Biomedical subjects

C F Vahl

Publications and source records attributed to C F Vahl.

At least 37 records · Page 2Linked to original sources

PubMed2001

[Myocardial revascularization after pretreatment with the GPIIb/IIIa receptor blocker abciximab].

AIM: The present prospective study analysis whether preoperative abciximab treatment 1) increases perioperative risks, 2) alters the quality of the surgical treatment, 3) whether secondary organ complications occur and 4) whether and how the perioperative surgical management has to be modified. METHODS: The perioperative results of patients operated upon after preoperative abciximab treatment (n = 31, 1/1994-4/2000) were compared with an optimal control group (elective patients and no preoperative intervention in the hemostaseological system) and with other patients (elective, urgent, emergency operations) receiving different strategies of preoperative hemostaseological interventions (n = 926, 1/1994-4/2000). All patients were operated upon with a well-defined strategy (one surgeon). 1100 perioperative items/patient were prospectively recorded and analyzed. The 30-day and 6 month follow-up was complete. RESULTS: The mean time interval between end of abciximab therapy and onset of operation was 4.3 h (range: 36-0.5 h, median: 2 h). As compared with the optimal control group (n = 81), perioperative blood loss and the need for substitution of blood and blood products was increased. However, as compared with those patients receiving any type of preoperative intervention in the hemostaseological system (the majority of the patients), no difference was observed regarding intraoperative parameters (duration of extracorporeal circulation and of the operation) and postoperative results (neurological, renal complications, myocardial infarction, psychiatric disturbances, etc.) when abciximab patients were compared with the reference populations. No patient of the abciximab group died within 30 days or during the 6 month follow-up period. CONCLUSION: The data show that coronary artery bypass grafting can be performed with similar results in abciximab-pretreated patients as in patients with other types of preoperative anticoagulation. Only slight modifications of the surgical management are recommended. As indicated by similar use IMA-grafts the quality of surgical treatment was not reduced.

Abciximab↗

PubMed2001

Downregulation of myocardial contractility via intact ventriculo--arterial coupling in the brain dead organ donor.

OBJECTIVE: To test the hypothesis that altered loading conditions play a key role in hemodynamic instability and cardiac dysfunction in the brain dead (BD) organ donor. METHODS: BD was induced by inflation of a subdural balloon catheter. In the first part of the study, left ventricular function was assessed in a canine in situ cross-circulated heart model (n=6). Pre- and afterload and coronary perfusion pressure were kept identical in all hearts throughout the experiment. In the second part of the study, hearts (n=6) were investigated in vivo allowing the interaction between left ventricular contractility and arterial load. Left ventricular pressure--volume loops were obtained by a combined conductance-pressure catheter and the slope of the endsystolic pressure--volume relationship (Ees), arterial elastance (Ea), stroke work (SW), pressure--volume area, ventriculo--arterial coupling ratio (VAC) and mechanical efficiency (Eff) were calculated. RESULTS: Induction of BD led to a hyperdynamic response in both models with a significant increase of most hemodynamic parameters. In the in situ isolated heart model, left ventricular contractility returned to baseline without any further deterioration. In contrast, in the intact circulation the hemodynamic parameters declined significantly in comparison to baseline 4 h after BD (Ees: 4.07+/-0.51 vs. 8.06+/-1.09 mmHg/ml, P<0.05, Ea: 3.17+/-0.39 vs. 4.42+/-0.30 mmHg/ml, P<0.05). However, VAC (0.78+/-0.09 vs. 0.65+/-0.14 n.s.) and Eff (73.4+/-2.1 % vs. 76.8+/-3.7 %, n.s.) remained constant over the time. CONCLUSION: BD induction leads to an initial hyperdynamic reaction followed by hemodynamic instability. The facts that no cardiac dysfunction occurred if loading conditions were kept constant and the ventriculo--arterial coupling ratio and mechanical efficiency remained constant in the intact animal model indicate that decreased contractility reflects to decreased arterial elastance after brain death. Therefore, reduced contractile function after brain death at a decreased afterload may contribute to stroke work optimization.

Animals↗

PubMed2001

Does the completeness of revascularization affect early survival after coronary artery bypass grafting in elderly patients?

