Cardiac transplantation: A review of current status and emerging innovations

Abstract

Heart transplantation (HTx) is a life-saving procedure for patients with end-stage heart failure and has undergone remarkable advancements since the first successful transplant in 1967. The introduction of cyclosporine in the 1970s significantly improved patient outcomes, leading to a global increase in transplants, including in India, where the practice has grown despite initial challenges. This review provides an extensive overview of HTx, focusing on current practices, technological advancements, and the ongoing challenges the field faces today. It explores the evolution of surgical techniques, such as minimally invasive and robotic-assisted procedures, and the management of posttransplant rejection through tailored immunosuppressive strategies, including new monoclonal antibodies and personalized therapies. The review also highlights emerging innovations such as mechanical circulatory support devices and xenotransplantation as potential solutions to donor shortages while acknowledging the ethical and logistical challenges these approaches entail. Furthermore, the analysis delves into the implications of using extended-criteria donors and the role of multidisciplinary teams in evaluating absolute and relative contraindications. Despite the progress made, the persistent issues of organ scarcity and ethical concerns underscore the need for ongoing research and innovation to further enhance the efficacy, safety, and accessibility of HTx.

Key Words: Heart transplantation; End-stage heart failure; Donor selection; Immunosuppression; Mechanical circulatory support; Xenotransplantation; Regenerative medicine; Surgical techniques; Donor management; Transplantation outcomes

Core Tip: Cardiac transplantation remains a vital treatment for end-stage heart disease. Recent advancements in artificial hearts, mechanical circulatory support devices, and xenotransplantation have tackled both technological and ethical challenges, providing new solutions for managing severe heart failure and addressing organ shortages. Innovations in regenerative medicine and stem cell therapy are offering fresh approaches to cardiac repair, while remote monitoring technologies are improving post-operative care and outcomes. Ongoing research is transforming heart transplantation, aiming to enhance patient prognosis and quality of life while addressing existing limitations, and shaping the future of this crucial field.

INTRODUCTION

A heart transplant (HT) is a life-saving surgical procedure in which a patient’s failing heart is replaced with a healthy heart from a deceased donor. This treatment is primarily reserved for patients with advanced heart failure, where the ability of the heart to pump blood is significantly impaired. Typically, these patients have a history of long-standing heart disease that progressively worsens despite medical interventions[1]. Since the first successful HT in 1967, heart transplantation (HTx) has become a widespread and crucial therapeutic option for end-stage heart disease. The development of cyclosporine immunosuppression in the 1970s significantly improved the success rate of these transplants[2]. Over the years, HT rates have steadily increased worldwide, with a notable surge in recent years. As of 2021, HT rates reached 106.2 transplants per 100 patient-years, the highest in the past decade[3]. In the United States, the number of HTs has markedly increased, particularly since 2011, with the number of adult transplants increasing by 85.8% to 3668 in 2022. Pediatric HTs have also increased, although the rate has recently declined. However, advancements in donor heart procurement and transplantation techniques have improved posttransplant survival rates[4]. In India, HTs rose sharply, from 53 in 2014 to 241 in 2018, before slightly declining to 187 in 2019[5].

The first HT was performed by doctor Christiaan Barnard in 1967 at Groote Schuur Hospital in Cape Town, South Africa[6]. Despite the initial patient surviving only 18 days, the procedure marked a groundbreaking moment in medical history and set the stage for future advancements in cardiac transplantation[6]. The first HT in India was attempted by doctor Prafulla Sen in 1968, shortly after the first successful transplant worldwide[7]. However, progress in the field has been slow due to various challenges, including a lack of healthcare infrastructure and legal barriers. The first successful HT from a brain-dead donor in India was performed in 1994 at the All-India Institute of Medical Sciences by Professor Venugopal[8]. Shortly thereafter, doctor Cherian KM conducted a transplant at the Madras Medical Mission. Progress in the field was slow until 2012, with only approximately 30 transplants performed nationwide[9]. Tamil Nadu was a pioneer in streamlining organ donation and distribution processes, supported by significant contributions from nongovernmental agencies[10].

