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American Journal of Transplantation 06/2006; 6(5 Pt 1):1086-7. · 6.39 Impact Factor
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M C Deng,
H J Eisen,
M R Mehra,
M Billingham,
C C Marboe,
G Berry,
J Kobashigawa,
F L Johnson,
R C Starling,
S Murali,
D F Pauly,
H Baron,
J G Wohlgemuth,
R N Woodward,
T M Klingler,
D Walther,
P G Lal,
S Rosenberg,
S Hunt
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ABSTRACT: Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT > or = 3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0-40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT > or = 3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade > or = 3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.
American Journal of Transplantation 01/2006; 6(1):150-60. · 6.39 Impact Factor
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ABSTRACT: Cardiac allograft vasculopathy is a diffuse, obliterative form of arteriosclerosis that is characterized by the production of a neointima rich in vascular smooth muscle cells that progressively obstructs the lumen. Pathophysiologically, after heart transplantation, alloantigens (e. g. on donor endothelial cells) are presented by antigen presenting cells to the T-cells of the body's immune system. With the appropriate costimulatory signal, this signal pattern generates a differentiated T-cell, B-cell, and inflammatory cell response whereas without the second signal, the immune cells undergo apoptosis. In case of immune cell proliferation and differentiation, a coordinated pattern of cytokine release is initiated. Cells of innate immunity, monocyte-derived macrophages, are involved in this process. The inflammatory response culminates in rolling, sticking, and diapedesis through the coronary vascular endothelium and migration and phenotype switch of medial smooth muscle cells mediated by generation of growth-promoting cytokines.
DMW - Deutsche Medizinische Wochenschrift 11/2004; 129(41):2193-7. · 0.53 Impact Factor
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M C Deng,
J B Young,
L W Stevenson,
M C Oz,
E A Rose,
S A Hunt,
J K Kirklin,
J Kobashigawa,
L Miller,
M Saltzberg,
M Konstam,
P M Portner,
R Kormos
The Journal of Heart and Lung Transplantation 05/2003; 22(4):365-9. · 4.33 Impact Factor
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ABSTRACT: Studies of outcome in cardiac transplantation have focused primarily on identifying patient- and donor-related factors associated with patient mortality. Less consideration has been given to the impact of the transplant center. This study was undertaken to assess variability in heart transplantation outcome in Eurotransplant centers to provide a framework for auditing.
In a 2-year period, 1,401 adult patients underwent heart transplantation in 45 centers. The 1-year patient survival rate was 76% (95% CI, 74%-78%) with a range of 0% to 100% at the center level. The risk-adjusted center effect on mortality was estimated by calculating a standardized difference between the observed number of deaths 1 year after transplantation and the expected number of deaths based on the case mix. By assessing within- and between-center variations with empirical Bayes (EB) methods, after adjustment for all registered prognostic factors, an improved estimate of the true center effect was obtained. Compared with the standard risk-adjusted center effect method, fewer outlying centers were identified with the EB method.
EB methods, because they are known to incorporate more information from the data, enable a more precise and realistic portrayal of heart transplant centers' performances, compared with other risk-adjusted center effect methods. In the context of auditing procedures, EB methods should preferably be used for the identification of centers that deviate significantly from quality standards.
Transplantation 02/2003; 75(1):90-6. · 4.00 Impact Factor
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T Möllhoff,
C Schmidt,
H Van Aken,
E Berendes,
H Buerkle,
P Marmann,
T Reinbold,
R Prenger-Berninghoff,
T D T Tjan,
H H Scheld, M C Deng
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ABSTRACT: Myocardial ischaemia and infarction are major complications immediately after coronary artery bypass grafting. They may be due to incomplete surgical revascularization, perioperative anaesthetic management or vasospasm of arterial grafts, e.g. the internal mammary artery. Infusions of nifedipine or milrinone have been advocated to prevent spasm of the mammary artery. The study compared the incidence of myocardial ischaemia after continuous infusion of either nifedipine (0.2 microg kg(-1) min(-1)) or milrinone (0.375 microg kg(-1) min(-1)) in patients with compromised left ventricular function scheduled for elective coronary artery bypass graft.