OBJECTIVE: Usefulness and risks of incomplete versus complete revascularization are still matters of ongoing discussions. Because an increasing number of elderly patients are undergoing coronary artery bypass grafting (CABG), the question arises whether a less extensive surgical approach is more prudent than complete revascularization. METHODS: Of 6531 patients undergoing isolated CABG, 859 were 75 and older at the time of operation. Mean age of the 859 patients was 77+/-2.7 years (median: 76 years); 65% were men. Follow-up enquiry by questionnaire was performed at the 180th postoperative day with a completeness of 95.6%. Assessment of the impact of incomplete revascularization utilized both multivariable analysis and propensity score matching to account for selection factors. RESULTS: Incomplete revascularization was performed in 133 patients (16%). The most common reasons for incomplete revascularization were small vessels (55%) and massive calcification (32%). Mortality until 180 days after CABG was higher (n=32; 24%) after incomplete than after complete revascularization (n=105; 15%; P=0.005). By logistic multivariable regression, incomplete revascularization was identified as an independent risk factor for death (Odds ratio, 1.8; P=0.015). By time-related analysis, incomplete revascularization predominantly affected the early period after CABG (P=0.001). Aortic cross clamping time was only slightly shorter for the group with incomplete (59+/-27 min (median: 55 min) vs. 63+/-26 min (median: 58 min); P=0.1). CONCLUSIONS: Incomplete revascularization increases the early risk of death after CABG in patients aged 75 years and older. The potential compensating benefit of the shorter aortic cross clamping time does not outweigh the advantages of complete revascularization. Thus, in the era of high-volume interventional approaches and minimally invasive techniques, the advantages of complete revascularization need to be considered.

Aged↗

PubMed2001

The role of endothelin-B receptors in myocardial and endothelial reperfusion injury after heart transplantation.

BACKGROUND: This study was designed to investigate the effects of the selective endothelin-B (ET-B) receptor agonist IRL1620 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia and reperfusion. METHODS: Isogenic intraabdominal heterotopic heart transplantation was performed on Lewis rats. After one hour of cold ischemic preservation, reperfusion was started either after application of saline vehicle or IRL1620 or BQ788 or both. Left ventricular pressure-volume relations and myocardial blood flow were assessed after one and 24 hours of reperfusion. Endothelium-dependent vasodilatation to acetylcholine (ACH) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined. RESULTS: IRL1620 attenuated and BQ788 improved myocardial contractility significantly as indicated by the left or upward shift of the systolic pressure-volume relation, respectively, and significantly changed myocardial blood flow during early reperfusion (p<0.05). Although myocardial function and baseline myocardial blood flow were similar in both groups after 24 hours of reperfusion, endothelium-dependent vasodilatation was still significantly lower in the IRL1620 and higher in the BQ788 group (p<0.05). CONCLUSIONS: These results suggest that activation of the ET-B receptors contributes to reperfusion injury after cardiac preservation in a rat heart transplant model.

Acetylcholine↗

PubMed2001

3D evaluation of myocardial edema: experimental study on 22 pigs using magnetic resonance and tissue analysis.

BACKGROUND: Myocardial edema (ME) adversely affects ventricular function. Thus, we performed an animal study to demonstrate (1) 3D-ME using magnetic resonance imaging (MRI), which can show ME depending on myocardial location, (2) type of cardioplegic solution, and (3) quantification tools. METHODS: Pig hearts (n = 22) were perfused using Bretschneider's solution (BRET, n = 8), butanedionemonoxime (BDM, n=8), or no cardioplegia as controls (CTRL, n = 6). Hearts underwent MRI (T(1)-inversion recovery). Myocardial water content (MWC, reference method) was determined from left ventricle anterior, posterior (PW), lateral wall, interventricular septum, papillary muscle, right ventricle wall. Images underwent 3D reconstruction using ray-tracing. Gray-value analysis was performed on "virtual" samples. For statistical analysis, ANOVA, Student's t-test, and the Student-Newman-Keuls test were used. RESULTS: (1) ME was induced (p < 0.0001 vs. control). Localization differed in MWC, p = 0.003 (BRET), p = 0.023 (BDM), highest at PW (p < 0.01). (2) Differences between the cardioplegia groups were not significant. (3) "Virtual" samples showed equal distribution (BRET: p = 0.007, BDM: p = 0.003), highest at PW (p < 0.01). CONCLUSIONS: We validated 3D assessment of induced ME in pig hearts using MRI. The method may therefore become an exact tool in monitoring cardioplegia.

