Global challenges and development of heart transplantation: Wuhan Protocol development and clinical implementation

Heart failure represents a growing pandemic as it affects ~64 million individuals globally,[1] and it has an annual incidence of 2 million cases per year, one-third of which are in China.[2,3] Of these, 10% progress to end-stage disease, for which cardiac transplantation remains the sole curative therapy. Despite this critical need, profound disparities persist: Only 6000 heart transplants are performed annually worldwide, with <500 pediatric cases, thus resulting in a staggering supply–demand gap of 1:100 (The International Society for Heart and Lung Transplantation, 2023 Registry).[2] This critical disparity—which leads to >30% of waitlisted patients dying annually while <1% receive transplants—requires urgent innovations in donor optimization and recipient-specific therapeutic strategies. Geographical inequities also exist in heart transplantation. While donor heart utilization rates reach 65% in Europe and North America, the underutilization of marginal donors (<10%) persists despite the potential to expand the donor pool. Concurrently, 10-year survival rates plateau at 55%, which is constrained by aging recipient populations and rising comorbidities. In contrast, Asia-Pacific countries face specific challenges: (1) donor-recipient weight mismatch occurs in 30% of cases, double the Western rate (15%)[4]; (2) pediatric transplants constitute <5% of total procedures, thus reflecting cultural and technical barriers.[5] Alarmingly, human leukocyte antigen sensitization rates in Asian recipients surpass Western counterparts due to human leukocyte antigen gene diversity, prior blood transfusion history, and pregnancy history (18%), thus escalating rejection risks. Latin America and Africa perform <50 annual transplants combined, with mechanical circulatory support (MCS) accessible to <1% of eligible patients. Over 80% of pediatric candidates died awaiting transplantation in some African countries. This underscores the need for context-specific innovations addressing regional biological, socioeconomic, and infrastructural realities. Recent advancements remain geographically constrained and do not completely address persisting challenges. While TransMedics’ normothermic perfusion system extends cold ischemia tolerance for up to 6 h, it still does not prevent mitochondrial injury during prolonged transports.[6] Similarly, the HeartMate 3 achieves an 83% three-year survival in adults; however, it is inadequate for pediatric patients and those with biventricular failure.[7] These innovations highlight the urgent need for scalable, holistic solutions that are adaptable to diverse health care ecosystems. Persistent Challenges in Modern Transplantation: Despite technological leaps, two fundamental barriers perpetuate global inequities in transplantation access. Critical donor shortage is the first major crisis, which originates from complex sociocultural, legal, and logistical barriers. In Asia, cultural beliefs about bodily integrity and ancestral reverence, along with underdeveloped legal frameworks, suppress organ donation rates to <3 per million population. This contrasts with Spain’s ‘opt-out’ system, where citizens are presumed to be donors unless they explicitly refuse, leading to the achievement of a donation rate of 40 per million, the highest in the world. Geographical constraints exacerbate shortages in nations that include the United States, where >35% of potential donor hearts are nonviable when transported over 500 miles due to cold ischemia limitations. These inefficiencies highlight the need for solutions that have the collective goal of equitable transplant access, such as drone-based organ delivery. Another challenge is the technical complexity of complicated transplant surgeries. Multiorgan en bloc transplants (e.g., heart–liver or heart–kidney) require precision in vascular anastomoses and ischemia time management. The risk of primary graft dysfunction (PGD) escalates in multiorgan cases, especially when preexisting organ failure. The incidence of postoperative complications following heart transplantation in patients with complex congenital heart diseases, such as double right ventricular outlets and transposition of large arteries, is high. This difference can be attributed to abnormal anatomical structures, increased pulmonary vascular resistance, immunosuppression, and infection risks. Of these, procedures that involve dextrocardia (right-sided heart) have the highest technical barriers. Dextrocardia highlights the need for anatomical ingenuity and advanced perioperative support, as mirrored anatomy complicates donor–recipient alignment. The rapid evolution of MCS technologies underscores global inequities in advanced heart failure care. While China has achieved a 20-fold expansion of extracorporeal membrane oxygenation (ECMO) centers over the last decade, the long-term ventricular assist device (VAD) adoption and application rate is low.