After Institutional Review Board approval, this double-blinded randomized clinical study enrolled 30 adult patients with compromised left ventricular function (ejection fraction < 0.4) scheduled for elective coronary artery bypass grafting after written informed consent had been obtained. Ischaemia was detected by Holter electrocardiographic monitoring. The incidence of myocardial cell death was monitored by serial determinations of the creatine kinase-MB (CK-MB) and troponin-I.
New ST elevation > or = 0.2 mV or new ST depression < or = 0.1 mV occurred in five of 15 patients in the milrinone group (33.3%) and in 13 of 15 patients (86.6%) in the nifedipine group (P < 0.05). There were increases in CK-MB and troponin-I in both groups. Twenty-four hours postoperatively, CK-MB (P = 0.003) and troponin-I (P = 0.001) were significantly higher in the nifedipine group.
Perioperative continuous infusion of milrinone, compared with nifedipine, results in a significantly lower incidence of myocardial ischaemia and myocardial cell damage after elective coronary artery bypass grafting.
European Journal of Anaesthesiology 11/2002; 19(11):796-802. · 2.23 Impact Factor
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ABSTRACT: In the context of contemporary medical and surgical therapy, the revolutionary procedure of cardiac transplantation should be redefined in its relative role. Based on the assumption that its goal is to prolong life while improving its quality, and in the absence of randomized clinical trial data testing its benefit, data from early breakthrough studies, more recent observational cohort studies, and studies testing other therapies in advanced heart failure must be analyzed to characterize clinical profiles of patients who should be considered too well for cardiac transplantation at specific stages of their disease processes. These profiles likely include advanced heart failure with (1) low risk according to the Heart Failure Survival Score, (2) peak oxygen consumption greater than 14 to 18 mL/kg/min without other indications, (3) left ventricular ejection fraction less than 20% alone, (4) history of New York Heart Association class III to IV symptoms alone, (5) history of ventricular arrhythmias alone, (6) no previous attempt at comprehensive neurohormonal blockade, and (7) no structured cardiac transplantation evaluation in a designated cardiac transplantation center. The evaluation may identify the potential transplant candidate, who could be placed on a national potential transplant candidate list, combining the psychologic benefit of acceptance by the program with an ongoing openness to the diversity of advanced heart failure treatment modalities.
Current Opinion in Cardiology 04/2002; 17(2):137-44. · 2.33 Impact Factor
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ABSTRACT: The study objective was to assess the cardiac expression of interleukin-6 (IL6) and its receptor (IL6R) in advanced heart failure.
While IL6 plasma levels are elevated and associated with an impaired prognosis in advanced heart failure, little is known about the intracardiac expression of the IL6 system.
Heart tissue was obtained from 20 patients (n=10, idiopathic dilated cardiomyopathy, age 44+/-15 years; n=10, ischemic cardiomyopathy, age 55+/-8 years) at the time of transplantation. Left and right ventricular tissue was subjected to in situ hybridization, Northern blot analysis, and RT-PCR. Signals were quantified by densitometric scanning and corrected for G3PDH-mRNA levels. Right ventricular biopsy specimens (n=11) of patients with arrhythmias and normal cardiac function served as controls. In addition, data were correlated with cardiac catheterization and echocardiography data obtained at transplant evaluation.
Ventricular IL6 and IL6R transcripts were detected in all explant specimens examined. Expression of both mRNA species was higher than in controls (P=0.001). Left ventricular IL6 mRNA levels correlated positively with heart rate (r=0.77; P=0.009), pulmonary capillary wedge pressure (r=0.53; P=0.03), right atrial pressure (r=0.77; P=0.003), and inversely with left ventricular ejection fraction (r=-0.61; P=0.03). Right ventricular IL6 mRNA levels correlated inversely with cardiac index (r=-0.48; P=0.05). IL6R expression did not correlate with hemodynamic data.
In advanced heart failure, cardiac IL6/IL6R mRNA expression is increased and may play a role in the pathophysiology of advanced heart failure.
European Journal of Heart Failure 09/2001; 3(4):415-21. · 4.90 Impact Factor
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ABSTRACT: We hypothesized that a temporary cardiopulmonary bypass (CPB)-induced reduction of endotoxin antibody levels contributes to elevated endotoxin levels and the associated inflammatory consequences, with a significant influence on the postoperative ventilation time period.
Cardiac surgery using CPB induces a systemic inflammatory response syndrome with an associated risk of increased postoperative morbidity and mortality.