Animals↗

PubMed2001

Does the completeness of revascularization contribute to an improved early survival in patients up to 70 years of age?

OBJECTIVE: In the era of a renewal of incomplete revascularization approaches, the controversy reappears as to whether the approach for complete revascularization is of prognostic value. The clear advantage of complete revascularization in elderly patients has recently been published. However, for the younger patient group, there is no conclusive information available so far. The aim of our study was to investigate the effect of complete vs. incomplete revascularization in patients up to 70 years of age. PATIENTS AND METHODS: 6531 patients underwent isolated CABG. 5003 of these patients were aged up to 70 years at the time of operation. RESULTS: Incomplete revascularization was performed in 534 (10.7 %) patients. The most common reasons for incomplete revascularization were small vessels and massive calcification. The differences in mortality up to the 180(th) day after CABG are statistically significant. By Kaplan-Meier analysis, the time relationship between incomplete revascularization and death affects predominantly the very early period after CABG. By logistical regression, incomplete revascularization was found to be an independent risk factor for death after CABG. CONCLUSION: Incomplete revascularization affects the early outcome after CABG in patients up to 70 years of age as an independent risk factor for death. In view of recent approaches for primarily incomplete CABG, our results indicate the necessity to reconsider the advantages of complete revascularization.

Age Factors↗

PubMed2001

[Preoperative administration of new GPIIb/IIIa inhibitors].

The influence of preoperative abciximab treatment on perioperative risks was analyzed. Six groups were formed in consecutive patients (n = 957, 1/1994-3/2000) operated upon for CABG according to the urgency of the intervention and the type of preoperative haemostaseological treatment. Thirty-one patients underwent urgent/emergency CABG with preceding abciximab treatment. After pretreatment with abciximab the surgical results did not differ from patients with other types of preoperative haemostaseological treatment. CABG can be performed with similar results in abciximab pretreated patients as in patients with other types of preoperative haemostaseological treatment.

Abciximab↗

PubMed2000

Three-dimensional color Doppler reconstruction of intracardiac blood flow in patients with different heart valve diseases.

An improved perception of the magnitude and dynamics of intracardiac flow disturbances has been made possible by the advent of 3-dimensional (3-D) color Doppler, a new diagnostic procedure developed at our institution. This study describes the new insights derived from 3-D reconstruction of color Doppler flow patterns in patients with different heart valve diseases. The color Doppler flow data from 153 multiplanar transesophageal or transthoracic echocardiographic examinations has been obtained from 133 patients with heart valve disease; 73 patients had mitral regurgitation, 15 had mitral stenosis, 18 had aortic regurgitation, 26 had aortic stenosis, and 21 patients had tricuspid regurgitation. Four patients had pulmonary regurgitation associated with mitral valve disease. The 3-D reconstructions of color Doppler flow signals were accomplished by means of the "Heidelberg Raytracing model," developed at our institution. The 3-D color Doppler reconstructions were obtained in all patients. The 3-D images revealed for the first time the complex spatial distribution of the blood flow abnormalities in the heart chambers caused by different heart valve diseases. New patterns of intracardiac blood flow disturbances were observed and classified. Three-dimensional color Doppler provides a unique noninvasive method that can be easily applied for studying intracardiac blood flow disturbances in clinical practice.

Aortic Valve Insufficiency↗

PubMed2000

Role of neural and humoral factors in hyperdynamic reaction and cardiac dysfunction following brain death.

