The journey started in 1905 with Alexis Carrel and Charles Guthrie at the University of Chicago [1]. During experiments on vascular anastomosis, the researchers performed limb reimplantation and organ transplants, including the heart. In one case, a small dog’s heart was transplanted into a larger dog’s neck, where it began beating for about an hour after surgery. However, due to a lack of aseptic techniques, thrombi formed, ending the experiment within two hours [2].

The pioneer of this field was Dr. Demikhov, who performed the first intrathoracic canine heart transplants in the early 1950s [3]. He left the recipient’s heart in place yet excluded it from the circulation by ligating the great vessels. Of the 22 canines, one regained consciousness after anesthesia but died 15 hours post-surgery due to superior vena cava thrombosis.

Based on Dr. Demikhov’s findings, the next milestone was orthotopic transplantation. In 1953 Neptune et al. [4] dedicated themselves to this landmark achievement and initiated the use of topical hypothermia.

Four years later Webb and Howard [5] preserved canine hearts by instilling them with cold potassium citrate before transplanting them. With this finding, they paved the way for long-distance organ procurement.

In 1958 Golberg et al. [6] at the University of Maryland performed the first orthotopic heart transplant in dogs, pioneering the left atrial cuff technique, which became the standard for decades. Around the same time, Webb et al. [7] used hypothermic preservation, achieving survival times of 30 to 450 minutes. Cass and Brock [8] refined the procedure by introducing right atrial anastomosis, further shaping modern transplantation methods.

Heterotopic heart transplantation (HHT) is a rare procedure in which recipient’s native heart is left in place, and the donor heart is transplanted into the patient’s thoracic cavity. One of the key advantages of this approach is that the patient’s native heart continues to function alongside the donor’s heart, providing additional circulatory support [13]. This protective role was once considered the primary benefit of HHT, but its importance diminished following the introduction of cyclosporins in the 1980s, which significantly improved rejection management.

Another potential benefit of HHT is its utility in cases of donor-recipient size mismatch, in which orthotopic heart transplantation (OHT) may not be feasible. In such scenarios, HHT can be considered to shorten waiting times without significantly increasing morbidity [14].

HHT may also be valuable in pediatric patients with advanced cardiomyopathies, where the scarcity of appropriately sized donor hearts presents a major challenge. In these cases, HHT can serve as a bridge to transplant, reducing waiting time and allowing for left ventricular unloading. This unloading may, in some instances, support the recovery of the native heart’s function [15].

Taegtmeyer et al. [16] postulated that patients undergoing HHT may experience lower systolic blood pressure compared to those receiving OHT. This observation is based on the hypothesis that the retained native heart valve continues to contribute to the homeostatic regulation of blood pressure.

Despite these potential advantages, HHT is associated with severe complications. The presence of an additional heart in the thoracic cavity can compress the right lung, particularly its lobes, leading to atelectasis, impaired ventilation, and an increased risk of pulmonary infections [17]. In patients with ischemic cardiomyopathy and pre-existing angina pectoris, symptoms may persist even after transplantation, negatively impacting quality of life. Furthermore, progression of native valvular disease can continue postoperatively and may be detected during follow-up evaluations [13].

Patients with dilated cardiomyopathy and an enlarged native heart are at higher risk of postoperative embolic events. To mitigate this risk, anticoagulation therapy is recommended, although this introduces additional challenges and risks following transplantation.

Currently, OHT remains the standard and preferred technique when a suitable donor organ is available. Due to advancements in immunosuppressive therapies and availability of mechanical circulatory support, HHT is now used infrequently. However, it may still be considered in select cases, depending on patient prognosis and available treatment options.

OHT is the established gold standard for patients requiring heart transplantation. Biatrial OHT was introduced by Lower and Shumway [18] in 1960 and is a still widely utilized technique due to its simplicity and thereby inherent reduced ischemia time. However, this technique is known for inferior hemodynamic outcomes as well as higher postoperative arrhythmia rates. In 1990 Yacoub and his group [19] introduced bicaval OHT. This method requires, in addition to the atrial anastomosis, a separate caval anastomosis. Due to the more complex surgical procedure, longer surgery times are expected; however, hemodynamics are better, and arrhythmia rates are lower [20].