[8] This dichotomy reflects larger global patterns: In low-income nations, MCS-related mortality rates are triple those of high-income countries (3.2:1 ratio), which is exacerbated by fragmented supply chains for device maintenance and a critical shortage of specialized intensivists. Pediatric heart failure management faces particularly dire constraints because no third-generation VADs are available. The HeartMate 3 remains the only option for children; however, its use is limited due to thoracic capacity and low-flow physiological demands. These disparities persist despite MCS’s proven potential, thus revealing an urgent need for cost-adaptive innovations, global training partnerships, and pediatric-focused device development. Wuhan Protocol: Addressing Global Challenges through Innovation: Wuhan Union Hospital (Hubei, China) has developed the ‘Wuhan Protocol’ to address current challenges in heart transplantation and improve the 10-year survival rate from 54.7% (The International Society for Heart and Lung Transplantation) to 73%: (1) an innovative donor heart preservation technique; (2) optimized surgical approaches for complex heart transplantation; (3) independently developed MCS systems (Extra-VAD, DuoCor, D-miniCor, and D-Shant); and (4) precision perioperative organ support. Innovative donor heart preservation technique: The current golden standard for donor heart preservation in Histidine-Tryptophan-Ketoglutarate/University of Wisconsin solutions is limited to a cold ischemia time of <4 h. Wuhan Union Hospital developed a ‘rapid arrest combined with prolonged energy storage’ method. This led to establishing a novel “cold crystalloid combined with organ preservation UW solution” approach in which a heart was held in a triple-layer sterile bag containing UW solution in a custom-constructed transport device that maintained 4°C constant hypothermia with integrated anti-collision stabilization. The donor heart with CIT (cold ischemic time) >4 h underwent intraoperative reperfusion (500 mL UW solution (The University of Wisconsin solution) at 4°C) before implantation. This established protocol effectively allowed safe CIT from 4 to 8 h.[9] The utilization rate of donor hearts preserved >4 h increased to 77.4%. Optimized surgical approaches for complex heart transplantation: Conventional heart transplantation techniques often fail to meet the surgical demands of complex congenital heart disease or situations involving donor–recipient anatomical or size mismatches. We pioneered the “left atrial precision volume adaptation” technique, which uses the anatomical location of the left atrial ridge to accommodate a point-to-point atrial cuff anastomosis. This strategy allows for accurate accommodation of the donor left atrium to the recipient anatomy to counter issues related to size mismatch. Auxiliary methods, such as enlarging the pericardial space and delaying closure of the chest, facilitate transplantation in difficult clinical situations. Using this method, we are able to change the acceptable donor-to-recipient body weight ratio from the standard international ratio of 2.0 to 6.5, thus substantially enlarging the number of potential donors. After considering anatomical challenges, we developed the “cardiac rotational positioning” technique in which the donor heart is rotated approximately 90° clockwise on the left atrial axis. The donor acquisition includes an en bloc harvest of the superior vena cava (SVC) with an extended inferior vena cava (IVC) to accommodate anatomical differences. The recipient cardiectomy with IVC is completed in continuity, leaving a long atrial cuff. The rotated positioning enhanced spatial orientation, hemodynamics, and enabled a 40% reduction in procedure time.[10] We completed the world’s largest series of 10 right-sided heart transplantations with a surgery success rate of 100%. Advancements in novel mechanical circulatory support devices development: MCS represents a pivotal advancement in heart failure management; it serves as a critical therapeutic option for end-stage patients requiring bridging or those who are ineligible for transplantation. For patients with advanced heart failure accompanied by cardiogenic shock, we developed Extra-VAD, an intelligent magnetically levitated extracorporeal ventricular assist device with a unique percutaneous implantation pathway. The 30-day post-transplant survival rate reached 88.9%, substantially surpassing outcomes associated with conventional ECMO bridging strategies domestically (<50%).[11] We created DuoCor, the world’s first integrated dual ventricular assist system for biventricular support for patients with refractory biventricular failure. This paradigm shift enables long-term circulatory support for complex patients who are awaiting transplantation or who are not offered transplantation due to severe pulmonary hypertension or HLA sensitization. Our team also designed D-miniCor, the world’s smallest magnetically levitated ventricular assist device for children. Clinically used in a total of 16 cases, the 6-month survival rate was 87.5%. We developed the world’s first retrievable precision-controlled atrial shunt device, D-Shant for patients with end-stage heart failure experiencing pulmonary congestion. It reduces left atrial pressure and alleviates heart failure symptoms. D-Shant has been used in 320 cases, and it has achieved 100% procedural success, with 58.2% of patients demonstrating improved cardiac function at 6-month follow-up.