BACKGROUND: Although hemodynamic instability and cardiac dysfunction after brain death are reported in the potential organ donor, the underlying mechanisms, for example, neurohumoral changes, myocardial injury, and altered loading conditions, have not been differentiated in clinical and experimental settings. In the present study, we performed a load-independent analysis of cardiac function, focusing on the influence of brain death-associated neural and humoral factors. METHODS: In a canine in situ cross-circulated heart model, brain death was induced by inflation of a subdural balloon catheter. Preload, afterload, and coronary perfusion pressure were kept identical in all hearts throughout the experiment. In Group H (humoral factors), the hearts of healthy dogs were perfused with blood from brain-dead support dogs (n = 6). In Group N (neural factors), the hearts of brain-dead dogs were perfused with blood from healthy support dogs (n = 6). In Group H + N (humoral and neural factors), the hearts of brain-dead dogs were perfused parabiotically in situ with the animals' own blood (n = 6). Systolic and diastolic pressure-volume relationships and coronary blood flow were measured. RESULTS: Induction of brain death led to a significant hyperdynamic response in all groups, with a maximal reaction in Group H + N followed by Group H and Group N. After the initial hyperdynamic phase, cardiac function returned to baseline within 15 minutes and remained stable in all groups for the 2-hour observation period. CONCLUSIONS: (1) Both neural and humoral factors contribute to the initial hyperdynamic reaction after brain death, and only in combination do they cause a maximal hemodynamic effect. (2) If loading conditions and perfusion pressure are kept constant, no cardiac dysfunction occurs after brain death. This indicates that poor cardiac function in the potential donor may reflect altered loading conditions and impaired coronary perfusion rather than neurohumorally mediated direct myocardial injury.

Animals↗

PubMed2000

Acute triiodothyronine administration does not reverse depressed contractile performance following catecholamine exposure in isolated rat cardiomyocytes.

BACKGROUND: It has been previously suggested that triiodothyronine (T3) may reverse depressed cardiac contractile performance occurring after excessive catecholamine stimulation. We therefore investigated the effects of T3 on intracellular calcium transients and contractile performance in isolated ventricular rat myocytes. METHODS: Isolated rat myocytes were loaded with the calcium indicator FURA-2/AM (50 micromol/L) and superfused with Krebs-Henseleit solution (pH 7.4). Cells were illuminated by ultraviolet light and fluorescent images obtained with a target camera at 340 nm and 380 nm excitation wavelengths (ratio method). Simultaneous measurements of calcium transients and cell shortening (35 degrees C, electrical field stimulation: 0.5 Hz) were done. At steady state conditions, FURA-2 loaded myocytes were superfused for 60 min with epinephrine (0.1 micromol/L). After 60 min the effect of T3 (10 micromol/L) on calcium transients and shortening were measured. As control, only the effect of 10 micromol/L T3 was analyzed. RESULTS: Epinephrine significantly increased cell shortening and FURA-2 signals to 148.6+/-8.8% and 109.5+/-3.1% (p < 0.01: n = 21; 5 min) respectively. With longer epinephrine exposure, the increase in cell shortening continuously declined to 134.6+/-7.9% with no change in FURA-2 fluorescence. Acute administration of T3 after epinephrine exposure lowered contractile performance from 136.2 +/- 15.5% to 102 +/- 8.2 %, after 10 minutes. In control experiments acute administration of T3 increased basal contractile response from 100% to 115.8+/-3.3% (p<0.01; n = 8; 5 min). CONCLUSIONS: This study confirms previous reports of impaired cardiac function after high catecholamine exposure. High catecholamine exposure is associated with a desensitization of contractile proteins for calcium. Acute T3 administration increased contractility in untreated myocytes, but further depressed myocyte shortening in epinephrine-treated cells. Our results show that T3 is ineffective at restoring myocardial contractility after excessive catecholamine stimulation.

Animals↗

PubMed2000

Vascular tracheobronchial compression syndromes-- experience in surgical treatment and literature review.

