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Biomedical subjects

A E Fiane

Publications and source records attributed to A E Fiane.

At least 19 recordsLinked to original sources
PubMed2002

Role of complement in xenotransplantation.

The xenotransplantation research is driven by the increasing gap between the number of patients with end-stage organ failure on waiting lists for transplantation and the supply of allografts. The lack of success in developing suitable artificial organs for permanent treatment of organ failure has further strengthened the need for xenotransplantation research. Pigs are now generally accepted to be the source animal of choice. Transplantation of pig organs to humans faces several barriers which have to be overcome before it comes to clinical application: (1) anatomical and physiological conditions; (2) immunological rejection mechanisms; (3) molecular compatibility between signal molecules of the two species; (4) risk of transmission of microorganisms, particularly pig endogenous retroviruses; and (5) legal and ethical aspects both with respect to the animal and the recipient. Here we will focus on the role of the complement system in the rejection of immediately vascularized pig-to-primate xenografts. The hyperacute rejection occurring within minutes after transplantation is mediated by binding of natural antibodies to the Galalpha(l-3)Gal epitope on the endothelial cells with subsequent complement activation. Whereas inhibition of complement activation protects against hyperacute rejection, the role of complement in the later rejection phases is less clarified.

Animals↗
PubMed2001

Human serum-induced expression of E-selectin on porcine aortic endothelial cells in vitro is totally complement mediated.

BACKGROUND: Whereas complement is a key mediator of hyperacute xenograft rejection, its role in acute vascular rejection (AVR) is a matter of controversy. AVR is associated with de novo synthesis of endothelial cell-derived inflammatory mediators, including the leukocyte-recruiting adhesion molecule E-selectin. Here we investigate the role and mechanism of complement in human serum-induced porcine endothelial cell activation. METHODS: An in vitro xenotransplantation method was designed using porcine aortic endothelial cells stimulated with human serum in microculture wells. E-selectin expression was measured by cell-enzyme immunoassay. Complement inhibitors acting at different levels in the cascade were investigated for their effect on E-selectin expression. RESULTS: E-selectin was strongly induced by normal human serum but not by heat-inactivated serum. Compstatin, a synthetic C3 inhibitor, markedly reduced human serum-induced E-selectin expression. Purified C1-inhibitor suppressed E-selectin induction completely, indicating activation through the classical or lectin pathway. Furthermore, a monoclonal antibody (mAb) that inhibits cleavage of C5 or another mAb that blocks the function of C7, completely inhibited the expression of serum-induced E-selectin, consistent with the terminal C5b-9 complement complex being the mediator of the endothelial cell activation. Inhibition of the alternative pathway using a novel antifactor D mAb did not reduce E-selectin expression. CONCLUSION: Human serum-induced expression of porcine E-selectin is totally complement dependent, induced by a C1-inhibitor regulated pathway and mediated through the terminal complement complex. The data may have implications for therapeutic strategies, particularly of C1-inhibitor and anti-C5 mAb, to protect against endothelial cell activation and subsequent AVR of porcine xenografts.

Animals↗
PubMed2001

Human cytomegalovirus productively infects porcine endothelial cells in vitro.

BACKGROUND: The possibility that human cytomegalovirus (HCMV) may infect porcine endothelial cells (ECs) was investigated. This may be relevant during xenotransplantation of porcine cells or organs into human recipients. METHODS: HCMV was inoculated into low-passage porcine ECs. Replication of virus was detected by development of characteristic cytopathogenic effect. Appearance of immediate early, early, and late antigens was studied by immunocytochemical staining. Infectious virus was detected in human fibroblast cells. Presence of HCMV RNA was studied by Northern Blot and reverse transcriptase polymerase chain reaction. RESULTS: All parameters indicated that a fresh clinical HCMV isolate productively infects porcine ECs. The same cells do not fully support replication of the laboratory strain Ad 169. CONCLUSION: Our results may indicate the possibility of cross-species infectivity of HCMV to porcine cells.

Animals↗
PubMed2000

Pig endogenous retrovirus--a threat to clinical xenotransplantation?

Transplantation shows good results for patients with end-stage disease, but there is an increasing lack of organs. Xenotransplantation, the transfer of live animal cells, tissues, or organs to another species, offers a potential solution to this shortfall. Pig is regarded as the animal of choice for this purpose. Meanwhile demonstration of pig endogenous retrovirus (PERV) in all porcine herds has caused serious concern with respect to a possible transmission of the virus to humans with a transplanted organ. Transmission to human cells has been documented under certain in vitro conditions. However, no such transmission has been demonstrated in vivo. The possible consequences of introducing PERV into immunocompromised human organisms are not known and it is necessary to collect more information. Novel and sensitive genomic assays to detect PERV infection are now available in addition to established virological, immunoserological and molecular methods. In order to minimise the risk of PERV transmission rigorous procedures should be established. International guidelines to reduce the risk should be followed. Although a number of immunological, physiological and virological questions need to be answered before the introduction of xenotransplantation as an alternative clinical treatment, some problems can only be solved by judicious clinical trials.

