The number of patients eligible for heart transplantation has steadily increased over recent decades and is expected to continue rising in the coming years. However, the availability of donor hearts has not grown at the same pace. Although long-term ventricular assist devices are now an established therapy, their use is largely limited to patients with isolated left ventricular failure. Consequently, a substantial proportion of patients require alternatives to both allotransplantation (conventional heart transplantation) and mechanical circulatory support. For many years, xenotransplantation has been proposed as a potential future solution to this unmet clinical need.

The first critical step in xenotransplantation is the selection of the donor species. While it might intuitively seem that nonhuman primates would be the most suitable donors, pigs are currently preferred. This preference is based on several factors: porcine physiology closely resembles human physiology, pigs are widely used as laboratory animals, genetic editing is more feasible, and breeding is faster and more practical than in primates.

The main obstacle to xenotransplantation is the innate immune response and the biological incompatibility between tissues from different species. Advances in genetic engineering have made it possible to suppress the expression of specific porcine proteins and to introduce human genes that attenuate immune-mediated rejection of the porcine heart. The principal genetic modifications implemented in contemporary xenotransplantation models are summarized below:

• The primary mediators of the immediate immune response between the human immune system and porcine tissues are three membrane carbohydrates (αGAL, Neu5Gc, and β4GalNT2). Current donor pigs are genetically engineered to lack expression of these molecules (knockout animals).
• To further reduce immune reactivity against other porcine tissue antigens, two immunomodulatory proteins (hCD47 and hHO-1) have been introduced into the porcine genome.
• Porcine endothelium triggers activation of the human complement system. To counteract this effect, two genes encoding human complement regulatory proteins (hCD46 and hDAF) have been incorporated.
• Contact between human blood and porcine endothelium also promotes a hypercoagulable state. This prothrombotic tendency is mitigated by inserting two genes encoding human anticoagulant proteins (hTBM and hEPCR).
• Porcine hearts have a tendency to develop hypertrophy after xenotransplantation. This phenomenon is multifactorial, influenced by higher systemic blood pressure in humans and the young age of donor pigs. To reduce post-transplant cardiac overgrowth, the porcine growth hormone receptor has been deleted.

Using this genetically modified porcine model, the first human cardiac xenotransplantation was performed in 2020. The recipient was a patient on extracorporeal membrane oxygenation (ECMO) for cardiogenic shock who was not a candidate for either allotransplantation or durable mechanical circulatory support. The procedure was initially successful. However, 20 days later, a porcine cytomegalovirus infection—undetected in the donor animal—was identified, necessitating a reduction in immunosuppression. The patient subsequently developed cardiac rejection with severe ventricular hypertrophy and diastolic dysfunction, required reinstitution of ECMO, and ultimately died.

The most recent published cardiac xenotransplant involved a woman with advanced heart failure who was likewise ineligible for allotransplantation and long-term mechanical support. The transplantation itself was uncomplicated. On postoperative day 13, biopsy revealed areas of rejection, likely antibody mediated, prompting plasma exchange. Unfortunately, the plasma units administered contained antibodies against porcine antigens, exacerbating humoral rejection and leading to the patient’s death.

COMMENTARY:

At present, xenotransplantation remains an experimental therapy that is not yet ready for widespread clinical implementation. This article clearly outlines the major challenges facing this approach and the strategies currently being pursued to overcome them, offering a comprehensive overview of the current landscape of cardiac xenotransplantation. In addition to the substantial technical and immunological hurdles, important bioethical considerations must also be addressed. In recent years, several professional societies, including the International Society for Heart and Lung Transplantation (ISHLT), have worked to define the appropriate conditions and timing for the application of xenotransplantation. Nevertheless, significant debate persists regarding the use of these techniques in human recipients.

In summary, cardiac xenotransplantation is currently an experimental therapy with multiple barriers that must be overcome before it can be applied on a broader scale.

REFERENCE:

Phillips KG, Aljabban I, Wolbrom DH, Griesemer A, Leacche M, McGregor C, et al. Cardiac Xenotransplantation: Current State and Future Directions. Circulation. 2025 Jul 8;152(1):58-73. doi: 10.1161/CIRCULATIONAHA.124.070875.