Between January 1988 and December 1997 a total of 22 patients (age: 8 days-46 years) were operated for vascular airway compression syndromes with respiratory insufficiency. Vascular anomalies in tracheal compression were double aortic arch in 7 patients, (2 previously operated elsewhere), right aortic arch + left ligamentum arteriosum in 1, and pulmonary artery sling in 3. Three of these patients had secondary long-segment tracheomalacia. Compression of trachea and a main bronchus existed in 2 patients with right aortic arch + left ligamentum. Isolated main bronchus obstruction was present in 9 patients (abnormal insertion of ligamentum arteriosum in 1, status post (s.p.) previous operation for PDA in 4, s. p. surgery for coarctation in 1, right aortic arch + left ligamentum arteriosum in 2, and right lung aplasia + left ligamentum in 1). 3 of these cases had secondary long-segment bronchomalacia. All patients had a complex respiratory anamnesis [long-term intubation in 7, s.p. tracheostomy in 2 (over 3 months - 3 years), and progressive respiratory insufficiency in 13). In tracheal compression, surgical correction included transsection of the underlying ring or sling components (with additional anterior aortic arch translocation in 5 patients resection-reimplantation of left pulmonary artery in 3, segmental tracheal resection in 1, and external tracheal suspension in 2). In the 2 cases with compression of the trachea and a main bronchus, aortic "extension" by a prosthetic tube was necessary. In isolated main bronchus obstruction, surgical decompression basically consisted of transsection of the ligamentum arteriosum or resection of its scarry remnant forming the "corner point" of a compression between aorta and pulmonary artery. In 3 patients with secondary long-segment malacia, additional external bronchus suspension was performed. Effective decompression and re-expansion of the airway segment concerned was achieved, and was demonstrated by intraoperative endoscopy in all patients. There were 3 postoperative deaths (sepsis 2; massive, irreversible edema of the tracheal mucosa 1). Of the 19 surviving patients 16 could be extubated between the 1st and 17th (mean = 7.5) postoperative day. In 1 case the preoperative long-term tracheostomy had to be left in place for inoperable additional laryngeal stricture. 2 patients had to be reoperated (segmental cervical tracheal resection after 5 months for primary long-term intubation-related subglottic stenosis in 1, esophageal decompression for residual dysphagia after 57 months related to a traction phenomenon at the right descending aorta in the other), both with gratifying results. In all other patients clinical, endoscopic, and radiographic examinations (follow-up = 2 months - 6 years) demonstrate good results.

Adolescent↗

PubMed2000

Target, application, and interpretation of scores and alternative methods for risk assessment in cardiac surgery.

BACKGROUND: The more popular the use of different methods for risk adjustment becomes, the more often data are applied without any regard about the primary target and/or about important assumptions. Furthermore, risk adjustment is no longer restricted for quality assurance purposes, but became a "tool" of health policy. Few working groups currently use risk adjustment for the development of new therapeutic concepts. The aim of our study is to clarify possibilities and limitations of popular risk adjustment methods. PATIENTS AND METHODS: 4985 Patients underwent isolated CABG. Statistics was performed by calculating descriptive statistics, Parsonnet, and Higginsscores. Furthermore, the parametric, time-adjusted hazard function by Blackstone was used. RESULTS: Descriptive statistics allows intra-, and interinstitutional comparisons of single items to identify "outlying" results. Risk scores aim to predict preoperatively the risk category of the patient who undergoes cardiac surgery. However, since different scores are based on a score-specific combination of variables, and different definitions of the investigation interval, different results may occur, when different scores are calculated for a single patient. However, the use for example, of scores in patient groups allows description of changing risk structures. Most of the scores derive from univariate analyses and monophasic functions. However, survival curves are predominantly multiphasic and require a consideration of the time-dependency of "risk factors". DISCUSSION: An increasing number of patients with severe comorbidity undergoes cardiac surgery. To evaluate reliably present and futurous therapeutic options, risk adjustment is necessary. Since various tools for risk-adjustment are available, a serious discussion about reliability and application is necessary.

Aged↗

PubMed2000

Three-dimensional color Doppler flow reconstruction and its clinical applications.

The visualization and quantification of intracardiac blood flow have always been a challenging task for the cardiologist. The advent of color Doppler flow imaging substantially enhanced the clinical diagnosis of heart valve disease. Three-dimensional (3-D) color Doppler, a new diagnostic procedure, refines the diagnostic value of color Doppler by providing unique spatial and temporal information about the actual extension, direction, origin, and size of intracardiac flows. Here, we describe the procedure for 3-D color Doppler reconstruction of intracardiac blood flow velocities and reveal the varied findings in different heart pathologies that cause blood flow disturbances. An automated procedure for the segmentation of turbulent and laminar flows, which allows for the measurement of mitral regurgitant jet volumes, is one of the first 3-D quantitative approaches to the clinical assessment of mitral valve regurgitation. The major technical advances of this procedure include the direct use of digital color Doppler velocity data and an automatic voxel count of the turbulent jet flows. Three-dimensional color Doppler not only can disclose the spatial complex geometry of intracardiac blood flow disturbances but also can quantitatively assess the severity of mitral valve regurgitation.

