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Axel Haverich

Publications and source records attributed to Axel Haverich.

At least 127 records · Page 7Linked to original sources
PubMed2003

In vivo model for cross-species porcine endogenous retrovirus transmission using tissue engineered pulmonary arteries.

OBJECTIVE: Acellularised porcine scaffolds have been successfully used for cardiovascular tissue engineering. However, there is concern about the possibility of porcine endogenous retrovirus (PERV) transmission. In this study we developed an in vivo model for cross-species PERV transmission. METHODS: In vitro autologous repopulated porcine pulmonary arteries (n=6) were implanted in sheep in orthotopic position. Blood samples were collected regularly up to 6 months after implantation and tested for PERV by means of polymerase chain reaction and reverse transcriptase-polymerase chain reaction. Explanted tissue engineered pulmonary arteries were tested for PERV sequences. RESULTS: PERV DNA was detectable in acellularised porcine scaffolds. No PERV sequences were detectable 6 months after implantation of in vitro repopulated acellularised porcine pulmonary arteries and in all tested peripheral blood samples. CONCLUSIONS: Acellularised porcine matrix scaffolds can be used for cardiovascular tissue engineering of autologous grafts without risk of PERV transmission.

Animals↗
PubMed2003

Hypothermic circulatory arrest during ascending and aortic arch surgery: the theoretical impact of different cerebral perfusion techniques and other methods of cerebral protection.

Operations on the thoracic aorta using hypothermic circulatory arrest are still associated with significant morbidity and mortality due to neurological complications. During the last decades, different cerebral protection techniques have been introduced into clinical practice to reduce the incidence of such complications. Furthermore clinical as well as basic researches have been performed to improve the outcome after these operations. Currently different cerebral perfusion methods are in clinical use and the superiority of one or the other method is a matter of controversial discussion. This review has been undertaken to evaluate the theoretical impact of these different methods of cerebral protection. Based on the experience of the authors the pros and cons are discussed with clinical and experimental reports from the literature.

Aorta↗
PubMed2003

Bioartificial grafts for transmural myocardial restoration: a new cardiovascular tissue culture concept.

OBJECTIVE: Survival of bioartificial grafts that are destined to restore cardiac function stands and falls with their nutrient supply. Engineering of myocardial tissue is limited because of lack of vascularization. We introduce a new concept to obtain bioartificial myocardial grafts in which perfusion by a macroscopic core vessel is simulated. METHODS: We have designed an experimental reactor with multiple chambers for the production of bioartificial tissue or tissue precursors. By introduction of in- and output lines of distinct diameter and insertion of a core vessel into each chamber, we established pulsatile, continuous flow through the embodied three-dimensional tissue culture. In the present study, collagen components served as the ground matrix wherein neonatal rat cardiomyocytes were inoculated. For the assessment of cellular viability and distribution in comparison to static, non-perfused culture, fluor-desoxy-glucose-positron-emission-tomography and life/dead assays were employed. RESULTS: We obtained 3D constructs of 8-mm thickness, which display high viability and metabolism (6.0+/-1.3(e-03) in the perfused vs. 4.0+/-0.3(e-03) in the unperfused chambers). The core vessel has the size of a human coronary and remained patent during the entire culture process. We observed centripetal migration of the embedded cardiomyocytes to the site of the core vessel. Cardiomyocytes partially resumed a spindle like form without additional stretch. CONCLUSIONS: The present dynamic tissue culture concept is highly effective in manufacturing thick, viable grafts for cardiac muscle restoration, which could be surgically anastomosable. The bioreactor may accommodate multiple types of cells and tissues for innumerable in vitro and in vivo applications.

Animals↗
PubMed2003

Functional endurance capacity and exercise training in long-term treatment after heart transplantation.

OBJECTIVE: The aim of this study was to investigate the influence of cardiac denervation on endurance exercise capacity in heart transplant recipients (HTR) in comparison to patients with coronary artery disease (CAD). METHODS: We performed two successive incremental tests and a 30-min constant load test (CLT) in 20 HTR (55 +/- 7 years old, 4.9 +/- 2.2 years after transplantation) and in 13 patients with CAD (58 +/- 8 years). RESULTS: Maximal workload in HTR was 106 +/- 25 W (163 +/- 41 W; p < 0.01). In CLT at anaerobic threshold of 55 +/- 6 W (97 +/- 34 W; p < 0.01), lactate increased from 0.9 +/- 0.2 (1.0 +/- 0.2) to 2.9 +/- 1.3 (3.3 +/- 1.3) after 10 min and to 3.1 +/- 1.6 (3.4 +/- 1.5; NS) mmol. l(-1) after 30 min, confirming that the anaerobic threshold reflects a steady state. The CLT kinetics of heart rate (+6 beats in HTR and in CAD between 10th and 30th min) and lactate are comparable in HTR and CAD, demonstrating that endurance kinetics are not influenced by cardiac denervation.

