In Vivo Study Of Lyophilized Bioprostheses: 3 Month Follow-up In Young Sheep [estudo In Vivo Do Comportamento De Bioprótese Liofilizada: Seguimento De 3 Meses Em Carneiros Jovens]

Objective: Glutaraldehyde is currently used in bovine pericardium bioprosthesis to improve mechanical and immunogenic properties. Lyophilization is a process that may decrease aldehyde residues in the glutaraldehyde treated pericardium decreasing cytotoxicity and enhancing resistance to calcification. The aim of this study is to evaluate bioprosthetic heart valves calcification in adolescent sheep and to study the potential of lyophilization as a mechanism to protect calcification. Methods: Two groups were evaluated: a control group in which a bovine pericardium prosthetic valve was implanted in pulmonary position and a lyophilized group in which the bovine pericardium prosthetic valve was lyophilized and further implanted. Sixteen sheeps 6 months old were submitted to the operation procedure. After 3 months the sheeps were euthanized under full anesthesia. Results: Six animals of the control group reached 95.16 ± 3.55 days and six animals in the lyophilized group reached 91.66 ± 0.81 days of postoperative evolution. Two animals had endocarditis. Right ventricle/pulmonary artery (RV/PA) mean gradient, in the control group, at the implantation was 2.04 ± 1.56 mmHg, in the lyophilization group, the RV/PA mean gradient, at the implantation was 6.61 ± 4.03 mmHg. At the explantation it increased to 7.71 ± 3.92 mmHg and 8.24 ± 6.25 mmHg, respectively, in control and lyophilization group. The average calcium content, after 3 months, in the control group was 21.6 ± 39.12 μg Ca+2/mg dry weight, compared with an average content of 41.19 ± 46.85 μg Ca+2/mg dry weight in the lyophilization group (P=0.662). Conclusion: Freeze drying of the bovine pericardium prosthesis in the pulmonary position could not demonstrate calcification mitigation over a 3 month period although decreased inflammatory infiltration over the tissue.274592599Rahimtoola, S.H., Choice of prosthetic heart valve in adults an update (2010) J Am Coll Cardiol., 55 (22), pp. 2413-2426David, T.E., Armstrong, S., Maganti, M., Hancock II bioprosthesis for aortic valve replacement: The gold standard of bioprosthetic valves durability? (2010) Ann Thorac Surg., 90 (3), pp. 775-781Clark, J.N., Ogle, M.F., Ashworth, P., Bianco, R.W., Levy, R.J., Prevention of calcification of bioprosthetic heart valve cusp and aortic wall with ethanol and aluminum chloride (2005) Ann Thorac Surg., 79 (3), pp. 897-904Ruel, M., Kulik, A., Rubens, F.D., Bédard, P., Masters, R.G., Pipe, A.L., Late incidence and determinants of reoperation in patients with prosthetic heart valves (2004) Eur J Cardiothorac Surg., 25 (3), pp. 364-370Poirer, N.C., Pelletier, L.C., Pellerin, M., Carrier, M., 15-year experience with the Carpentier-Edwards pericardial bioprosthesis (1998) Ann Thorac Surg., 66 (6 SUPPL.), pp. S57-S61Duran, C.G., Gunning, A.J., Whitehead, R., Experimental aortic valve heterotransplantation (1967) Thorax., 22 (6), pp. 510-518Duran, C.M., Whitehead, R., Gunning, A.J., Implantation of homologous and heterologous aortic valves in prosthetic vascular tubes (1969) Thorax., 24 (2), pp. 142-147Borgognoni, C.F., Maizato, M.J., Leirner, A.A., Polakiewicz, B., Beppu, M.M., Higa, O.Z., Effect of freeze-drying on the mechanical, physical and morphological properties of glutaraldehyde-treated bovine pericardium: Evaluation of freeze-dried treated bovine pericardium properties (2010) J Appl Biomater Biomech., 8 (3), pp. 186-190Maizato, M.J., Higa, O.Z., Mathor, M.B., Camillo, M.A., Spencer, P.J., Pitombo, R.N., Glutaraldehyde-treated bovine pericardium: Effects of lyophilization on cytotoxicity and residual aldehydes (2003) Artif Organs., 27 (8), pp. 692-694Flameng, W., Meuris, B., Yperman, J., de Visscher, G., Herijgers, P., Verbeken, E., Factors influencing calcification of cardiac bioprostheses in adolescent sheep (2006) J Thorac Cardiovasc Surg., 132 (1), pp. 89-98Schoen, F.J., Levy, R.J., Calcification of tissue heart valve substitutes: Progress toward understanding and prevention (2005) Ann Thorac Surg., 79 (3), pp. 1072-1080McClure, R.S., Narayanasamy, N., Wiegerinck, E., Lipsitz, S., Maloney, A., Byrne, J.G., Late outcomes for aortic valve replacement with the Carpentier-Edwards pericardial bioprosthesis: Up to 17-year follow-up in 1,000 patients (2010) Ann Thorac Surg., 89 (5), pp. 1410-1416Jamieson, W.R., Lewis, C.T., Sakwa, M.P., Cooley, D.A., Kshettry, V.R., Jones, K.W., St Jude Medical Epic porcine bioprosthesis: Results of the regulatory evaluation (2011) J Thorac Cardiovasc Surg., 141 (6), pp. 1449e2-1454e2The Italian study on the Mitroflow postoperative results (ISTHMUS): A 20-year, multicentre evaluation of Mitroflow pericardial bioprosthesis (2011) Eur J Cardiothorac Surg., 39 (1), pp. 18-26. , ISTHMUS InvestigatorsBeauchamp Jr., R.O., St Clair, M.B., Fennell, T.R., Clarke, D.O., Morgan, K.T., Kari, F.W., A critical review of the toxicology of glutaraldehyde (1992) Crit Rev Toxicol., 22 (3-4), pp. 143-174Golomb, G., Schoen, F.J., Smith, M.S., Linden, J., Dixon, M., Levy, R.J., The role of glutaraldehyde-induced cross-links in calcification of bovine pericardium used in cardiac valve bioprostheses (1987) Am J Pathol., 127 (1), pp. 122-130Guldner, N.W., Jasmund, I., Zimmermann, H., Heinlein, M., Girndt, B., Meier, V., Detoxification and endothelialization of glutaraldehyde-fixed bovine pericardium with titanium coating: A new technology for cardiovascular tissue engineering (2009) Circulation., 119 (12), pp. 1653-1660Clark, J.N., Ogle, M.F., Ashworth, P., Bianco, R.W., Levy, R.J., Prevention of calcification of bioprosthetic heart valve cusp and aortic wall with ethanol and aluminum chloride (2005) Ann Thorac Surg., 79 (3), pp. 897-904Hahn, S.K., Ohri, R., Giachelli, C.M., Anti-calcification of bovine pericardium for bioprosthetic heart valves after surface modi-fication with hyaluronic acid derivatives (2005) Biotechnol Bioprocess Eng., 10, pp. 218-224Zilla, P., Fullard, L., Trescony, P., Meinhart, J., Bezuidenhout, D., Gorlitzer, M., Glutaraldehyde detoxification of aortic wall tissue: A promising perspective for emerging bioprosthetic valve concepts (1997) J Heart Valve Dis., 6 (5), pp. 510-520Weissenstein, C., Human, P., Bezuidenhout, D., Zilla, P., Glutaraldehyde detoxification in addition to enhanced amine cross-linking dramatically reduces bioprosthetic tissue calcification in the rat model (2000) J Heart Valve Dis., 9 (2), pp. 230-240Santibáñez-Salgado, J.A., Olmos-Zúñiga, J.R., Pérez-López, M., Aboitiz-Rivera, C., Gaxiola-Gaxiola, M., Jasso-Victoria, R., Lyophilized glutaraldehyde-preserved bovine pericardium for experimental atrial septal defect closure (2010) Eur Cell Mater., 19, pp. 158-165Zilla, P., Brink, J., Human, P., Bezuidenhout, D., Prosthetic heart valvae: Catering for the few (2008) Biomaterials., 29 (4), pp. 385-40