Aortic Valve Stenosis↗

PubMed2000

A lumped parameter model of left ventricular filling-pressure waveforms.

Assessment of left-ventricular function and quantification of valve stenosis are important in clinical practice as well as in physiological research. This paper describes a mathematical model of diastolic ventricular filling and flow across the mitral valve. The model primarily consists of a system of three first-order, non-linear ordinary differential equations. The equations are solved in MATLAB using the ode45 command. The model generates pressure versus time waveforms for the atrium and ventricle, and flow versus time waveforms for mitral valve flow. Comparisons between model outputs and in-vivo data collected in two porcine experiments show excellent agreement.

Diastole↗

PubMed2000

CardioOp: an integrated approach to teleteaching in cardiac surgery.

INTRODUCTION/PURPOSE: The complexity of cardiac surgery requires continuous training, education and information addressing different individuals: physicians (cardiac surgeons, residents, anaesthesiologists, cardiologists), medical students, perfusionists and patients. Efficacy and efficiency of education and training will likely be improved by the use of multimedia information systems. Nevertheless, computer-based education is facing some serious disadvantages: 1) multimedia productions require tremendous financial and time resources; 2) the obtained multimedia data are only usable for one specific target user group in one specific instructional context; 3) computer based learning programs often show deficiencies in the support of individual learning styles and in providing individual information adjusted to the learner's individual needs. In this paper we describe a computer-system, providing multiple re-use of multimedia-data in different instructional sceneries and providing flexible composition of content to different target user groups. TOOLS AND METHODS: The ZYX document model has been developed, allowing the modelling and flexible on-the-fly composition of multimedia fragments. It has been implemented as a DataBlade module into the object-relational database system Informix Dynamic Server and allows for presentation-neutral storage of multimedia content from the application domain, delivery and presentation of multimedia material, content based retrieval, re-use and composition of multimedia material for different instructional settings. Multimedia data stored in the repository, that can be processed and authored in terms of our identified needs is created by using a next generation authoring environment called CardioOP-Wizard. High-quality intra-operative video is recorded using a video-robot. Difficult surgical procedures are visualized with generic and CT-based 3D-animations. RESULTS: An on-line architecture for multiple re-use and flexible composition of media data has been established. The system contains the following instructional applications (prototypically implemented): a multimedia textbook on operative techniques, an interactive module for problem based-training, a module for creation and presentation of lectures and a module for patient information. Principles of cognitive psychology and knowledge management have been employed in the program. These instructional applications provide information ranging from basic knowledge at the beginner's level, procedural knowledge for the advanced level to implicit knowledge for the professional level. For media-annotation with meta-data a metainformation system, the CardioOP-Clas has been developed. The prototype focuses on aortocoronary bypass grafting and heart transplantation. CONCLUSION: The demonstrated system reflects an integrated approach in terms of information technology and teaching by means of multiple re-use and composition of stored media-items to the individual user and the chosen educational setting on different instructional levels.

Computer Simulation↗

PubMed2000

Myocardial performance after brain death: studies in isolated hearts.

OBJECTIVES AND METHODS: Brain death related hemodynamic instability and/or cardiac dysfunction is frequently described in the potential organ donor which may lead to exclusion of the heart from transplantation. The underlying mechanisms are controversely discussed. Therefore, in the present study, potential brain death associated cardiodepressant factors were evaluated separately in cross-circulated canine heart models. Brain death was induced by inflation of a subdural balloon catheter. Loading conditions and coronary perfusion pressure were kept identical in all cross-circulated hearts throughout the experiment. RESULTS: Induction of brain death led to a significant hyperdynamic response in all groups, with a maximal effect by the combination of neural and humoral pathways. After the initial reaction all hemodynamic parameters returned to baseline and remained stable until the end of experiments. Even if the hearts were explanted from brain dead donors with typical hemodynamic deterioration in vivo, they showed no significant differences in comparison to the other groups including healthy controls ex vivo. CONCLUSIONS: Therefore we conclude, that hemodynamic instability in the potential donor may rather reflect altered loading conditions and impaired coronary perfusion than neuro-humorally mediated direct myocardial injury.

