Cardiac Xenotransplantation: Challenges, Evolution, and Advances

Abstract

The increased need for heart transplantation in patients with advanced heart failure has introduced demand for a greater supply of donor hearts. Progress in cross-species experimental models has led to promise for ushering in the clinical use of xenotransplantation (XTx) as a potential solution to the organ shortage worldwide. In this review, the authors first highlight the historical advances that led to the first pig-to-human heart transplantation, a landmark moment in the field of advanced heart failure. The authors discuss immunologic, infectious, and physiological challenges for implementation of XTx, as well as innovations in the science of genetic manipulation that allowed clinical translation of this therapy. The authors consider ongoing barriers that affect ongoing translation of this technology into clinical care in the current era. Finally, the authors propose a framework for advancing clinical application of XTx.

Keywords: CRISPR/Cas9, clustered regularly interspaced short palindromic repeats–associated RNA-guided DNA endonuclease Cas9; GH, growth hormone; Gal, α-galactose 1,3-galactose; HF, heart failure; HTx, heart transplantation; NHP, nonhuman primate; PERV, porcine endogenous retrovirus; XTx, xenotransplantation; cardiac transplantation; gene editing; xenotransplantation.

Graphical abstract

Central Illustration

The Barriers to Xenotransplantation Translation Into the Clinical Realm

Figure 1

Clusters of Differentiation and Inflammation in Xenotransplantation Ab = antibody; alpha-Gal = α-1,3-galactosyltransfer; anti-SLA = anti–swine leukocyte antigen antibody; Beta4GalNT2 = β1,4-N-acetylgalactosyltransferase; CMAH = CMP-N-acetylneuraminic acid hydroxylase; hEPCR = human endothelial protein C receptor; hHO1 = human hemeoxygenase-1; HLA-E = human leukocyte antigen E; hTM = human thrombomodulin; MAC = membrane attack complex; NK = natural killer.

Figure 2

Physiological Adaptations in Xenotransplantation GH = growth hormone.

Figure 3

10-Gene-Edited Pig Used in the First Pig-to-Human Heart Transplantation Alpha-Gal = α-1,3-galactosyltransferase; Beta4GalNT2 = β1,4-N-acetylgalactosyltransferase; CMAH = CMP-N-acetylneuraminic acid hydroxylase; GH = growth hormone; hEPCR = human endothelial protein C receptor; hHO1 = human hemeoxygenase-1.