Reduction of hyperacute rejection and protection of metabolism and function in hearts of human decay accelerating factor (hDAF)-expressing pigs

Ryszard T. Smolenski, Monica Forni, Massimo Maccherini, Maria Laura Bacci, Ewa M. Slominska, Hongjun Wang, PierMaria Fornasari, Roberto Giovannoni, Felicetta Simeone, Augusta Zannoni, Giacomo Frati, Ken Suzuki, Magdi H. Yacoub, Marialuisa Lavitrano

Research output: Contribution to journalArticle

Abstract

Objective: The use of pig hearts can solve the problem of shortage of donor hearts for transplantation. However, targeting rejection by single genetic modification was proven to be ineffective, highlighting the requirement for complex genetic modifications and more effective methods for transgenic animal production. We evaluated here whether hearts of hDAF transgenic pigs generated using our technique sperm-mediated gene transfer (SMGT) will be protected from structural damage, metabolic changes, and mechanical dysfunction during perfusion with human blood. Methods: Hearts from control (C, n = 6) or transgenic (T, n = 5) pigs were perfused ex vivo for 4 h with fresh human blood using the ex vivo working mode system allowing monitoring of the function, metabolism, and structure. Results: Cardiac output (mean ± SEM) was maintained in T constant throughout the experiment, at 3.58 ± 0.36 and 3.83 ± 0.14 l/min after 30 min and 4 h, respectively, while cardiac output decreased to 1.95 ± 0.35 l/min in C after 30 min of perfusion (p <0.01 vs. T). The maximum increase in coronary perfusion pressure was reduced in T to 154 ± 16% as compared to C (237 ± 10%, p <0.001). Myocardial ATP after 4 h was 21.1 ± 1.1 nmol/mg dry wt (similar to initial) in T, while it decreased in C to 17.2 ± 1.4 (p <0.05). Deposition of complement factors C3 and C5b9 was present in C but not in T after perfusion. Conclusion: We have shown that hearts from hDAF transgenic pigs produced by SMGT are protected during perfusion with human blood and are metabolically stable and maintain mechanical function above the threshold level for life support.

Original languageEnglish
Pages (from-to)143-152
Number of pages10
JournalCardiovascular Research
Volume73
Issue number1
DOIs
Publication statusPublished - Jan 1 2007

Keywords

  • Cardiac function
  • Hyperacute rejection
  • SMGT
  • Transgenic pigs
  • Xenotransplantation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Smolenski, R. T., Forni, M., Maccherini, M., Bacci, M. L., Slominska, E. M., Wang, H., Fornasari, P., Giovannoni, R., Simeone, F., Zannoni, A., Frati, G., Suzuki, K., Yacoub, M. H., & Lavitrano, M. (2007). Reduction of hyperacute rejection and protection of metabolism and function in hearts of human decay accelerating factor (hDAF)-expressing pigs. Cardiovascular Research, 73(1), 143-152. https://doi.org/10.1016/j.cardiores.2006.10.027