Animals↗

PubMed1999

Prolonged allograft survival but no tolerance induction by modulating CD28 antibody JJ319 after high-responder rat heart transplantation.

BACKGROUND: Allograft rejection depends on T cell immune responses requiring antigen recognition and costimulatory signals through accessory T cell receptors, including CD28. Inhibition of CD28 signaling with a CTLA-4-immunoglobulin (Ig) fusion protein has resulted in immunosuppression and occasional T cell anergy in mouse transplant models, but not in rats. Because this approach also inhibits a potentially tolerizing signal through CTLA-4, selective blockade of CD28 ligation might induce more profound immunosuppression and transplant tolerance. METHODS: The effects of escalating doses of the rat CD28 monoclonal antibody JJ319 on allograft survival were studied after vascularized heterotopic heart transplantation in a high responder strain combination (DA to Lewis). CD28 antigen modulation and circulating antibody levels were monitored by flow cytometry. RESULTS: CD28 antibody JJ319 markedly prolonged cardiac graft survival compared with untreated controls (7 days, range: 6-8). A strictly dose-dependent increase in median graft survival time was demonstrated with a maximum of 36 days (range: 30-40; p <0.001) after the administration of 8 x 1 mg JJ319 i.p. (days -1 to +6 before/after transplantation). However, indefinite graft survival and tolerance could not be induced by JJ319 treatment. At the maximal dose, flow cytometry showed complete down modulation of the CD28 receptor for 10-14 days without T cell depletion in close temporal relation to antibody presence in serum. In vitro, CD28-modulated T cells showed significantly reduced responses to activation. CONCLUSIONS: CD28 antibody JJ319 induces profound immunosuppression after rat heart transplantation, however without development of transplant tolerance. The underlying mechanism seems to be receptor modulation during primary alloantigen recognition. While still potentially applicable clinically, there are no qualitative or quantitative differences to the treatment with CTLA-4/lg or the blockade of CD2 or LFA-1, as reported elsewhere. Thus, a CD28-modulating approach seems not to allow therapeutic exploitation of a tolerizing signal delivered by CTLA-4 but may still be clinically applicable, especially in combined immune interventions.

Abatacept↗

PubMed1999

Influence of brain death and cardiac preservation on systolic and diastolic function and coronary circulation in the cross-circulated canine heart.

Previous studies have demonstrated hemodynamic instability and cardiac dysfunction in the brain-dead organ donor. It remains unclear if primary cardiac dysfunction is responsible for hemodynamic deterioration or decreased cardiac function is secondary to brain death-associated altered loading conditions. Therefore in the present study the effects of brain death on hemodynamics and cardiac function were analyzed in vivo in an open chest model and ex vivo in a cross-circulated heart preparation. In a second protocol, the impact of brain death-associated hemodynamic changes on postischemic graft function was investigated. Brain death was induced injecting saline in a subdural Foley catheter. Induction of brain death led to a hyperdynamic reaction followed by hemodynamic deterioration with a decrease of systemic vascular resistance and myocardial contractility. If the hearts were explanted and assessed ex vivo, no differences were found between control and brain-dead hearts. Furthermore, both control and brain-dead hearts showed full functional recovery after 4 hours of hypothermic ischemic storage. Despite hemodynamic deterioration in situ after brain death, there were no differences between the postischemic function of control and brain-dead hearts. These results indicate that myocardial dysfunction is not irreversible and may be secondary to altered loading conditions, and that the recovery of cardiac function after long-term hypothermic storage is not impaired by the hemodynamic changes observed in situ after brain death induction. These data may also indicate that potential donor hearts might not be excluded from transplantation on the basis of impaired hemodynamic characteristics, especially if they are evaluated by load-dependent parameters.

Analysis of Variance↗