A total of 100 consecutive patients undergoing elective coronary artery bypass graft surgery using CPB were prospectively investigated. Endotoxin core antibodies (immunoglobulin [Ig] M/IgG against lipid A and lipopolysaccharide), endotoxin, interleukin (IL)-1-beta, IL-6, IL-8 and tumor necrosis factor-alpha were measured serially from 24 h preoperatively until 72 h postoperatively.
Eighty-five patients had no complications (group 1), whereas 15 patients required prolonged ventilation (group 2). In both groups, there was a decrease of all antibodies 5 min after CPB onset, compared with baseline values (p < 0.001), an increase of endotoxin and IL-8 peaking at 30 min postoperatively (p < 0.001) and an increase of IL-6 peaking 3 h postoperatively (p < 0.001). In group 2, preoperative antibody levels were lower (p < 0.01)--specifically, the decrease in IgM was significantly stronger and of longer duration (p < 0.002)--and levels of endotoxin (p < 0.001) and IL-8 (p < 0.001) were higher at 30 min postoperatively.
We conclude that an CPB-associated temporary reduction of anti-endotoxin core antibody levels contributes to elevated endotoxin and IL-8 release. Furthermore, lower levels of IgM anti-endotoxin core antibodies were associated with a greater rise in endotoxin and IL-8, as well as prolonged respirator dependence.
Journal of the American College of Cardiology 08/2001; 38(1):124-30. · 14.16 Impact Factor
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European cytokine network 04/2001; 12(1):15-21. · 1.73 Impact Factor
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ABSTRACT: The COCPIT study, performed in a complete national cohort of adult patients consecutively listed for cardiac transplantation in Germany in 1997, found a beneficial effect only in the group that was at high risk of dying from heart failure without transplantation. If these results can be reproduced in other countries, the discussion on the respective roles of pharmacological and organ-saving surgical therapies for advanced heart failure, medical urgency and waiting time as heart transplantation allocation criteria, and the feasibility of a randomized clinical trial testing the survival benefit of transplantation must be reopened.
Current Opinion in Cardiology 04/2001; 16(2):97-104. · 2.33 Impact Factor
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ABSTRACT: Medical malpractice claims against surgeons are increasing. In Germany, as in most other European countries, there is no central registry of medical malpractice claims. It is not known at which rate medical liability claims are decided in favor of the physician or the patient.
All cases of reproaches of medical malpractice in which our clinic was involved within the 10-year period between 1989 to 1999 were reviewed. To compare our results with the general experience in the field of thoracic and cardiovascular surgery, we reviewed the data of the regional medical society in the same time period.
From 1989 to 1999, our Clinic was involved in 74 medical liability disputes. There were 28 reproaches of medical malpractice against our department (0.1% of cases performed). Malpractice was detected in only 7 of 74 claims (9.5%). Most reproaches were made for incorrectly performed operations (80%), but only 4 (6.8%) of 59 claims were regarded as medical malpractice.
Reliable data on reproaches of medical malpractice are virtually absent. Only 10% of all reproaches in our study were finally regarded as medical malpractice. A central registry of medical malpractice cases would allow analysis of the areas in which we have to improve performance, and how unjustified reproaches of medical malpractice can be avoided.
The Thoracic and Cardiovascular Surgeon 03/2001; 49(1):60-3. · 0.88 Impact Factor
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ABSTRACT: Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) can lead to a systemic inflammatory response syndrome with organ failure and increased morbidity and mortality. The mechanisms of these findings are still under discussion. We investigated whether anti-endotoxin core antibodies, endotoxin, and proinflammatory cytokines influence the clinical course after cardiac surgery. Seventy-eight patients undergoing CABG using CPB were investigated. Anti-endotoxin core antibodies, endotoxin, interleukin (IL)-6, IL-8, IL-1beta, and TNF-alpha were measured 24 h preoperatively and up to 72 h postoperatively. Patients with a postoperative mechanical ventilation time below 24 h (n = 65; Group A) were compared to patients with prolonged respirator therapy (>24 h; n = 13; Group B). Preoperative antibody levels were significantly lower in Group B (P < 0.001). In this group, antibody levels remained decreased during the observation period (P < 0.001). Endotoxin significantly increased 30' postoperatively in both groups (P < 0.002). The increase in Group B was 3-fold higher (P< 0.001). IL-8 increased postoperatively in both groups, peaking 3 h after surgery (P < 0.001). In Group B, the IL-8 release was significantly higher than in Group A (P < 0.001). IL-6 significantly increased in both groups, reaching its maximum 24 h postoperatively (P < 0.001). No differences between groups were observed. No significant changes of IL-1beta and TNF-alpha were observed. We conclude that anti-endotoxin core antibodies may be predictive of adverse outcome after cardiac surgery. The imbalance between antibodies and endotoxin results in an exaggerated increase in endotoxin and IL-8 with an impact on clinical outcome.
