Since the first heart transplant in 1967, significant advancements have been made in heart transplantation. However, in the past two decades, there have been few major breakthroughs in clinical practice. Core issues such as graft dysfunction, cardiac allograft vasculopathy (CAV), and long-term immune tolerance remain unresolved1,2,3,4. Despite numerous findings in basic research, these discoveries have been challenging to translate into clinical applications, leading to a stagnation in the progress of heart transplant treatments. Therefore, effectively evaluating new technologies and therapies has become a critical issue, which highlights the importance of animal models, especially appropriate preclinical models, in addressing these challenges.
While mouse models have been widely used in heart transplantation research, they have significant limitations due to anatomical and physiological differences from humans, making it difficult to fully replicate the clinical heart transplant procedure and postoperative immune responses. Moreover, the immune system is relatively different, which fails to adequately reflect the complex immune responses seen in large animal models5,6,7. Additionally, due to their small size, heart transplants in mice are limited to heterotopic transplants, which diverges from the clinical practice of orthotopic heart transplantation8,9,10,11. Therefore, the use of appropriate large animal models, particularly pigs, is crucial.
Pig models offer significant advantages in heart transplantation research, especially in orthotopic heart transplantation. The pig heart is anatomically similar to the human heart, and pigs exhibit immune responses and organ physiological functions that are much closer to those of humans, making them an ideal platform for heart transplantation studies. Furthermore, pig models provide more complex and detailed experimental data, enabling researchers to better evaluate new immunosuppressive strategies, cardiac protection methods, and long-term outcomes post-transplant12,13,14,15. While some studies have utilized abdominal heterotopic models in pigs, which avoid the use of cardiopulmonary bypass and reduce surgical complexity, they fail to fully replicate the clinical scenario of orthotopic heart transplantation16. Therefore, in this study, we have established a dual-atrium orthotopic heart transplantation model in Bama miniature pigs, providing a more clinically relevant experimental platform for advancing heart transplantation techniques.