Methotrexate associated to lipid core nanoparticles improves cardiac allograft vasculopathy and the inflammatory profile in a rabbit heart graft model

<div><p>Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and has no effective treatment. A lipid nanoemulsion (LDE) can carry chemotherapeutic agents in the circulation and concentrates them in the heart graft. The aim of the study was to investigate the effects of methotrexate (MTX) associated to LDE. Rabbits fed a 0.5% cholesterol diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg·kg–1·day–1 orally) and allocated to treatment with intravenous LDE-MTX (4 mg/kg, weekly, n=10) or with weekly intravenous saline solution (control group, n=10), beginning on the day of surgery. Animals were euthanized 6 weeks later. Compared to controls, grafts of LDE-MTX treated rabbits showed 20% reduction of coronary stenosis, with a four-fold increase in vessel lumen and 80% reduction of macrophage staining in grafts. Necrosis was attenuated by LDE-MTX. Native hearts of both LDE-MTX and Control groups were apparently normal. Gene expression of lipoprotein receptors was significantly greater in grafts compared to native hearts. In LDE-MTX group, gene expression of the pro-inflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-18, vascular cell adhesion molecule-1, and matrix metalloproteinase-12 was strongly diminished whereas expression of anti-inflammatory interleukin-10 increased. LDE-MTX promoted improvement of the cardiac allograft vasculopathy and diminished inflammation in heart grafts.</p></div

Diclofenac plasma protein binding: PK-PD modelling in cardiac patients submitted to cardiopulmonary bypass

Twenty-four surgical patients of both sexes without cardiac, hepatic, renal or endocrine dysfunctions were divided into two groups: 10 cardiac surgical patients submitted to myocardial revascularization and cardiopulmonary bypass (CPB), 3 females and 7 males aged 65 ± 11 years, 74 ± 16 kg body weight, 166 ± 9 cm height and 1.80 ± 0.21 m2 body surface area (BSA), and control, 14 surgical patients not submitted to CPB, 11 female and 3 males aged 41 ± 14 years, 66 ± 14 kg body weight, 159 ± 9 cm height and 1.65 ± 0.16 m2 BSA (mean ± SD). Sodium diclofenac (1 mg/kg, im Voltaren 75® twice a day) was administered to patients in the Recovery Unit 48 h after surgery. Venous blood samples were collected during a period of 0-12 h and analgesia was measured by the visual analogue scale (VAS) during the same period. Plasma diclofenac levels were measured by high performance liquid chromatography. A two-compartment open model was applied to obtain the plasma decay curve and to estimate kinetic parameters. Plasma diclofenac protein binding decreased whereas free plasma diclofenac levels were increased five-fold in CPB patients. Data obtained for analgesia reported as the maximum effect (EMAX) were: 25% VAS (CPB) vs 10% VAS (control), P<0.05, median measured by the visual analogue scale where 100% is equivalent to the highest level of pain. To correlate the effect versus plasma diclofenac levels, the EMAX sigmoid model was applied. A prolongation of the mean residence time for maximum effect (MRTEMAX) was observed without any change in lag-time in CPB in spite of the reduced analgesia reported for these patients, during the time-dose interval. In conclusion, the extent of plasma diclofenac protein binding was influenced by CPB with clinically relevant kinetic-dynamic consequence