control group. At the same time it was 19.6+/-6.2 ng/ml in sepsis and 0.7+/-0.4 ng/ml in systemic inflammatory response syndrome patients (P<0.05). In transplanted patients we could find the following PCT-values: Gr.I: 0.18+/-0.06 II: 0.30+/-0.09 III: 1.63+/-1.16 IV: 0.21+/-0.09 ng/ml (P<0.05 comparing group III with I, II and IV). CONCLUSIONS:These results show that extracorporeal circulation (ECC) and systemic inflammatory response syndrome do not initiate a PCT-secretion. Septic conditions cause a significant increase of PCT. In addition, PCT is a reliable indicator concerning the essential differentiation of bacterial or fungal--not viral--infection and rejection after heart transplantation.

For the testing of heart assist devices most animal models of acute cardiac failure that are usually used show certain disadvantages. We therefore developed a new method using the beta-adrenoceptor antagonist carazolol. We administered a bolus injection of 1 mg/kg followed by a continuous infusion of 1 mg/kg/h in adult German 'Landrasse' pigs. Blood pressure, heart rate, cardiac output and maximum left ventricular pressure rise time showed a significant (P < 0.05) reduction of the control value varying between 40% and 59%. The method is suitable for the testing of surgical approaches in heart failure.

The results of orthotopic heart transplantation (OHTx) are still burdened with considerable early mortality due to graft rejection or infection. Sternum osteomyelitis is an infrequent postoperative complication. We report a case of deep sternal wound infection (2 months after OHTx) that was treated with hyperbaric oxygen therapy in addition to local surgical treatment.

Background: In order to optimize regional utilization of transplantable thoracic organs, the seven university hospitals in North-Rhine-Westfalia have formed a transplant cooperation meanwhile approved by Eurotransplant. Methods: Heart transplant and organ donation activities of the cooperating hospitals in the year before the foundation of the cooperation (period A, 7/95 - 6/96) and in the year thereafter (period B, 7/96 - 6/97) were retrospectively analysed. Results: In period A, a total of 39 heart transplants and 74 heart donations were performed, whereas in period B 67 heart transplantations and 78 heart donations could be achieved. The regional utilization of the donor organs increased from 4% to 30% with a significantly shorter ischemia time of regionally or locally allocated donor hearts than of nationally or internationally allocated ones. Conclusions: A high rate of regional or local heart transplant procedures with short ischemia times clearly demonstrate the benefits of a regionalization of heart transplant medicine for medical as well as economical reasons.

BACKGROUND:The reasons for a systemic inflammatory response syndrome (SIRS) following ECC are not yet fully understood. Procalcitonin (PCT) blood levels may distinguish between bacterial infections and a non-bacterial systemic inflammation. We investigated the influence of ECC, ECC modified by application of aprotinin, systemic inflammation, and bacterial infection on the PCT values.METHODS:20 CABG patients were randomized and divided in two groups. Group A served as the control group, while group B perioperatively received a high dose of aprotinin. Blood samples for measurement of PCT were taken 6 times perioperatively. Furthermore, blood samples were taken from 20 preoperatively comparable patients who suffered from bacterial infection (n = 10) (group C) or a SIRS (n = 10) (group D) after ECC; in these groups PCT was determined daily after the onset of inflammation.RESULTS:There was no significant elevation of PCT in group A or B at any time. In sepsis patients a significant elevation of PCT was seen, with the peak level of 18.6+/-6.3 ng/ml on the second day after diagnosis; the PCT level of SIRS patients remained constantly low (<0.9 ng/ml).CONCLUSIONS:In this study it was demonstrated that ECC and the use of aprotinin did not have any influence on the secretion of PCT. A systemic bacterial infection caused a significant increase of PCT, whereas PCT values remained normal in case of a SIRS. So it seems to be possible to distinguish between a primary SIRS and a bacterial sepsis by means of PCT.