The primary objective of this review is to provide a comprehensive overview of the current status of HTx and to explore the latest innovations in the field. This review provides a comprehensive overview of HTx by examining current practices, including patient selection, donor management, surgical techniques, immunosuppressive strategies, and outcomes. It also explores new developments, such as artificial hearts, mechanical support systems, and advancements in xenotransplantation (XTx), regenerative medicine, and monitoring technologies. The review also discusses the current challenges, including ethical concerns, organ shortages, and ongoing research, while also considering future possibilities and breakthroughs that could improve patient outcomes and expand treatment options.

LITERATURE REVIEW

Search strategy

A narrative and comprehensive search was conducted across multiple electronic databases, including PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar. To optimize the search strategy, a combination of medical subject headings terms and keywords was employed. The relevant terms included “Heart Transplantation”, “End-Stage Heart Disease”, “Cardiac Transplantation”, “Donor Selection”, “Immunosuppression”, “Heart Failure”, “Mechanical Circulatory Support”, “Artificial Hearts”, “Xenotransplantation”, “Regenerative Medicine”, “Stem Cell Therapy”, “Gene Editing”, “Personalized Medicine”, “Heart Disease Innovations”, “Organ Preservation”, “Post-Transplant Outcomes”, and “Survival Rates”. Various combinations of these terms were used to ensure a comprehensive search.

Inclusion criteria

Studies and articles were considered for inclusion if they contributed to the historical context, development, or evolution of HTx. While the primary focus was on peer-reviewed research, historical documents, books, and gray literature were also included to provide a comprehensive narrative. To ensure a thorough exploration of the field, no publication date limits were imposed. Only articles published in English were considered.

Data collection

We began by screening the search results on the basis of titles and abstracts to find articles and documents that were relevant to our topic. During this initial step, we excluded any studies that did not fit the scope of our narrative review. Once we had a short list, we conducted a thorough full-text review of the remaining articles and documents.

Assessment criteria

Given the narrative nature of this review, formal quality assessment tools such as the Cochrane Risk of Bias Tool, the Assessment of Multiple Systematic Reviews checklist, and the Newcastle-Ottawa Scale were not applied. These tools, typically used for systematic reviews, were deemed unnecessary for our approach. Instead, sources were evaluated on the basis of their relevance, historical accuracy, and credibility.

CURRENT STATUS OF HTX

Indications for HTx

HTx remains a critical intervention for patients with end-stage heart failure, offering a life-saving option when all other medical or surgical treatments have failed. In adults, the leading causes of HTx are nonischemic cardiomyopathy (53%) and ischemic cardiomyopathy (38%). Other conditions, such as valvular heart disease and the need for retransplantation, account for a smaller portion of cases[11]. The stepwise evaluation process for HT eligibility is detailed in Table 1. In outpatient settings, HTx should be considered for patients with chronic heart failure who continue to have debilitating symptoms during exertion while receiving guideline-directed medical therapy (GDMT). These patients are typically classified as New York Heart Association class 3 or class 4 or American College of Cardiology stage D. Frequent hospitalizations (≥ 2 admissions within 12 months) for heart failure exacerbation while on GDMT are also an indication to assess the need for transplant. Other signs include worsening renal function due to cardiorenal syndrome; side effects from medications such as hypotension; contraindications such as renal failure that prevent the use of GDMT; worsening right ventricular function; increasing pulmonary artery pressure due to left heart failure; and frequent ventricular arrhythmias despite optimal medical and electrophysiological treatments. Additionally, symptoms such as anemia, weight loss, hyponatremia, or liver dysfunction caused by heart failure may also lead to a referral for transplantation[12].

Table 1 Stepwise evaluation process for heart transplant eligibility.

Step	Criteria	Consideration	Outcomes
Initial assessment	End-stage heart failure	Failure of medical and surgical therapies	Proceed to next step if criteria met
	Severe functional limitations (NYHA class III-IV)	Patient quality of life severely affected
Evaluation of comorbidities	Presence of comorbid conditions (e.g., diabetes, renal failure)	Impact of comorbidities on transplant success	Disqualify if comorbidities are too severe
Psychosocial assessment	Mental health status	Ability to adhere to the posttransplant regimen	Disqualify if psychosocial factors are a risk
	Support system availability	Long-term care and support from family or caregivers
Evaluation of contraindications	Active substance abuse	Risk of noncompliance	Disqualify if contraindications present
	Advanced age	Reduced life expectancy
Cardiopulmonary assessment	Pulmonary vascular resistance	Risk of right heart failure posttransplant	Proceed to next step if criteria met
	Lung function tests	Determine compatibility and function
Risk-benefit analysis	Risk of surgical complications	Comparison of survival with and without transplant	Approve if benefits outweigh risks
	Expected posttransplant survival	Evaluation of patient’s overall health status
Final review by transplant committee	Comprehensive review of all assessments	Multidisciplinary team decision	Final decision: Approve or disqualify

NYHA: New York Heart Association.