[12] The above MCS devices reduce medical expenses by over 50% compared to similar imported products. Precision perioperative organ support: We implemented an optimized hemodynamic strategy combining VA-ECMO with the D-Shant atrial shunt device for patients with end-stage heart failure who need bridging to transplantation. This approach enables fully minimally invasive ECMO implantation while effectively decompressing the left atrium. Intra-aortic balloon pump (IABP) support has been used in ischemic cardiomyopathy cases, while the Extra-VAD system has served as a bridge-to-decision intervention in acute cardiogenic shock. A staged MCS algorithm was systematically implemented for post-transplant low cardiac output syndrome, as initial IABP therapy augments cardiac output by approximately 10% while reducing ECMO dependency by 32%. Synchronized IABP-VA ECMO with pulsatile flow preservation has been activated when myocardial recovery remained insufficient, demonstrating an 18% improvement in 30-day survival compared to traditional ECMO. Future Directions: The following strategies will drive the next evolution of cardiac transplantation. First, donor pools will be expanded via Donation after Cardiac Death (DCD) heart transplantation. Although conventional Donation after Brain Death protocols dominate, DCD procurement could expand the global donor pool by 30–40%. Pioneering work at Sydney’s St. Vincent’s Hospital has demonstrated 85% 1-year survival with DCD hearts using normothermic regional perfusion, yet challenges persist, namely, irreversible ischemic injury during the 30-minute “hands-off” period and mitochondrial dysfunction. Concurrently, machine perfusion systems integrating real-time metabolomics profiling (e.g., lactate/pH-guided perfusion) could be optimized to salvage marginal DCD grafts.[13] Second, the evolution of MCS is poised to overcome limitations through biomimetic pulsatility and intelligent hemodynamic adaptation. Modern magnetically levitated biventricular devices integrate closed-loop control algorithms that are capable of processing >10,000 hemodynamic data points per minute, including coronary perfusion pressure and cerebral oxygen saturation. Concurrent breakthroughs in hemocompatible materials, such as endothelialized nanocomposite coatings, demonstrate 80% reductions in platelet adhesion in preclinical models, substantially mitigating long-term MCS-associated morbidity. For pediatric patients, miniaturized pumps with impeller diameters as small as 10 mm, combined with expandable cannula designs, now support infants weighing under 3 kg, a pivotal advancement for a cohort historically excluded from durable mechanical support. Globally, collaborative efforts, such as National Institutes of Health funded pediatric VAD programs, are accelerating the translation of these innovations, ensuring equitable access to life-saving technologies across diverse clinical and socioeconomic contexts. Third, artificial intelligence (AI) is redefining post-transplant management through three synergistic innovations. An AI platform will integrate multi-dimensional biological data (genomic, proteomic, and real-time clinical metrics) to allow early prediction of critical post-transplant events, such as cardiogenic shock, PGD, and acute rejection. Moreover, the integration of continuous learning algorithms ensures ongoing optimization of predictive accuracy and therapeutic guidance as real-world evidence accumulates. Fourth, xenotransplantation will become more common. A 2022 breakthrough porcine-to-human heart transplant (57-day survival) exposed both progress and persisting hurdles. Although clustered regularly interspaced short palindromic repeats-mediated α-Gal knockout prevented hyperacute rejection, late-onset thrombotic microangiopathy and coagulopathy led to graft failure.[14] Strategies target these limitations through multi-gene editing (NOTCH2/CD46/SLA-I) to stabilize porcine endothelial function and inhibit platelet aggregation via αvβ3 integrin blockade during ex vivo perfusion. Concurrently, chimeric cell therapies combining porcine hematopoietic stem cells with recipient-derived regulatory T cells aim to induce immune tolerance, thus achieving 180-day rejection-free survival in non-human primates without immunosuppression. The Wuhan Protocol was established through decades of rigorous clinical refinement. It is a transformative cardiac transplantation framework that elevates outcomes by expanding the donor pool, overcoming technical barriers in complex transplantation, improving survival in MCS-bridged cases, and optimizing perioperative multi-organ precision support. Future real-world multicenter trials are needed to consolidate its evidence base. The Wuhan Protocol integrates theoretical and practical innovation to redefine the transplantation field in China and also offers a scalable model to advance global standards, ultimately making end-stage heart failure a treatable condition worldwide. Funding This work was supported by the National Natural Science Foundation of China (No. 82470423) and Hubei Provincial Natural Science Foundation Projects (No. JCZRYB202500142). Conflits of interest None.