A recent systematic review by Zijderhand et al. [21] looked at short-term outcomes—such as tricuspid regurgitation, mitral regurgitation, permanent pacemaker implantation rates as well as long term survival of patients undergoing a bicaval versus a biatrial OHT, demonstrating more favorable outcomes in the bicaval group across all aspects.

Immunosuppression has been a pivotal factor in enhancing patient outcomes after HTx. Initially, the focus was on high-dose corticosteroids and azathioprine. The introduction of calcineurin inhibitors (CNIs), such as tacrolimus or cyclosporin further improved graft survival rates. Subsequent incorporation of antimetabolites such as mycophenolate mofetil and signal transduction inhibitors like sirolimus and everolimus further optimized the process. The International Society for Heart and Lung Transplantation (ISHLT) currently recommends a triple therapy consisting of Calcineurin Inhibitors, Antimetabolites and Corticosteroids [22]. Strict post-transplant monitoring through endomyocardial biopsies, echocardiography and biomarker assessments aims to detect potential graft rejection at an early stage.

The correct balance between over- and underimmunosuppression is key. Underimmunosuppression can cause rejection, and overimmunosuppression can lead to higher rate of infections, nephrotoxicity as well as malignancies.

ABO incompatibility (ABOi) has traditionally been a contraindication for organ transplantation due to the high risk of hyperacute rejection. This occurs because blood group antigens are not only present on red blood cells but also on endothelial cells of tissues and organs, where they can activate the complement system. This type of immune tolerance begins to develop during infancy [23]. ABOi heart transplantation (ABOi HTx) in adults presents unique immunological challenges, necessitating specialized desensitization protocols to ensure graft survival and reduce the risk of antibody-mediated rejection. Desensitization protocols in adults ABOi HTx are designed to reduce isohemagglutinin titers and lower the risk of antibody-mediated rejection (AMR). These protocols often include plasmapheresis or immunoadsorption to remove circulating anti-ABO antibodies, combined with pharmacologic agents such as intravenous immunoglobulins, rituximab (a monoclonal antibody) and sometimes bortezomib or eculizumab to suppress B-cell and plasma cell activity [24]. The timing and intensity of these therapies vary depending on the patient’s antibody levels and sensitization status. Some centers utilize pretransplant desensitization regimes followed by aggressive post-transplant immunosuppression to maintain low antibody levels and prevent AMR.

In 2001 West et al. [25] reported a case series involving ten infants who underwent ABOi HTx demonstrating that this procedure can be safely performed in early infancy, prior to the onset of isohemagglutinin production. The aim of this approach is to expand the donor pool, especially within the pediatric population, where high mortality rates are observed among children born with congenital heart diseases on the waiting list. This undertaking is based on the relative immaturity of their immune system, which in turn leads to better acceptance of transplanted organs than at any later time in life. Long-term data have shown comparable outcomes in the ABO and ABOi groups in terms of acute rejection and graft vasculopathy [26]. A retrospective database analysis by Chauhan et al. [27] analyzed the data of 1368 infants under one year of age, who underwent ABO-incompatible transplants and found that these transplants did not increase risk of mortality, acute, rejection, or prolonged hospital stay. One, five-, and ten-year survival rates were comparable between ABO-compatible and ABO-incompatible groups (90% vs. 88%, 82% vs. 79%, and 77% vs. 73%, respectively). Further advances in pediatric ABOi and abdominal ABOi transplantations led to the exploration of adult ABO incompatible HTx. An analysis of the ISHLT registry reported no difference in the incidence of death or re-transplantation between ABO and ABOi HTx patients who were transplanted after 2005 [23]. Although ABOi HTx in adults is less common than in pediatric populations, emerging data suggest that with proper desensitization strategies, outcomes can be comparable to those of ABO-compatible transplants [28].

