Recipients with blood group A associated with longer survival rates in cardiac valvular bioprostheses.

BACKGROUND: Pigs/bovines share with humans some of the antigens present on cardiac valves. Two such antigens are: the major xenogenic Ag, "Gal" present in all pig/bovine very close to human B-antigen of ABO-blood-group system; the minor Ag, pig histo-blood-group AH-antigen identical to human AH-antigen and present by some animals. We hypothesize that these antigens may modify the immunogenicity of the bioprosthesis and also its longevity. ABO distribution may vary between patients with low (<6 years) and high (≥15 years) bioprostheses longevity. METHODS: Single-centre registry study (Paris, France) including all degenerative porcine bioprostheses (mostly Carpentier-Edwards 2nd/3rd generation heart valves) explanted between 1985 and 1998 and some bovine bioprostheses. For period 1998-2014, all porcine bioprostheses with longevity ≥13 years (follow-up ≥29 years). Important predictive factors for bioprosthesis longevity: number, site of implantation, age were collected. Blood group and other variables were entered into an ordinal logistic regression analysis model predicting valve longevity, categorized as low (<6 years), medium (6-14.9 years), and high (≥15 years). FINDINGS: Longevity and ABO-blood group were obtained for 483 explanted porcine bioprostheses. Mean longevity was 10.2 ±â€¯3.9 years [0-28] and significantly higher for A-patients than others (P = 0.009). Using multivariate analysis, group A was a strong predictive factor of longevity (OR 2.09; P < 0.001). For the 64 explanted bovine bioprosthesis with low/medium longevity, the association, with A-group was even more significant. INTERPRETATION: Patients of A-group but not B have a higher longevity of their bioprostheses. Future graft-host phenotyping and matching may give rise to a new generation of long-lasting bioprosthesis for implantation in humans, especially for the younger population. FUND: None.

Use of arginine-glycine-aspartic acid adhesion peptides coupled with a new collagen scaffold to engineer a myocardium-like tissue graft.

BACKGROUND: Cardiac tissue engineering might be useful in treatment of diseased myocardium or cardiac malformations. The creation of functional, biocompatible contractile tissues, however, remains challenging. We hypothesized that coupling of arginine-glycine-aspartic acid-serine (RGD+) adhesion peptides would improve cardiomyocyte viability and differentiation and contractile performance of collagen-cell scaffolds. METHODS: Clinically approved collagen scaffolds were functionalized with RGD+ cells and seeded with cardiomyocytes. Contractile performance, cardiomyocyte viability and differentiation were analyzed at days 1 and 8 and/or after culture for 1 month. RESULTS: The method used for the RGD+ cell-collagen scaffold coupling enabled the following features: high coupling yields and complete washout of excess reagent and by-products with no need for chromatography; spectroscopic quantification of RGD+ coupling; a spacer arm of 36 A, a length reported as optimal for RGD+-peptide presentation and favorable for integrin-receptor clustering and subsequent activation. Isotonic and isometric mechanical parameters, either spontaneous or electrostimulated, exhibited good performance in RGD+ constructs. Cell number and viability was increased in RGD+ scaffolds, and we saw good organization of cell contractile apparatus with occurrence of cross-striation. CONCLUSIONS: We report a novel method of engineering a highly effective collagen-cell scaffold based on RGD+ peptides cross-linked to a clinically approved collagen matrix. The main advantages were cell contractile performance, cardiomyocyte viability and differentiation.

[Pleural diffusion of amoxicillin 1 and vancomycin in patients treated for post-surgical empyema]. / Empyème après chirurgie d'exérèse pulmonaire: étude de la diffusion pleurale de l'amoxicilline et de la vancomycine.

INTRODUCTION: Treatment of post surgical thoracic empyema consists of chest tube drainage, antibiotic administration, and in some cases surgical lavage of infected spaces. Data in human on the diffusion of antibiotics in pleural cavity after post surgical empyema are lacking. METHODS: We studied on 9 patients with post surgical thoracic empyema (including 6 pneumonectomy) the diffusion of 2 antibiotics commonly used in this situation: amoxicillin (for 7 patients) and vancomycin (for 2 patients). Antibiotics concentrations were measured after at least 3 days of treatment (3-12 days), in order to reach a plateau concentration in the pleural space. RESULTS: The ratio pleural/plasma antibiotic concentration was 1.96 (range: 0.6-4.9). The pleural infection was cured for 8 on 9 patients. The last patients required thoracostomy, and the outcome was favorable after this procedure. CONCLUSION: That the penetration of amoxicillin and vancomycin in pleural space after post surgical empyema is good. Pleural antibiotics concentrations are in the majority of cases higher than plasmatic concentrations.

Effect of human immunoglobulins on the immunogenicity of porcine bioprostheses.