The criteria for inpatient referral include refractory cardiogenic shock that persists despite maximum inotropic support or mechanical circulatory assistance, refractory pulmonary edema that does not respond to diuretics and requires ventilation and positive pulmonary pressure, and refractory ventricular arrhythmias unresponsive to medical or electrophysiological therapies[12]. Orthotopic HT is typically recommended for patients with end-stage heart disease that cannot be managed by other treatments. The key criteria include a maximal oxygen consumption of less than 10 mL/kg/minute with the onset of anaerobic metabolism, severe ischemia that limits routine activities and cannot be treated with revascularization, and recurrent symptomatic ventricular arrhythmias that are resistant to treatment. Additional criteria include a maximal oxygen consumption of less than 14 mL/kg/minute with significant limitations in daily activities, recurrent unstable angina that is not treatable by revascularization, and unstable fluid balance or renal function that is not due to patient noncompliance[13]. Absolute contraindications for transplantation include major systemic diseases, active cancer within the past five years, severe infections, and significant psychiatric disorders or substance abuse that could compromise posttransplant care and safety. Relative contraindications such as severe pulmonary hypertension, irreversible renal or hepatic dysfunction, and morbid obesity still pose significant risks. This highlights the need for a multidisciplinary team to evaluate patients on a case-by-case basis to determine eligibility, ensuring that donor organs are appropriately allocated[14].

Donor selection and management

Donor selection is a critical aspect of HTx influencing recipient outcomes. The process involves careful evaluation of the donor’s medical history, imaging studies, and specific anatomical and physiological parameters to ensure that the heart is suitable for transplantation. As the demand for donor hearts exceeds the available supply, the criteria for donor selection have evolved, incorporating advanced diagnostic tools and expanding the pool to include extended-criteria donors (ECDs). A variety of imaging and diagnostic tools are utilized to assess the suitability of donor hearts. Computed tomography angiography has emerged as an alternative to traditional coronary angiography, particularly in cases where coronary artery disease is suspected in the donor. Pharmacological stress echocardiography is employed to differentiate between irreversible coronary artery disease or cardiomyopathy and reversible left ventricular dysfunction[15]. Strain rate imaging helps distinguish between ischemic and stunned myocardium[16], whereas contrast-enhanced echocardiography improves myocardial visualization in cases of suboptimal imaging. Although cardiac magnetic resonance imaging provides detailed information about the structure and function of the heart, its use is limited by the availability of the technology and the time required to perform the examination[17]. When considering older donors or those with risk factors for coronary artery disease, coronary angiography remains a valuable tool, particularly for identifying significant coronary artery lesions that might contraindicate the use of the heart for transplantation[18].

The concept of ECDs has been developed to address the increasing demand for donor hearts and the shortage of available organs. ECDs include donors whose characteristics such as older age, lower left ventricular ejection fraction, or certain comorbidities, are traditionally excluded from consideration[19-21]. For example, donor hearts with an left ventricular ejection fraction of less than 45% are now considered viable if further testing, such as dobutamine stress echocardiography, suggests that the dysfunction is reversible[22]. This approach has expanded the donor pool significantly, particularly for recipients who are difficult to match owing to size or immunological considerations.

Hearts from donors with valvular abnormalities or those who have undergone prior noncardiac solid organ transplants can also be considered under certain circumstances, particularly for critically ill recipients. In the case of valvular abnormalities, pretransplant surgical repair may be performed if the recipient’s condition warrants such an approach. Similarly, hearts from donors who have undergone prior chest surgery or who are receiving extracorporeal membrane oxygenation support are increasingly being utilized[23], with careful screening and perioperative management to mitigate risks. A unique aspect of ECD utilization is domino transplantation, where the heart explanted from a heart-lung transplant recipient is used for a second HT recipient. This strategy not only increases the number of available hearts but also maximizes the use of donated organs[24].