Animals↗
PubMed1999

[Transplantation from animal to man].

Because of a severe shortage of donor organs, organ transplantation therapy can only be offered to a fraction of all patients needing it. This has sparked an increasing interest in xenotransplantation. Transgenic pigs could potentially provide tissue and organs to thousands of patients on waiting lists world-wide. Xenografts may be used as bridges or as permanent alternatives to organ allotransplants. Clinical trials of transplantation of pig cells and tissues to treat diabetes and neurodegenerative disorders are in progress. The most striking immunologic obstacle to xenotransplantation of solid organs, that of hyperacute rejection, is close to being overcome. Next steps in research are to refine immunosuppression, improve our knowledge of physiology and to allow for small and strictly regulated clinical studies. However, the risk for the recipients from infectious agents, particularly retroviruses, and potential dissemination of these in the human population cannot be ignored and must be thoroughly investigated. Ethical, safety, and monitoring guidelines are needed to control the development of xenotransplantation.

Animals↗
PubMed1999

Inhibition of platelet aggregation by the GPIIb/IIIa antagonist reopro does not significantly prolong xenograft survival in an ex vivo model.

Effects on hyperacute rejection were studied in a discordant model with the platelet GPIIb/IIIa antagonist Reopro. Pig kidneys perfused with human blood survived median 118 min in the Reopro group and 103 min in the controls (P = 0.22). Platelet and leukocyte counts decreased, whereas plasma thrombospondin and soluble as well as platelet membrane P-selectin increased significantly in both groups without significant intergroup differences. beta-Thromboglobulin and myeloperoxidase increased significantly more in the control group than in the Reopro group (P = 0.009 and P = 0.02, respectively). The classical complement pathway was substantially and similarly activated in both groups. Light and electron microscopy revealed arterial thrombi and numerous glomerular platelet aggregates in the control group in contrast to the Reopro group. In conclusion, Reopro reduced platelet aggregation, and platelet and leukocyte activation to some extent, but had no effect on complement activation and did not significantly prolong xenograft survival, even though better preservation of morphology was shown.

Abciximab↗
PubMed1999

Is atrial fibrillation caused by extracorporeal circulation?

BACKGROUND: Atrial fibrillation is the most common rhythm disturbance encountered after open heart operations, with a reported incidence up to 40%. Despite its high incidence and clinical relevance its etiology remains obscure. It has been hypothesized that atrial fibrillation might be related to extracorporeal circulation. We performed a retrospective study (January 1, 1997 to December 31, 1997) comparing the incidence of atrial fibrillation in 3 groups of patients revascularized with and without extracorporeal circulation. METHODS: The first group comprised patients with coronary artery disease operated on with standard revascularization technique with cardiopulmonary bypass (n = 685). The second group included patients who had minimally invasive coronary artery bypass grafting without the use of extracorporeal circulation (n = 19). Patients in the third group had off-pump transmyocardial laser revascularization (n = 19). RESULTS: There was no significant difference in the incidence of atrial fibrillation in the group that had conventional coronary artery bypass and the group that had minimally invasive coronary artery bypass without cardiopulmonary bypass. The incidence of atrial fibrillation was significantly lower in the transmyocardial laser group compared with the other two groups. CONCLUSIONS: The present study found that postoperative atrial fibrillation is not caused solely by extracorporeal circulation, but patients who had transmyocardial laser revascularization had a significantly lower incidence of atrial fibrillation.

Aged↗
PubMed1999

C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte and platelet activation in an ex vivo pig-to-human perfusion model.

Xenotransplantation may be a future alternative due to increased shortage of organs. Classical complement activation is central in hyperacute rejection in pig-to-human combinations. We investigated the effects of C1-inhibitor (C1-INH), a regulator of the complement and contact systems, on hyperacute rejection. Pig kidneys were perfused with fresh human blood to which either C1-INH (n = 6) or human serum albumin (n = 6) was added. The survival of the C1-INH perfused kidneys (mean 327 min) was significantly longer (p < 0.00001) than the controls (79 min). C1-INH substantially inhibited complement activation (C1rs-C1-INH complexes, C4bc, C3bc and terminal complement complex) (p < 0.001 for all) compared with the marked complement activation in the controls. No contact activation was found. Leukocytes and platelets were substantially activated (counts, myeloperoxidase, beta-thromboglobulin, thrombospondin, soluble P-selectin) in the control group, and this activation was markedly reduced by C1-INH (p < 0.02 for all). Immunohistochemistry showed less C1q, C3, TCC, IgG and fibrin deposition in the C1-INH group. C1-INH may be useful to attenuate hyperacute rejection, probably through inhibition of complement. The reduced activation of neutrophils and platelets may mainly be secondary to inhibition of complement.