Many strategies have been put in place to keep up with the growing demand of donor hearts. One of these is donation after cardiac death (DCD-HTx). A center-level analysis by Urban et al. [29] demonstrated a dramatic increase in transplant rates (from 67 vs. 207 per 100 person-years), doubling the chances of receiving a transplant, without significant differences in waitlist mortality in the USA While transplantations were previously limited to organs from brain-dead donors, DCD donations have become a feasible alternative in recent years. DCD criteria vary across different countries, shaped by legal, ethical and medical frameworks. While the consensus is similar, the exact definitions differ on when and how DCD can occur. The first key distinction in organ donation policies is whether a country follows an opt-in or opt-out system. In opt-out countries—like the UK, Spain, the Netherlands, and Austria—individuals are presumed to consent to organ donation unless they have explicitly declined. In contrast, opt-in countries such as Germany, Canada, and Japan require individuals to actively register their consent. Another important framework is the Maastricht classification for Donation after Circulatory Death (DCD). Categories I and II refer to uncontrolled DCD, typically involving sudden or unexpected deaths. Categories III to V involve controlled DCD, including situations where life support is withdrawn or, in some countries, legally permitted euthanasia [30]. In most countries, a mandatory ‘stand-down’ period of about five minutes is instituted after circulatory arrest before organ retrieval can begin, to ensure that irreversible death has occurred [30].

DCD donations raise concerns regarding ischemic injury, graft dysfunction, and the long-term risk of allograft vasculopathy. With the introduction of ex vivo perfusion (EVP) devices and normothermic regional perfusion (NRP), heart transplantations from donation after circulatory death are increasingly becoming a feasible option [31]. Extraction teams need to be fast to ensure that no lasting ischemic injury is sustained by the donor heart. In the case of EVP, the heart is retrieved and perfused in a machine in a warm beating state. In the case of NRP, after sternotomy, the patient is canulated and connected to an extracorporeal circuit like during regular cardiac surgery. Due to ethical concerns the aortic arch vessels are ligated or transected to prevent any blood flow to the cerebrum. DCD heart transplantation is emerging as a safe, scale and impactful strategy to expand the donor pool—both in the USA and internationally. High-impact studies support its adoption, demonstrating similar patient outcomes to brain-dead donors while significantly increasing the donor pool [32]. Nevertheless, further research is needed to refine protocols for warm ischemia time, donor selection, and recipient matching [33, 34].

According to Eurotransplant statistics from 2024, more than 13,000 patients were on the waiting list for an organ in the eight Eurotransplant regions alone. This signifies that human donors alone cannot meet the rising organ demands; hence, alternatives must be found. Due to similarities in size and physiology, pig hearts are considered the most compatible when considering xenotransplants [35]. The main concern in xenotransplantation is a cross-species molecular incompatibility [36]. Advances in gene editing, such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), have enabled the deletion of key antigens that trigger hyperacute rejection, particularly alpha-1,3-galactosyltransferase (GalT). These modifications, along with transgenic expression of human complement-regulatory proteins, have significantly improved graft survival in preclinical models [37]. On January 7, 2022, the world’s first successful pig-to-human cardiac xenotransplantation was performed in Baltimore. A 57-year-old patient suffering from end-stage nonischemic cardiomyopathy received a genetically modified pig heart [38]. The patient died two months after the procedure from heart failure. Although there were no direct signs of organ rejection, the multidisciplinary team of physicians assumed that the patient became more vulnerable to organ rejection through his own antibodies, since he could not be prepped with the standard immunosuppression regiment due to his poor clinical state prior to transplant. Furthermore, a latent porcine cytomegalovirus was found in the transplanted heart during autopsy. Lawrence Faucette was the second patient to receive a modified porcine heart in 2023, Maryland. Although the transplant initially showed promising results, he unfortunately passed away six weeks after the transplant due to signs of organ rejection [39]. Xenotransplantation’s advancement is hindered by a complex set of scientific, ethical, and practical challenges. The primary obstacle lies in overcoming immunological barriers such as hyperacute rejection and long-term graft survival, despite recent progress with genetically modified pig donors [40]. Ethically, concerns persist around animal welfare, the moral status of genetically engineered animals, and the potential for zoonotic disease transmission, which could become a public health burden [41]. Practically, ensuring rigorous long-term monitoring, developing regulatory frameworks, and achieving public trust remain major hurdles before widespread clinical implementation can occur. Despite these issues, ongoing clinical trials and experimental procedures continue to shape the future of xenotransplantation as a viable solution to end-stage organ failure.

It has been suggested that conducting a greater number of xenotransplantation procedures is essential to establish a learning curve and improve long-term outcomes. While significant challenges remain, xenotransplantation may offer a promising solution to the ongoing organ shortage crisis [42].