Anatomical anomalies in donor hearts, such as persistent left superior vena cava and coronary artery anomalies, present unique challenges in transplantation[25]. While hearts with persistent left superior vena cava can be successfully transplanted with appropriate surgical planning, certain coronary artery anomalies, such as Anomalous Coronary Artery from the Opposite Sinus, are contraindicated owing to the increased risk of sudden cardiac events[26]. Furthermore, patent foramen ovale, a common congenital heart defect, is routinely screened for and closed before transplantation to prevent postoperative complications[27]. The selection of donor hearts is also informed by various risk scores developed to predict posttransplant outcomes. While these scores provide a standardized approach to evaluating donor risk, their predictive ability is limited, and clinical judgment remains paramount. International practices in donor selection vary, with some countries adopting opt-in or opt-out systems for organ donation. Despite these differences, emphasis remains on improving organ donation rates through public awareness, education, and streamlined national processes[28]. An algorithm for the selection of donor hearts is depicted in the Supplementary Figure 1.

Surgical techniques and innovations

Orthotopic HTx is the most common procedure in which the recipient’s heart is removed, leaving only the cuffs of the right and left atria. The donor’s heart is then transplanted, with anastomosis performed between the donor’s and recipient’s atria, aorta, and pulmonary artery. In the bicaval technique, the recipient's right atrium is excised, and the donor’s vena cavae are directly anastomosed to the donor’s right atrium. This approach offers a more precise fit and reduces complications related to atrial size mismatch[11,29]. Heterotopic HTx is less common and involves transplanting the donor heart without removing the recipient’s heart. Anastomosis is performed between the donor and recipient atria, aorta, and pulmonary artery. This technique is used in specific situations where the recipient’s heart cannot be removed or when the donor’s heart is not strong enough to function independently[11,29].

In recipient heart excision, the procedure begins with a sternotomy and pericardiotomy to access the heart. The aorta and vena cavae are cannulated for cardiopulmonary bypass. The left atrium is excised first, followed by the superior vena cava and right atrium, leaving an atrial cuff. The aorta and pulmonary artery are then removed, and the donor heart is prepared for implantation. The great vessels are unclamped to initiate reperfusion, followed by rewarming and deairing of the heart. Post-surgery, mediastinal drains are placed, and heparin is reversed with protamine before the chest is closed[11,29]. A flowchart detailing the steps of the HTx process is presented in Figure 1.

Figure 1 Flowchart of the heart transplantation process, outlining patient evaluation, donor matching, surgical procedures, and postoperative care. ICU: Intensive care unit.

Minimally invasive and robotic-assisted techniques have introduced less invasive alternatives to traditional sternotomy. These methods use smaller incisions and advanced tools or robotic systems, leading to reduced trauma, shorter recovery times, and fewer complications. Minimally invasive techniques are increasingly applied to complex procedures, including HTx, demonstrating safety and effectiveness in selected cases[30,31]. In robotic heart surgery, the surgeon controls the robotic arms and camera through small incisions between the ribs, allowing for precise movements and enhanced recovery. Postoperative care includes a brief hospital stay and a recovery period of several weeks, with careful monitoring to ensure optimal outcomes[32].

Post-transplantation care and management involves several challenges. Hemodynamic instability often arises due to graft reperfusion injury, inflammatory responses, and fluid imbalances. Vasoactive medications and exogenous catecholamines are used to support cardiac output and manage systemic hypotension. Bleeding and volume status require careful monitoring and management, including platelet and plasma infusions, to control hemorrhage and diuretics to address fluid overload[33,34]. Hypertension is common postoperatively, often due to catecholamine dysregulation or the use of immunosuppressive medications[35]. Donor size mismatching can lead to complications such as systemic hypertension if the donor’s heart is significantly larger than the recipient’s heart[36]. Arrhythmias are frequent, and managing them may involve continuous infusions of isoproterenol or pacing[37-39]. Elevated pulmonary vascular resistance is another concern and is managed with pulmonary vasodilators such as nitric oxide[40,41]. The common complications after HTx are tabulated in Table 2.