Animals↗
PubMed1999

Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts.

Compstatin, a newly described C3-binding peptide, inhibits complement activation by blocking C3 convertase-mediated cleavage of C3. As the complement activation is an essential part of the rejection reaction, we evaluated the ability of Compstatin to delay or prevent hyperacute rejection in an ex vivo xenograft model. Pig kidneys were perfused with fresh human blood containing either Compstatin (n=6) or a control agent (n=6). Graft survival and activation of complement, leukocytes and platelets both in the fluid-phase and in the tissue were examined. The survival of the Compstatin-perfused kidneys (median, 380 min) was significantly (P=0.0036) longer than that of the controls (median, 90 min). The classical complement pathway (C1rs-C1inhibitor and C4bc) was significantly and equally activated in both groups during the first 60 min. C3 activation products increased fivefold and terminal complement complex eightfold in the control group, but no increase occurred in the Compstatin group during this period. Immunohistochemistry showed less C3 and fibrin deposition and immune electron microscopy showed less terminal SC5b-9 complement complex deposition in the Compstatin group. A significant change in total white cells, neutrophils, myeloperoxidase, and expression of the surface activation markers CD11b (CR3) and CD35 (CR1) and CD62L (L-selectin) was observed in both groups. Leukocyte activation was lower in the Compstatin group but the difference was not statistically significant. There were no differences in platelet counts, thrombospondin, soluble P-selectin or beta-thromboglobulin between the groups. We conclude that Compstatin prolongs graft survival and suggest that it may be a useful agent for attenuating hyperacute rejection by inhibiting C3 and thus terminal complement pathway activation.

Animals↗
PubMed1999

Monocusp valve in right ventricular outflow tract.

Sixty patients aged 5 days-10.3 years (mean 2.9 years) received monocusp valve implants in the right ventricular outflow tract in corrective surgery for congenital heart disease. The free edge of the monocusp valve was attached to the posterior wall of the new pulmonary tract to cover the entire root of the pulmonary tract when the monocusp valve closed. Follow-up was 3.8 (0-11.5) years. Early mortality was 8.3% (5/60) and late mortality 3.6% (2/55). Monocusp valve regurgitation developed in all patients. Moderate or severe valve failure was found in 30 patients at median 1.4, mean 2.2 (0.2-6.8) years postoperatively. Repeat surgery was performed in seven cases because of monocusp failure. It is emphasized that monocusps potentially give short-term reduction of pulmonary regurgitation when used for right ventricular outflow tract reconstruction. Only long-term follow-up can disclose whether all patients with a monocusp valve will require repeat surgery.

Child↗
PubMed1998

Up to eight years' follow-up of 997 patients receiving the CarboMedics prosthetic heart valve.

BACKGROUND: The aim of the study was to evaluate our clinical experience with the CarboMedics Heart Valve Prosthesis. METHODS: Nine hundred ninety-seven consecutive patients underwent mechanical valve implantation (aortic, 771; mitral, 169; double, 52; tricuspid, 5) with this prosthesis from September 1987 through December 1993. The mean age was 62.3+/-13.7 years (range, 0.4 to 84 years); 56.6% (564 patients) were men. Four hundred seventy patients (47.1%) underwent additional surgical procedures. Mean follow-up was 4.1+/-2.2 years (range, 0 to 8.3 years) with a total of 4,040 patient-years. RESULTS: Early mortality was 5.0% (50/997; aortic, 4.4%; mitral, 6.4%; double, 9.6%). Late mortality was 14.8% (140/947). Survival at 7 years was 75.9%+/-1.8% (aortic, 78.4%+/-2%; mitral, 70.7%+/-4.5%; double, 60.8%+/-7.4%). When matched for sex and age and compared with the normal Norwegian population, our patients had an increased standard mortality ratio in both men (1.9+/-0.4) and women (2.9+/-0.6). The linearized rate of major thromboembolism was 0.9% per patient-year, valve thrombosis 0.2% per patient-year, major bleeding event 0.6% per patient-year, paravalvular leak needing reoperation 0.5% per patient-year, prosthetic valve endocarditis 0.1% per patient-year, and of all reoperations 0.6% per patient-year. CONCLUSIONS: The CarboMedics Heart Valve Prosthesis has incidences of morbid events comparable with or better than reported for other mechanical valves.

Adolescent↗
PubMed1998

Immunoglobulin prolongs survival of pig kidneys perfused ex vivo with human blood.

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.

Animals↗
PubMed1997

[Extracorporeal heart pump--a bridge to heart transplantation. First Norwegian experiences].