For decades, static cold storage (SCS) has been the standard method for preserving donor hearts. In this technique, the heart is flushed with a cold cardioplegic solution and placed in an ice bath at 4 °C. While hypothermia slows cellular metabolism and delays tissue injury, prolonged ischemic time—typically beyond 4 hours—leads to increased risk of graft dysfunction and post-operative complications [38, 43, 44]. One type of injury that may occur during long transportation times with prolonged ischemia is ischemia-reperfusion injury (IRI) [45]. This process becomes evident postoperatively, with the patient requiring higher doses of inotropes, pressors and temporary mechanical circulatory support in the form of extracorporeal membrane oxygenation (ECMO) or an intra-aortic balloon pump [46]. To address these limitations, normothermic machine perfusion (NMP) has been introduced as a novel approach that maintains the donor heart in a warm, perfused, and beating state during transport. The Organ Care System (OCS) by TransMedics, for example, allows continuous delivery of oxygen and nutrients while removing waste products. This technology enables real-time functional monitoring, such as lactate clearance, coronary flow, and visual contractility assessment, providing a more accurate evaluation of marginal donor hearts. This prevents ischemic injury and allows the resuscitation and regeneration of marginal hearts to be procured [46]. A single center experience by Russo et al. [43] showed that, eight years post-transplant, the overall survival rate was 57.9% in the OCS group compared to 73.7% in the cold storage (CS) group, this difference was not statistically significant. Rates of freedom from cardiac allograft vasculopathy (CAV) were higher in the OCS group (89.5%) than the CS group (67.8%), with a p-value of 0.13. Similarly, freedom from non-fatal major adverse cardiac events (NF-MACE) was observed in 89.5% of OCS patients versus 67.5% in CS group. Survival without graft-related death at eight years was identical in both groups at 84.2%. Additionally, no statistically significant differences were found between the groups regarding rejection. An early USA experience reported in JACC found that NRP was associated with superior-short term survival and lower organ rejection rates when compared to direct procurement protocols (DPP) (NRP 1.4% vs DPP 9.6%) [47]. Furthermore, recent literature notes FDA approval of the OCS for DCD hearts and describes ex vivo normothermic perfusion’s ability to assess and preserve marginal donor hearts-extending the preservation times, minimizing ischemia perfusion injury and increasing geographic transplant reach [46].

The Paragonix SherpaPak® (Getinge, Sweden) Cardiac Transport System preserves the heart in a cold cardioplegic solution. It uses specialized phase-change cold packs to keep the temperature consistently between 4–8 °C. The intended storage time within the SherpaPak is up to 4 hours. The system holds the donor heart in a preservation solution within a sealed, pressure-regulated, rigid container. This ensures uniform cooling, protects against cold-related damage, maintains a stable temperature, and allows for continuous monitoring and data tracking. Other more experimentally used transport systems include XVIVO Heart Perfusion System (XVIVO Perfusion AB, Gothenburg, Sweden), LifeCradle® (TransMedics Group, Inc. Andover, Massachusetts, USA) as well as OrganOx metra (OrganOx Ltd. Oxford, UK). The first two are still undergoing trial phases, and the latter is more focused on liver procurement (See Table 1).

Subzero organ preservation, particulary through supercooling techniques, offers promising advancements over traditional cold storage by potentially enabling long-term preservation without ice formation. Recent developments show that supercooling can successfully preserve organs such as livers, for up to four days, although significiant challenges remain before widespread clinical application becomes feasible.

To minimize IRI and support cellular health during preservation, various cardioplegic solutions have been developed, each with unique biochemical properties tailored to mitigate cellular stress. These solutions typically include electrolytes for membrane stabilization, buffers to maintain physiological pH, energy substrates to support residual metabolism, and antioxidants to limit oxidative damage [48]. The first widely adopted solution was Euro Collins in the 1960s, followed by the University of Wisconsin (UW) solution, which incorporated impermeants and glutathione for enhanced cytoprotection, in the 1980s [49]. Today, over 150 commercially available solutions exist, with Histidine-Tryptophan-Ketoglutarate (HTK), UW and Celsior being the most widely used, each differing in their concentration of histadine, mannitol and other additives [50, 51]. Another solution that is not yet frequently used is HTK-N, which is characterized as an organ preservation solution that is electrolyte-balanced, enriched with iron chelators and amino acids, and contains an improved buffering system to enhance its protective effects [52] (See Table 2). New techniques like normothermic perfusion, combined with these solutions, show promise for restoring marginal or previously rejected donor hearts, such as those from donation after circulatory death [46].