Aged↗
PubMed2003

Role of inflammation in allogeneic and xenogeneic heart valve degeneration: immunohistochemical evaluation of inflammatory endothelial cell activation.

BACKGROUND AND AIM OF THE STUDY: Biological heart valve prostheses undergo degenerative changes which lead ultimately to dysfunction or even complete destruction. The study aim was to evaluate immunological factors and their potential role in biological heart valve destruction. METHODS: Allogeneic (n = 10) and xenogeneic (n = 3) aortic valve prostheses, as well as aortic valves retrieved from transplanted human hearts which had to be replaced due to chronic graft rejection (n = 4), were analyzed. Aortic valves from human donor hearts (n = 4) served as controls. Evaluated adhesion molecule expression included: selectin family ELAM-1, CD62; integrin family VLA-1, -2, -3, -4, -5 and -6; immuoglobulin supergene family PECAM-1, ICAM-1 and -2, and class I heavy chain proteins; complementary adhesion molecules CD34, CD44 and von Willebrand factor. RESULTS: ELAM-1, ICAM-1 and -2, CD34, CD44 and class I heavy chain proteins, which play significant roles during inflammatory processes, showed stronger expression patterns in allogeneic and xenogeneic aortic heart valve prostheses compared to native or chronically rejected valves. Furthermore, allogeneic and xenogeneic valves showed a strong thrombogenicity which stained positive for von Willebrand factor outside endothelial cells on these valves. Integrin molecules as well as CD62 showed only mild differences. CONCLUSION: Immunological reactions play a pivotal role in the degeneration of biological heart valve prostheses. As immunosuppressive therapy after heart valve replacement is not a viable option, novel approaches in 'tissue engineering' may help to avoid tissue degeneration while preserving the advantage of biological tissue origin.

Adult↗
PubMed2003

Three-year survival rates for all consecutive heart-only and lung-only transplants performed in Eurotransplant, 1997-1999.