By February 1997, the number of heart transplantations at the National Hospital had reached 265. In our department, the first bridge to transplantation in using Thoratec artificial heart was performed in 1995. A 44 year-old patient with life-threatening heart failure was placed for one week on cardiopulmonary assist with an intra-aortic balloon pump and a veno-arterial cardiopulmonary bypass. Due to unceasing heart failure a Thoratec left ventricular assist device was implanted as a bridge to transplant. The patient was successfully transplanted two days after implantation of Thoratec. After eight months follow-up he is in New York Heart Association (NYHA) functional class I. Another patient, 17 years of age, and with dilated cardiomyopathy, went into cardiogenic shock while awaiting heart transplantation. For three days he had cardiopulmonary assist with intra-aortic balloon pump and venoarterial bypass with an oxygenator. After seven weeks on the left ventricular assist device he was transplanted. Although one episode of severe rejection occurred, be is in NYHA functional class I after four months follow-up. Our early experience is encouraging. Ventricular assist devices should be considered as a life support for patients scheduled for heart transplantation and expected to die within a very short time.

Adolescent↗
PubMed1997

[Transplantation of animal organs (xenotransplantation). Status and future development].

The increasing shortage of human organs for allotransplantation has created intense interest for xenotransplantation. Pig organs have been suggested as suitable grafts for man. However, the immediate problem associated with discordant xenotransplantation is hyperacute rejection. Hyperacute rejection occurs because antibodies become attached to the endothelial cells of the xenotransplant organ, which activates the complement system, attracts platelets etc. This results in endothelial cell damage, oedema, loss of vascular integrity and thus rapid destruction of the graft. Organs from non-human primates often do not cause hyperacute rejection, but will probably not be acceptable donors. Transgenic pigs have been breeded which contain the genes for the human regulators of complement activation. It appears that insertion of such genes into pigs serves to prevent aggressive hyperacute rejection. Understanding the mechanisms of rejection gives cause for optimism. However, there are still many problems to evaluate and solve. One potential danger associated with xenotransplantation is the transmission of infectious disease from animals to man. Other problems relate to physiological adaptation of the xenograft. The legal, ethical, religious and economic aspects must also be taken into consideration. Despite the potential problems, it is likely that a xenotransplant of some kind will soon be attempted in man.

Cost-Benefit Analysis↗
PubMed1997

Percutaneous transluminal angioplasty and retransplantation due to transplant coronary artery disease.

Allograft vascular disease is a significant cause of death of cardiac transplant recipients after the first year of transplantation. With few exceptions, angina pectoris does not develop and objective examinations, including coronary angiography, are necessary to diagnose coronary arteriopathy. Between 1983 and 1994, 214 heart transplantations in 211 patients were performed in our unit. All survivors had coronary angiography performed yearly. Thirty patients had significant localized arterial stenoses. Twelve patients with critical stenosis were accepted for percutaneous transluminal coronary angioplasty. Five patients underwent retransplantation due to progressive graft vascular disease with development of congestive heart failure. Conventional revascularization with transluminal coronary angioplasty can safely be performed with primary good results. In selected patients, retransplantation is an option if patients otherwise fulfil standard criteria for cardiac transplantation.

Adolescent↗
PubMed1997

Carpentier-Edwards bioprosthesis. Experiences of 17 years with analysis of risk factors of early mortality.

Isolated aortic (AVR, N = 71), mitral (MVR, N = 103), tricuspid (TVR, N = 3), pulmonary (PVR, N = 8), combined AVR + MVR (N = 4), or combined MVR + TVR (N = 2) valve replacement with a Carpentier-Edwards porcine bioprosthesis was performed in 191 patients between 1979 and 1986. Mean age was 56.9 +/- 17 (range 5-80) years in the total cohort. The operative mortality rates were 5.6% and 8.7%, respectively, for AVR and MVR. Mean observation time was 8 +/- 4.2 (0-16.7) years (total = 1.467 patient-years). Follow-up was 100% complete with respect to mortality. There were 78 late deaths (44%). Actuarial survival rates at 5 and 10 years were 73.2 +/- 5.2 and 52.1 +/- 6.6 for AVR and 76.7 +/- 4.2 and 61.6 +/- 4.8 for MVR. Coronary artery disease, concomitant coronary artery bypass grafting and emergency operation were significant risk factors of early mortality (p < 0.05). Postoperatively, sepsis and multiorgan failure were associated with early mortality (p < 0.05). The 10-year actuarial freedom from structural deterioration for AVR was 89 +/- 4.6 and 76.4 +/- 4.3 for MVR. It is concluded that structural valve failure is the most important factor that adversely affects the performance of Carpentier-Edwards bioprosthesis.

Adolescent↗