This paper presents a new cardiac support device for left ventricular failure which consists of two inflatable bellows positioned dorsally and ventrally to the left ventricle. The implantable multichamber pump system (IMPS) is driven by a pneumatic pump system and controlled by a microcomputer using ECG-trigger and pacemaker modules. It was implanted via thoracotomy in 8 pigs. The circulatory parameters were measured in the animals on β-blockers, with cardiac failure and in ventricular fibrillation with an activated (IMPS on) and deactivated (IMPS off) system. IMPS significantly increased the left ventricular pressure (LVPsys IMPS off: 63 ∓ 6 mmHg vs IMPS on: 96 ∓ 8 mmHg) and the blood pressure in the common carotid artery (Bpca' IMPS off: 69/38 mmHg vs IMPS on: 95/40 mmHg). The IMPS proved to be highly efficient in the therapy of animals with acute cardiac failure and in ventricular fibrillation in the experimental model. Apart from its efficiency the advantages with this system are the ease of handling and its high biocompatibility due to the lack of contact with circulating blood.

Die Zahl der Patienten mit einer ischämischen Kardiomyopathie und begleitender chronisch schwerer Pumpstörung des linken und/oder rechten Ventrikels hat sich in den letzten 10 Jahren verdreifacht. Als Grunderkrankung stellt die ischämische Kardiomyopathie heute den zahlenmäßig größten Anteil aller Herztransplantierten. Die Ergebnisse unterscheiden sich dabei nicht von denen nach einer Transplantation aufgrund einer primären Kardiomyopathie. Nachdem die Herztransplantation heute zu einem klinischen Routineverfahren geworden ist, wird die Diskrepanz zwischen der Anzahl der vorhandenen Spenderorgane und der Anzahl der benötigten Organe immer deutlicher. Die größer werdenden Wartelisten und die länger werdenden Wartezeiten machen deshalb immer häufiger ein “Bridging” notwendig, daß inzwischen zu keiner Verschlechterung der Langzeitergebnisse nach Herztransplantation(HTX) mehr führt. Aufgrund der größer werdenden Erfahrungen mit mechanischer Assistenz, den gerätetechnischen Verbesserungen und dem Herausarbeiten von klaren Indikationen, sind für die Patienten durch Abnahme der Kachexie und des Organversagens häufig bessere Voraussetzungen zur HTX zu schaffen. Mit Hilfe der implantierbaren Ventrikel ist eine Mobilisierung der Patienten zu erreichen, wodurch eine hohe klinische Akzeptanz des Verfahrens besteht.

Mitral valve replacement (MVR) is still associated with a relatively high mortality. To investigate the influence of chordal preservation in MVR on left ventricular size and function, we studied a series of 82 patients who underwent MVR either with (group A n = 50) or without (group B n = 32) preservation of the subvalvular structures and compared the two groups. Echocardiography was performed preoperatively, and 7 days and 3 months postoperatively. Echocardiographic investigations included left atrial and ventricular diameters, right ventricular diameters and left ventricular length. Preoperatively there were no difference between the two groups of patients. Intraoperative and postoperative management was similar in the groups. Three months postoperatively echocardiographic examinations demonstrated that chordal preservation in MVR resulted in smaller left ventricular systolic and diastolic diameters (LVESD: gr. A 43.4 +/- 7.8 mm vs gr. B 48.8 +/- 9.2 mm P < 0.05, LVEDD: 57.3 +/- 7.8 mm vs 62.9 +/- 10.5 mm P < 0.05) and a significantly decreased left ventricular length (87.1 +/- 4.2 mm in gr. A vs 97.5 +/- 5.7 mm in gr. B P < 0.05). In addition, left ventricular ejection fraction in group A was significantly improved compared to group B (54.2 +/- 11.2% vs 48.1 +/- 12.4%, P < 0.05). We conclude that chordal preservation in MVR improves left ventricular function and reduces left ventricular diameters and volumes compared to resection of the mitral subvalvular appartus and that these beneficial effects can be maintained in the postoperative course.