The definition of proper patient selection criteria remains a prominent item in constant need of attention. While the concept of gathering evidence in order to determine practice continues to be hopelessly ambiguous, it can never be emphasized too much that these univariate results are just a first foray into analysing predictors of survival; all following results should be regarded and interpreted in this perspective. HEART TRANSPLANT SURVIVAL: The 3-year survival rate for heart transplant recipients under age 16 was 83% versus 72% for adult recipients. Acutely retransplanted adult heart recipients had a 3-year survival rate of 36% compared with 72% for recipients of a first heart allograft. Patients suffering from DCM had the best survival rates at 3 years (74%) compared with patients suffering from CAD (70%) or from another end-stage heart disease (67%). With advancing age of the adult recipient, the mortality risk increased. Patients aged 16-40 had a 3-year survival rate of 77%, compared with 74%, 70% and 61% for transplant recipients aged 41-55, 56-65 and over age 65, respectively. The 3-year survival rates for adult recipients transplanted with an heart allograft from a donor aged under 16 or between 16-44 were 78% and 74%, compared with 66% and 63% for donors aged 45-55 and over 55, respectively. The 3-year survival rates for recipients of hearts with cold ischemic times under 2 hours, 2-3, 3-4, 4-5, 5-6 and more than 6 hours were 74%, 75%, 70%, 65%, 54% and 40%, respectively. Transplanting a female donor heart into a male recipient was associated with the worst prognosis: the 3-year survival rates were 73%, 71%, 66% and 76%, respectively, for the donor/recipient groups male/male, male/female, female/male and female/female, respectively. When the donor-to-recipient body weight ratio was below 0.8, the 3-year survival rate was 64%, compared to 72% for weight-matched pairs and 74% for patients who received a heart from an oversized donor (p=0.004). Better survival rates were obtained for better HLA-matched transplants. The 3-year survival rates were 75%, 89%, 78%, 78%, 69%, 72%, and 71% for HLA-A,-B,-DR zero, 1, 2, 3, 4, 5 and 6 mismatched groups, respectively (p=0.04). Survival was significantly associated with the CMV serologic status of the donor and recipient; the 3-year survival rates were: D+/R+, 71%; D+/R-, 69%; D- R-, 76%; and D-/R+, 76% (p=0.04). Patients in an ICU had a 3-year survival rate of 62%, compared to 72% for patients in a general ward and 74% for outpatients (p<0.0001). Patients that were on a VAD and there-upon transplanted had a 3-year survival rate of 65%, compared to 73% for patients without a VAD (p=0.004). Being on a ventilator was a major risk factor for death after transplantation; patients on ventilator support at the time of the transplant had a 3-year survival rate of 52% compared to 73% for the other patients (p<0.0001). LUNG TRANSPLANT SURVIVAL: The 3-year survival rate for children (73%) appeared to be better than the adult rate (61%; p=0.8). Adult lung transplant survival was significantly worse in the case of a repeat lung transplant; a 3-year retransplant survival rate of 42% was obtained compared with 61% for first transplants (p=0.049). With respect to the underlying end-stage lung disease, no statistically significant difference in long-term survival could be detected in this cohort. The 3-year survival rates were: 62% for COPD/Emphysema, 70% for CF, 58% for IPF, 64% for Alpha-1 ATD and 56% for PPH (p=0.2). Our data demonstrated no effect of the recipient's age on long-term lung transplant survival, except for 2 senior patients in this cohort. At 3-years the survival rates for recipients aged 16-40, 41-55 and 56-65 were 65%, 60% and 62%, respectively (p=0.05). The 3-year survival rates for transplants performed with lungs from donors aged under 16, 16-44, 45-55 and over 55 was 57%, 64%, 55% and 62%, respectively (p=0.1) No association between the duration of cold ischemic time and 3-year survival was observed; under 3 hours, 3-4, 4-5, 5-6 and over 6 hours of ischemia resulted in 3-year survival rates of 53%, 59%, 64%, 68% and 57%, respectively (p=0.2). Early posttransplant outcome tended to be better for gender-matched transplants, while transplanting a female donor lung into a male recipient was associated with the worst prognosis. The 3-year survival rates were 65% for male/male, 63% for male/female, 48% for female/male and 61% for female/female (p=0.009). No effect of donor-to-recipient weight match was observed in this Eurotransplant cohort; when the donor-to-recipient weight ratio was below 0.8, the 3-year survival rate was 57%, compared with 59% for weight-matched pairs and 64% for patients who received a lung from an oversized donor (p=0.5). Long-term survival after lung transplantation was influenced by HLA matching. The 3-year survival rates were 100%, 68%, 70%, 65%, 54% and 55% for the HLA-A,-B,-DR 1, 2, 3, 4, 5 and 6 mismatched groups, respectively (p=0.06). A donor CMV+ and recipient CMV- match was a risk factor for long-term mortality, with 3-year survival rates of 56% for D+/R+, 55% for D+/R-, 71% for D-/R- and 62% for D-/R+ transplants (p=0.046). En-bloc transplantation of both lungs yielded worse early results, but the 3-year survival rates for patients who underwent single (60%), bilateral sequential double lung (63%) and en-bloc double lung transplantation (56%) were not different (p=0.2). Ventilator dependency was associated with a significantly reduced survival at 3 years. Patients on a ventilator support at the time of the transplant had a 3-year survival rate of 48% compared with 63% for other patients (p=0.006).

Adolescent↗
PubMed2002

Inhibition of aortic allograft vasculopathy by local delivery of platelet-derived growth factor receptor tyrosine-kinase blocker AG-1295.

BACKGROUND: Signal transduction through the platelet-derived growth factor (PDGF)/PDGF-receptor (PDGFR) system has been linked to vascular smooth muscle cell migration and proliferation leading to allograft vasculopathy. This study describes the effect of the tyrphostin AG-1295, a specific PDGFR tyrosine-kinase inhibitor, on neointimal formation in this disease. METHODS AND RESULTS: Rat aortic allografts transplanted from dark agouti (RT1 ) donors to Wistar-Furth (RT1 ) recipients were assessed in a new treatment model for local drug delivery from polymeric carrier matrices precoated with AG-1295. Matrices were wrapped around the graft immediately after transplantation. The recipients received no background immunosuppression. At day 80 posttransplantation, intimal thickness in AG-1295-treated grafts was reduced when compared to controls (11.8+/-9.1% intimal thickness vs. 23.7+/-6.4% intimal thickness; P=0.042). This finding corresponded to inhibition of intimal PDGFR-beta expression in AG-1295-treated grafts at day 20 posttransplantation (P =0.029 vs. allogeneic controls). CONCLUSIONS: The tyrphostin AG-1295 reduces neointimal formation in aortic allograft vasculopathy by inhibition of PDGFR-beta-triggered tyrosine phosphorylation. Local drug release of specific tyrosine-kinase inhibitors from perivascularly co-implanted polymeric carrier matrices is effective in the prophylaxis of allograft vasculopathy under selected experimental conditions.