Table 2 Common systemic complications after heart transplantation.

System	Complications
Cardiovascular	Coronary artery disease
	Arrhythmias
	Hypertension
	Graft vasculopathy (cardiac allograft vasculopathy)
Renal	Chronic kidney disease
	Acute kidney injury (often due to immunosuppressive drugs like calcineurin inhibitors)
Pulmonary	Opportunistic infections (e.g., CMV, fungal infections)
	Pulmonary edema
	Pleural effusion
Gastrointestinal	Peptic ulcer disease
	Gastrointestinal bleeding
	Hepatotoxicity (due to medications)
Hematologic	Anemia
	Leukopenia
	Thrombocytopenia
Endocrine	Diabetes mellitus (NODAT)
	Hyperlipidemia
	Osteoporosis
Neurological	Seizures
	Peripheral neuropathy
	Cognitive dysfunction
Infectious	CMV infection
	Bacterial infections (e.g., pneumonia, sepsis)
	Fungal infections (e.g., aspergillosis)
Immunologic	Acute rejection
	Chronic rejection
	PTLD
Musculoskeletal	Myopathy (due to steroids)
	Avascular necrosis
	Osteopenia

CMV: Cytomegalovirus; NODAT: New-onset diabetes after transplantation; PTLD: Posttransplant lymphoproliferative disorder.

Immunosuppression and rejection

Management of acute and chronic rejection: Acute cellular rejection often occurs within the first week after HTx and is mediated by T cells. Mild episodes usually do not require treatment, as they typically resolve on their own without impacting patient survival[42,43]. However, more significant rejection episodes, graded ≥ 2R, can occur in up to 40% of adult recipients within the first year, especially during the initial three months[44,45]. For any biopsy-proven grade ≥ 2R rejection, regardless of symptoms, treatment is usually necessary. The first-line treatment is typically pulsed intravenous corticosteroids, which are effective in most cases during the immediate postoperative period[43]. If there is no improvement or if the patient’s condition worsens, more aggressive treatment with cytolytic therapy, such as anti-thymocyte globulin (ATG), may be needed[46].

Humoral rejection is driven by an antibody-mediated response against antigens present in the donor’s heart and vascular endothelium. This type of rejection is distinct from cellular rejection, as it often shows minimal cellular rejection on endomyocardial biopsy and is characterized by left ventricular dysfunction and the presence of donor-specific antibodies in the recipient’s serum[47]. The initial treatment for humoral rejection mirrors that of cellular rejection, involving pulsed corticosteroids and ATG. However, additional therapies are often needed to address the antibody-mediated component of rejection. These methods may include plasmapheresis and intravenous immunoglobulin G, especially in pediatric patients[48,49]. Drugs such as cyclophosphamide and mycophenolate mofetil may also be used to suppress B-cell populations directly[50,51]. Rituximab (RTX), a monoclonal antibody that targets CD20 on B cells, has proven effective in treating humoral rejection[52].

Current immunosuppressive practices: Allosensitization is the phenomenon in which the immune system identifies non-self-human leukocyte antigen (HLA), leading to the production of anti-HLA antibodies. It is commonly observed in children with congenital heart disease who have multiple sensitizing events, such as the use of ventricular assist devices, previous blood transfusions, and the implantation of cryopreserved homografts in various surgical reconstructions before transplantation[53]. Although there is no universally accepted desensitization protocol, several agents have been used, including oral methotrexate, cyclophosphamide, and mycophenolate mofetil. However, their success has been limited. More recent strategies include RTX and intravenous immunoglobulin. The serial administration of RTX depletes CD20⁺ B cells, reducing the production of anti-HLA antibodies by plasma cells and gradually decreasing the levels of these antibodies over time[54].

Induction therapy involves the use of specific immunosuppressive agents during the pre- and perioperative periods to rapidly suppress the host’s immune response to the transplanted graft[55]. One such agent is the monoclonal anti-thymocyte antibody Muromonab, which targets the human T-cell CD3 receptor, disrupting its ability to respond to antigens. This leads to T-cell opsonization and removal by macrophages[56]. Another option is polyclonal ATG, which is available in equine and rabbit forms. Equine ATG is produced by immunizing horses with human T cells, whereas rabbit ATG is derived from immunizing rabbits with human thymocytes. Both produce polyclonal antibodies against various human antigens, including those on T lymphocytes and HLA antigens[57].