BACKGROUND: Glutaraldehyde fixation (GT) is known to reduce immunologic reactions and tissue degeneration after implantation in humans. Sterilization after glutaraldehyde fixation (G-ST) improves the safety and reduces the tendency of GT valves to calcify. Intravenous immunoglobulins (IVIg) have been shown to reduce xenogeneic response against porcine tissue. We have investigated the effect of these fixation procedures combined with and without IVIg on the antigenicity of bioprostheses. METHODS: Lewis adult rats were implanted subcutaneously with a fresh, GT, or G-ST porcine heart valve pre- or posttreated with different amounts of IVIg. We followed by enzyme-linked immunosorbent assay and IgM and IgG titers against protein extracts from the porcine heart valves after implantation. Cellular reactivity was assessed in xenogeneic lymphoendothelial coculture experiments. Calcification content was also examined. RESULTS: Glutaraldehyde fixation partially decreased the humoral response against proteins of the implant but elicited a cellular xenogeneic response. Sterilization reduced these reactivities, but retained antigenicity. Intravenous immunoglobulin postincubated with GT valves before implantation reduced the antigenicity of the tissue to the same extent as G-ST valves, but had no effect on valvular tissue calcification. CONCLUSIONS: Our studies demonstrate that IVIg or the sterilization procedure (ST) reduced the cellular response against glutaraldehyde-fixed valves (GT), whereas reduced calcification was observed only with ST.

Intravenous immunoglobulins for therapeutic use contain anti-idiotypes against xenophile antibodies and prolong discordant graft survival.

Xenotransplantation between discordant species leads to a graft survival of a few minutes, due to binding of natural antibodies to the xenogeneic endothelial cells, complement activation, and endothelial cell activation. Polyclonal human immunoglobulins for intravenous use (IVIg) from normal donors have been proven effective in a variety of antibody-mediated disorders and contain anti-idiotypic antibodies directed against a number of disease-associated and natural antibodies. We have shown that administration of IVIg delays rejection of a guinea pig heart to a rat. We demonstrate herein that IVIg can inhibit the binding of xenoreactive rat IgG antibodies to guinea pig endothelial cells. This inhibition is likely due to the presence, among IVIg, of anti-idiotypic antibodies as F(ab')2 fragments of IVIg were as effective as whole IVIg. In addition, natural anti-endothelium rat antibodies were retained on a column of F(ab')2 fragments of IVIg coupled to Sepharose. The degree of inhibition of binding of IgG natural antibodies correlated with the survival of the xenograft when IVIg was administered prior to transplantation. Thus IVIg prolong xenograft survival through idiotypic-anti-idiotypic interactions with natural xenoreactive antibodies of the IgG isotype.

Normal human immunoglobulins for intravenous use (IVIg) delay hyperacute xenograft rejection through F(ab')2-mediated anti-complement activity.

Xenotransplantation between discordant species leads to a hyperacute rejection mediated by natural antibodies, both of the IgG and IgM isotypes, activation of complement and endothelial cell activation. The combination of these mechanisms leads to a transplant survival of minutes to a few hours. Polyclonal human immunoglobulins for intravenous use (IVIg) from normal donors have proved effective in a number of antibody-mediated disorders, as well as in inflammatory disorders. We demonstrate that administration of IVIg in a guinea pig to rat model of cardiac xenografting can effectively delay hyperacute rejection. This effect is mediated by the F(ab')2 fragments of IVIg, and is correlated to an anti-complementary activity.

Human immunoglobulins inhibit thrombin-induced Ca2+ movements and nitric oxide production in endothelial cells.

Binding of natural antibodies to endothelial cell plays an important role in hyperacute xenograft rejection between discordant species. Human intravenous immunoglobulins (IVIg) delay this hyperacute rejection, but their mechanisms of action on endothelial cells have to be defined. Here we demonstrate that IVIg dose-dependently prevent thrombin from eliciting cytosolic Ca2+ movements and nitric oxide (NO) production in aortic endothelial cells from guinea pig. The Ca2+ response to thrombin was similarly affected by IVIg whether they were removed or not from the incubation medium before stimulation. Pretreatment by rat natural antibodies also suppress the thrombin-induced Ca2+ peak corresponding to Ca2+ release from intracellular stores but stimulate the subsequent sustained increase in [Ca2+]i and the release of NO. The action of human intravenous immunoglobulins seems to be selective for the thrombin receptor because they do not affect [Ca2+]i and NO responses to endothelin-1 or thapsigargin. However, these antibodies also suppress the first phase of the cytosolic Ca2+ response to ATP, which does not release NO under our experimental conditions. These observations raise the possibility that IVIg selectively interact with targets localized on plasma membrane of endothelial cells for controlling receptor-activated Ca2+ pathways and NO release.