Animals↗
PubMed2002

Construction of autologous human heart valves based on an acellular allograft matrix.

OBJECTIVE: Tissue engineered heart valves based on polymeric or xenogeneic matrices have several disadvantages, such as instability of biodegradable polymeric scaffolds, unknown transfer of animal related infectious diseases, and xenogeneic rejection patterns. To overcome these limitations we developed tissue engineered heart valves based on human matrices reseeded with autologous cells. METHODS AND RESULTS: Aortic (n=5) and pulmonary (n=6) human allografts were harvested from cadavers (6.2+/-3.1 hours after death) under sterile conditions. Homografts stored in Earle's Medium 199 enriched with 100 IU/mL Penicillin-Streptomycin for 2 to 28 days (mean 7.3+/-10.2 days) showed partially preserved cellular viability (MTT assay) and morphological integrity of the extracellular matrix (H-E staining). For decellularization, valves were treated with Trypsin/EDTA resulting in cell-free scaffolds (DNA-assay) with preserved extracellular matrix (confocal microscopy). Primary human venous endothelial cells (HEC) were cultivated and labeled with carboxy-fluorescein diacetate-succinimidyl ester in vitro. After recellularization under fluid conditions, EC were detected on the luminal surfaces of the matrix. They appeared as a monolayer of positively labeled cells for PECAM-1, VE-cadherin and Flk-1. Reseeded EC on the acellular allograft scaffold exhibited high metabolic activity (MTT assay). CONCLUSIONS: Earle's Medium 199 enriched with low concentration of antibiotics represents an excellent medium for long time preservation of extracellular matrix. After complete acellularization with Trypsin/EDTA, recellularization under shear stress conditions of the allogeneic scaffold results in the formation of a viable confluent HEC monolayer. These results represent a promising step toward the construction of autologous heart valves based on acellular human allograft matrix.

Aortic Valve↗
PubMed2002

High failure rate after valve-sparing aortic root replacement using the "remodeling technique" in acute type A aortic dissection.

BACKGROUND: Valve-sparing surgery including the replacement of the sinus of valsalvae were initially meant to be promising approaches in the treatment of acute type A aortic dissection. However, the long-term outcome after valve-sparing aortic root replacement in acute type A dissection is currently the subject of intense debate, and the evidence reported in the literature is sparse. Here we report on our experience on valve sparing aortic root replacement inpatients with acute type A dissection. METHODS: From August 1995 to November 2000, 30 patients with acute type A dissection received valve-sparing aortic root replacement. Two different techniques were performed: the "remodeling" technique, first described by Yacoub in 1983 (8 patients) and the "reimplantation" technique, initially described by David and Feindel, in 1992 (22 patients). Endpoints of the study were early and late mortality, as well as aortic valve-related complications and reoperations. RESULTS: The mean follow-up time was 22.6+/-15.4 months. The overall 30 day mortality was 17% (5/29) and the late mortality 4% (1/24). During the observation period, 4 patients had to be reoperated (n=3) for acute aortic valve regurgitation after aortic root remodeling and for acute aortic valve endocarditis (n=1) after aortic root reimplantation. In the 3 patients with acute aortic valve regurgitation, symptoms occurred 44, 24, and 17 months after the initial operation in these patients. Intraoperatively prolapsing aortic leaflets because of commissural detachment was found in all 3 cases. In all other patients the latest echocardiographic follow-up examination revealed freedom from aortic regurgitation higher than grade 1. CONCLUSIONS: The high failure rate of aortic root remodeling inpatients with acute type A aortic dissection is discouraging. Whether this technique should be applied in acute type A aortic dissection is questionable. In contrast, aortic root reimplantation lead to favorable midterm outcome. Thus, we recommend consideration of this technique for surgical treatment of patients with acute type A aortic dissection.