Shock 02/2001; 16 Suppl 1:44-50. · 2.85 Impact Factor
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M C Deng,
M Loebe,
A El-Banayosy,
E Gronda,
P G Jansen,
M Vigano,
G M Wieselthaler,
B Reichart,
E Vitali,
A Pavie,
T Mesana,
D Y Loisance,
D R Wheeldon,
P M Portner
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ABSTRACT: Use of wearable left ventricular assist systems (LVAS) in the treatment of advanced heart failure has steadily increased since 1993, when these devices became generally available in Europe. The aim of this study was to identify in an unselected cohort of LVAS recipients those aspects of patient selection that have an impact on postimplant survival.
Data were obtained from the Novacor European Registry. Between 1993 and 1999, 464 patients were implanted with the Novacor LVAS. The majority had idiopathic (60%) or ischemic (27%) cardiomyopathy; the median age at implant was 49 (16 to 75) years. The median support time was 100 days (4.1 years maximum). Forty-nine percent of the recipients were discharged from the hospital on LVAS; they spent 75% of their time out of the hospital. For a subset of 366 recipients, for whom a complete set of data was available, multivariate analysis revealed that the following preimplant conditions were independent risk factors for survival after LVAS implantation: respiratory failure associated with septicemia (odds ratio 11.2), right heart failure (odds ratio 3.2), age >65 years (odds ratio 3.01), acute postcardiotomy (odds ratio 1.8), and acute infarction (odds ratio 1.7). For patients without any of these factors, the 1-year survival after LVAS implantation including the posttransplantation period was 60%; for the combined group with at least 1 risk factor, it was 24%.
Careful selection, specifically implantation before patients become moribund, and improvement of management may result in improved outcomes of LVAS treatment for advanced heart failure.
Circulation 01/2001; 103(2):231-7. · 14.74 Impact Factor
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ABSTRACT: To determine whether there is a survival benefit associated with cardiac transplantation in Germany.
Prospective observational cohort study.
All 889 adult patients listed for a first heart transplant in Germany in 1997.
Mortality, stratified by heart failure severity.
Within 1 year after listing, patients with a predicted high risk had the highest global death rate (51% v 32% and 29% for medium and low risk patients respectively; P<0.0001), had the highest risk of dying on the waiting list (32% v 20% and 20%; P=0.0003), and were more likely to receive a transplant (48% v 45% and 41%; P=0.01). Differences between the risk groups in outcome after transplantation did not reach significance (P=0.2). Transplantation was not associated with a reduction in mortality risk for the total cohort, but it did provide a survival benefit for the high risk group.
Cardiac transplantation in Germany is currently associated with a survival benefit only in patients with a predicted high risk of dying on the waiting list. Patients with a predicted low or medium risk have no reduction in mortality risk associated with transplantation; they should be managed with organ saving approaches rather than transplantation.
BMJ 09/2000; 321(7260):540-5. · 14.09 Impact Factor
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ABSTRACT: Because of the growing discrepancy between the availability of donor organs and the number of patients with end-stage heart disease who need heart transplantation, a larger proportion of patients waiting for a suitable donor heart require pre-operative mechanical circulatory assistance. The criteria for the selection and management of these patients as applied at Muenster University Hospital are reviewed.
The study population consists of 631 patients referred to our center for transplantation between January 1, 1990, and December 31, 1996. Two hundred ninety-seven patients were listed for transplantation and 157 were transplanted. Of 41 patients who underwent implantation of a ventricular assist device (n = 34, Novacor; n = 6, TCI HeartMate; n = 1, Medos), 39 received the device as a bridge to transplantation and 2 as permanent support. For the purpose of the analysis, the study population was divided into 3 groups (elective bridging, urgent bridging, emergency bridging) and compared with heart transplant candidates who did not require mechanical circulatory assistance.