Background. To reduce blood consumption in cardiac surgery, aprotinin has been widely used for years. Because aprotinin is metabolized in the kidney, damage of the renal system has been discussed.Methods. To study these possibly unfavorable effects of aprotinin, a prospective, randomized, placebo-controlled study of 20 patients undergoing aortocoronary bypass operations was performed. A placebo group P was compared with group A, in which patients received high-dose aprotinin according to the ''Hammersmith'' regimen. Renal function was assessed for 5 postoperative days using sodium dodecyl sulfate gel electrophoresis and quantitative protein analysis of the urine.Results. During and after the operation, temporary renal dysfunction was found in all patients, with a substantial increase of all investigated indices. The alpha(1)-microglobulin level in the urine was significantly increased in the aprotinin group for 5 days in comparison with the placebo group, with a maximum on the third postoperative day (64.8 +/- 13.7 versus 21.0 +/- 6.5 mg/L; p < 0.05). Similarly, after sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the bands of proteins filtrated in the renal tubular system were almost tripled in the aprotinin group 5 days postoperatively (5.0 +/- 0.8 versus 2.1 +/- 0.2; p < 0.05). Although urine production was significantly increased in group A (4789 +/- 580 versus 3653 +/- 492 mL/24 h postoperatively; p < 0.05), no relevant changes in serum or urine creatinine levels could be observed in either group.Conclusions. Patients undergoing aortocoronary bypass operations demonstrate a temporary renal dysfunction. Aprotinin impairs renal function in addition by overloading the tubular reabsorption mechanisms. Patients with normal renal function preoperatively-as were included in this study-are able to compensate for both the perioperative renal dysfunction caused by the extracorporeal circulation and the additional tubular damage due to aprotinin.

The advantages of chordal preservation in mitral valve replacement have been demonstrated, but there is no detailed information available on the effect of chordal preservation in patients undergoing multiple valve operations. We assessed therefore a series of 61 patients who underwent multiple valvular procedures either with (Group A, n = 42) or without (Group B, n = 19) preservation of the subvalvular structures. Echocardiographic examinations were performed preoperatively, seven days and three months postoperatively. In addition clinical and electrocardiographic examinations were performed. Echocardiographic investigations included left atrial, left and right ventricular diameters and left ventricular length. Preoperatively there were no differences between the two groups. Intra- and postoperative management was similar in the two groups. Postoperative clinical and echocardiographic examinations demonstrated that, although beneficial effects were evident in both groups, improvement of left ventricular function and decrease in left ventricular size were more pronounced in patients in whom chordal preservation was possible.

In 71 patients with a mean age of 59 +/- 10 years and an ejection fraction of 40 +/- 16%, a total of 78 cardioverter/defibrillators of a newer generation was implanted. The majority of the patients had coronary artery disease (n = 51). The indications for implantation were ventricular fibrillation in 30, hemodynamically unstable ventricular tachycardia in 20, and both ventricular fibrillation and ventricular tachycardia in 21 cases. In 33 of 35 attempted procedures a transvenous-endocardial implantation could be performed.After a mean follow-up of 20 +/- 14 months, the total survival rate was 87.4% and total cardiac mortality was 9.4 %. Adequate interventions occurred in 33 patients. 25 of them received shocks which were either accompanied with syncope/presyncope or were given due to documented fast (> 230 bpm) tachyarrhythmic episodes. Of the remaining patients, the interventions were shocks in the setting of slower episodes in two or exclusively antitachycardia pacing in seven cases. In those individuals in whom antitachycardia pacing could be optimized by several inductions and terminations of stable ventricular tachycardias at predischarge electrophysiological testing, the success rate was 82 %. In a small number of patients (n = 11) without documented and known ventricular tachycardias, an antitachycardia program based on our experiences was blindly activated. During follow-up, 37 episodes were documented in four cases. In 57 % of these episodes, a shock was omitted because of successful antitachycardia pacing. False triggering was noted in four patients, due to atrial fibrillation with a fast ventricular rate (n = 3) and sinus tachycardia (n = 1). Oversensing due to technical reasons occurred in four individuals, due to electrode fracture in one, and connection problems in three cases. The whole majority of the episodes was of short duration (diverted shocks); in only three episodes (two cases), shocks were given. In those and in one patient with electrode fracture the surgical reintervention was necessary.Thus, due to several additional diagnostical and therapeutical features of the cardioverter/defibrillators of newer generation the long-term therapy is more effective and safe and in case of antitachycardia pacing more comfortable to the patients.