Acute Disease↗
PubMed2002

Absence of PERV specific humoral immune response in baboons after transplantation of porcine cells or organs.

Xenotransplantation of pig organs seems a promising way of overcoming the prevailing limitation on allotransplantation due to donor numbers. However, as porcine endogenous retroviruses (PERVs) can infect human cells in vitro, there is substantial concern regarding the risk of a PERV infection in xenogeneic transplant recipients. Cultured porcine endothelial cells, stimulated peripheral blood mononuclear cells, and pancreatic islet cells can release PERV infectious for human cells in vitro, but it is currently unknown whether PERV is released in vivo, whether these viral particles can infect the transplant recipient, and whether they are pathogenic. In a retrospective study 15 immunosuppressed baboons were tested for a specific immune response against PERV after transplantation of porcine endothelial cells, mononuclear blood cells, and lungs. Anti-PERV antibody expression was analyzed with peptide-based, enzyme-linked immunosorbent assays and highly sensitive Western Blot assays. This xenotransplantation study using nonhuman primates found no evidence of PERV specific humoral immune response. Our data suggest that no productive PERV infection and no continuous PERV release takes place in the nonhuman primates analyzed in this study.

Animals↗
PubMed2002

[Current status of lung transplantation: patients, indications, techniques and outcome].

BACKGROUND: Lung transplantation has evolved to a standard treatment modality for patients suffering from end-stage lung diseases. INDICATIONS: Accepted indications for lung transplantation include chronic obstructive pulmonary disease of the lung (COPD) and other causes of emphysema (i.e., alpha-1-antitrypsin deficiency), parenchymal diseases (i.e., idiopathic pulmonary fibrosis), genetic disorders such as cystic fibrosis, vascular diseases (i.e., primary pulmonary hypertension), chronic infectious diseases (i.e., bronchiectasis), as well as rare indications such as lymphangioleiomyomatosis or sarcoidosis. TREATMENT AND OUTCOME: This article reviews the current strategies in the treatment of lung transplant recipients, surgical techniques, limitations of and outcome after lung transplantation.

Adolescent↗
PubMed2002

Predictors of aneurysmal formation after surgical correction of aortic coarctation.

OBJECTIVES: We sought to identify the predictors of aneurysmal formation after surgical correction of aortic coarctation. BACKGROUND: In 9% of patients, aneurysms develop late after corrective surgery of coarctation of the aorta, with a 36% mortality rate if left untreated. However, the predictors of postsurgical aneurysmal formation are unknown. METHODS: Of 25 aortic aneurysms requiring corrective surgery 152 +/- 78 months after the initial coarctation repair, 8 were located in the ascending aorta (type A) and 17 at the site of previous repair (local type). Seventy-four patients without progression of the aortic diameter within 189 +/- 71 months after coarctation repair were used for categorical data analysis in an attempt to identify the predictors of postsurgical aneurysmal formation. RESULTS: Advanced age at coarctation repair (p = 0.004) and patch graft technique (p < 0.0005) independently predicted local aneurysmal formation. Type A aneurysm was univariately associated with the presence of a bicuspid aortic valve (p = 0.02), advanced age at coarctation repair (p = 0.044) and a high preoperative peak systolic pressure gradient of 74 +/- 21 mm Hg (p = 0.041). Conversely, multivariate analysis confirmed only the presence of a bicuspid aortic valve (p = 0.015) as an independent predictor of type A aneurysm. Receiver operating characteristic curve analysis revealed that 72% of patients with a postsurgical aneurysm had an operation at age 13.5 years or more, whereas 69% with no postsurgical aneurysm had an operation at a younger age. CONCLUSIONS: Use of the patch graft technique and late correction of coarctation can predict aneurysmal formation at the site of coarctation repair, although patients with a bicuspid aortic valve may be at risk for an aneurysm developing in the ascending aorta, particularly after late repair of aortic coarctation with high preoperative pressure gradients.

Adolescent↗
PubMed2002

Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations.

Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the "hybrid" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before.

Adolescent↗
PubMed2002

[Recent developments in surgery of the thoracic aorta].

Aortic surgery is under continuous development. This applies to the aortic root where more and more reconstructive efforts are being made but also to intraoperative means of organ protection. Likewise, the endoluminar stent graft approach to downstream pathologies of the aorta has broadened the classical treatment option "replacement" by "exclusion". Some of these evolving changes in operative strategies and indications are discussed on the basis of a single-center experience.

Aortic Dissection↗