Patients who underwent elective or urgent assist-device implantation were younger and had greater hemodynamic compromise than the remainder of patients waiting for heart transplantation, as suggested by a higher functional class and lower mean arterial pressure, cardiac index, serum sodium, and pulmonary artery wedge pressure. Survival of patients who electively underwent implantation of an assist device was better than that of patients who were stable on the waiting list and did not undergo heart transplantation during follow-up.
This finding suggests that earlier implantation of assist devices may facilitate resolution of organ dysfunction before heart transplantation.
The Journal of Heart and Lung Transplantation 09/2000; 19(8 Suppl):S77-82. · 4.33 Impact Factor
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The Thoracic and Cardiovascular Surgeon 07/2000; 48(3):183-5. · 0.88 Impact Factor
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ABSTRACT: We examined the distribution of metallothionein (MT), a stress-inducible protein, and the cardiomyocyte diameter in human hearts after left-ventricular assist device (LVAD) support.
Remodeling in end-stage heart failure is characterized by myocyte hypertrophy and alterations of several inducible proteins. LVADs used as a bridge to cardiac transplantation unload the left ventricle and may lead to a reversal of the remodeling, but little is known about the pathophysiology of this process.
The immunoreactivity for MT and the cardiomyocyte diameter was analyzed in left-ventricular tissue specimens of 17 patients with end-stage heart failure before and after LVAD support.
MT positive cells were mainly located sub-endocardially in vacuolized cardiomyocytes and in small vessels throughout the myocardium. During LVAD support, MT-positive myocytes decreased in the sub-endocardial (p < 0.008) and sub-epicardial region (p < 0.003), MT-positive vessels decreased similarly (p < 0.003). Cardiomyocyte diameter decreased significantly only in the sub-endocardium (p < 0.03). Hearts of patients supported longer than 88 days (= median) showed substantially lower MT reactivity at the time of LVAD explantation as compared to patients supported less than 88 days.
Our results suggest that unloading of the left ventricle during prolonged LVAD support leads to regression of cellular hypertrophy and a decrease of MT expression. The preferential reduction of MT-positive vacuolized cardiomyocytes in the sub-endocardium is comparable with the concept of greatest reduction of wall stress in this area of the myocardium and may be due to the improvement of myocardial blood flow and the energy balance.
The Journal of Heart and Lung Transplantation 07/2000; 19(7):668-74. · 4.33 Impact Factor
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ABSTRACT: Although transplant vasculopathy and native atherosclerosis are clinically and pathologically different entities, the pathogenesis of both diseases exhibits some common mechanisms. Both may be regarded as responses to injury within a broadened concept of the immune system. Alloantigens (e.g. on donor endothelial cells) or autoantigens (e.g. oxydized LDL cholesterol) are presented by antigen presenting cells to the T cells of the body's immune system. With the appropriate costimulatory signal, this signal pattern generates a differentiated T cell, B cell, and inflammatory cell response whereas without the second signal, the immune cells undergo apoptosis. In case of immune cell proliferation and differentiation, a coordinated pattern of cytokine release is initiated. Monocyte-derived macrophages are also involved in this process which culminates in rolling, sticking, and diapedesis through the coronary vascular endothelium and phenotype switch of medial smooth muscle cells mediated by generation of growth-promoting cytokines. Thus, viewed within a broadened paradigm of the immune system's role both disease entities may represent different vignettes of an integrated pathophysiological response to an endothelial injury.
Herz 04/2000; 25(2):95-9. · 0.92 Impact Factor
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ABSTRACT: Implantable left ventricular assist systems (LVAS) consist of implantable pumps with small control consoles and power sources that can be worn externally. These systems provide far greater patient mobility and independence than external pumps with bulky control consoles. Patients with implantable LVAS can be discharged from hospital and are able to return to work and resume active sports. Most patients have received these systems as a bridge to heart transplantation. Clinical status and quality of life improve dramatically after device implantation and survival on support (60-70% after approx. 100 days of support) is acceptable compared with transplant candidates on medical therapy. Patient selection and adverse events, primarily bleeding, thromboembolism and infection, are important issues with LVAS. In the future, long-term support and bridging to myocardial recovery may become important indications for LVAS.
European Journal of Heart Failure 04/2000; 2(1):13-8. · 4.90 Impact Factor