Efforts to optimize these solutions have led to the development of perfusion fluids tailored for machine perfusion systems, enhancing myocardial protection during ex vivo preservation.

While heart transplantation (HTx) remains the gold standard for treating end-stage heart failure, the advent of advanced cardiac resynchronization therapies, including defibrillators and left ventricular assist devices (LVADs), have significantly improved prognosis in recent years [53, 54]. LVADs have shown particularly strong outcomes, contributing significantly to improved survival and quality of life in patients not immediately eligible for transplant.

The REMATCH trial was pivotal in demonstrating the clinical benefits of LVADs, showing a one-year survival rate of 52% in the device group compared to 25% in the medical treatment group, although early devices like the HeartMate I were associated with complications such as infections, bleeding, and pump failure, which severely impacted quality of life and long-term outcomes [55, 56]. Continuous improvements in LVAD technology have led to newer devices such as the HeartMate 3, a third generation, magnetically levitated system that produces a pseudopulse. The MOMENTUM 3 study demonstrated superior hemocompatibility-related results, including reduced rates of pump thrombosis, decreased stroke and gastrointestinal bleeding rates[57].

Today, modern LVAD systems achieve two-year survival rates comparable to heart transplantation. However, complications persist—most notably driveline infections, often caused by skin flora [58]. The MOMENTUM 3 and ADVANCE trials reported infection rates of 23% and 26.7% within two years post-implantation, respectively, sometimes necessitating antibiotic treatment or surgical intervention [57, 59]. Despite this, a five-year overall survival in HeartMate 3 patients reached 58.4%, reinforcing the role of LVADs as a long-term solution for patients who are not transplant candidates [53]. These outcomes, in combination with limited donor organ availability, have established LVADs as a robust alternative to transplantation in carefully selected patients.

In acute scenarios, short term MCS options such as extracorporeal membrane oxygenation (ECMO) and the Impella 5.5 provide critical mechanical circulatory support. ECMO, particularly veno-arterial (VA) ECMO is used as a direct bridge to transplant. The United Network for Organ Sharing (UNOS) prioritizes these cases due to the severity of illness [43]. However, outcomes remain poor. For example, Lim et al. [60] reported a one-year survival of only 72.9% in ECMO-bridged transplant recipients compared to 95.8% in non-ECMO patients. Post-transplant mortality at 30 days in the ECMO group has been reported as high as 30%, mainly due to multi-organ dysfunction and complications arising from critical illness [61]. Additionally, prolonged ECMO support increases the risk of mortality and adverse outcomes, making it an option typically reserved for cases where other strategies are not feasible [62].

When feasible, transitioning patients from ECMO to durable MCS like an LVAD, once end-organ functions have stabilized, is often preferred. Alternatively, the Impella 5.5 microaxial flow pump has emerged as a promising short-term MCS device. It has been successfully used as a bridge to both transplantation and LVAD implantation. A Mayo Clinic study reported a one-year post transplant survival rate of 91% in patients supported with the Impella 5.5, with only 4% experiencing rejection requiring further treatment [63, 64]. Similarly, Paghdar et al. [65] reported a 95% 1-year survival in patients aged 50 and above, who received transplants after axillary Impella 5.5. support, with outcomes exceeding the national averages [66].

Despite classification as a short term MCS (approved for use up to 29 days in the United States of America), clinical experiences have shown that Impella 5.5. can provide stable support for longer durations with fewer complications compared to ECMO. The device allows for patient mobilization, facilitates left ventricular unloading, minimizes left ventricular distention—issues that can be exacerbated by ECMO’s afterload-increasing effects. Furthermore, axillary implantation enables outpatient management in some cases, adding to its clinical versatility. While current UNOS listing criteria group it with VA ECMO, emerging data suggest that Impella 5.5. should be considered independently, as its support profile and clinical outcomes more closely align with those of longer-term MCS devices.

In summary, MCS therapies now play a critical and evolving role in the management of advanced heart failure, particularly as bridges to transplantation and as destination therapy. Advances in both durable and short-term devices have expanded the therapeutic arsenal for clinicians, offering tailored support strategies that can improve survival, reduce complications, and extend the transplant window for select patient populations.