Immune maintenance therapy usually starts within the first few postoperative days, unless it is delayed by induction therapy. Most maintenance regimens use a triple-therapy approach: A calcineurin inhibitor, a cell cycle inhibitor, or a corticosteroid. Calcineurin inhibitors such as tacrolimus and cyclosporine work by inhibiting the phosphatase activity of calcineurin, a key enzyme in the production of cytokines such as interleukin (IL)-2. This inhibition prevents the expansion of CD4⁺ T cells and CD8⁺ T cells and their differentiation[57]. Cell cycle inhibitors, such as azathioprine, are converted into purine analogues that inhibit DNA synthesis, thus limiting T-cell and B-cell proliferation[58]. Additionally, mammalian target of rapamycin inhibitors such as sirolimus inhibit the kinase mammalian target of rapamycin. This enzyme is crucial for T-cell proliferation, growth, and differentiation of B-cell and T-cell lymphocytes, as well as for the proliferation of vascular smooth muscle cells[57,58]. Corticosteroids inhibit transcription factors such as activator protein-1 and nuclear factor kappa-B. These factors are vital for the production of various cytokines, including IL-1, IL-2, granulocyte-macrophage colony-stimulating factor, and Tumor necrosis factor-α. Typically, high doses are given during and immediately after surgery, followed by rapid tapering to lower maintenance doses. A common regimen includes 3-7 days of intravenous steroids during the perioperative period, followed by a tapering schedule[59]. For patients who cannot tolerate steroid avoidance or withdrawal, long-term steroid use is linked to an increased risk of late rejection, particularly in older recipients, who may become steroid dependent[60].

Innovations in immunosuppression: HT immunosuppression involves a mix of calcineurin inhibitors (such as cyclosporine or tacrolimus), purine inhibitors (such as azathioprine or mycophenolate), and corticosteroids. Despite their benefits, these treatments pose challenges such as nephrotoxicity, inconsistent drug levels, and heightened risks of malignancy and infections. Recent advances in immunobiology have introduced a range of therapeutic monoclonal antibodies, such as RTX, basiliximab, and eculizumab. These drugs are now used for induction therapy, managing difficult cases such as sensitized patients, and addressing cardiac allograft vasculopathy[61].

Outcomes and survival rates

HTx has become an increasingly successful treatment for end-stage heart failure, with significant improvements in survival rates over the years. The Index for Mortality Prediction After Cardiac Transplantation score, a validated 50-point system, considers 12 recipient-specific variables, such as age, heart failure pathogenesis, and mechanical circulatory support (MCS), to predict survival at 30 days, 1 year, and 5 years. The donor risk index accounts for donor-specific factors such as ischemic time and donor age. Older age, reliance on mechanical support, high pulmonary vascular resistance, and suboptimal donor heart quality are associated with poorer survival outcomes[62-64].

In the short term, approximately 9% of HT recipients die within the first 30 days after surgery, with the most common causes being acute rejection, multiorgan failure, and right heart failure. Interestingly, despite differences in baseline characteristics among recipients - such as prior cardiac surgeries, high urgency status, and the need for ventricular assist devices - the 30-day mortality rate has remained consistent across different periods of transplantation. Long-term outcomes are equally compelling. The overall mortality rate is 74 per 1000 patient-years, which decreases to 58 per 1000 patient-years for those who survive the first month. The causes of late mortality have evolved: In the first year posttransplant, infection and acute rejection are the leading causes of death, whereas malignancy and cardiac allograft vasculopathy become more significant in the following years. The survival rates for adult HT recipients are 77% at 1 year, 67% at 5 years, 53% at 10 years, and 42% at 15 years[65]. These figures are consistent with the latest data from the International Society of Heart and Lung Transplantation, which reports a 1-year survival rate of 84.5% and a 5-year survival rate of 72.5%, reflecting substantial progress compared with earlier decades[66].

In terms of quality of life, most HT survivors report minimal limitations in activity, with over 90% being New York Heart Association class I or II. Despite good quality of life overall, there was a decline in the months preceding death. Long-term survivors often face new health challenges, such as hyperlipidemia, renal dysfunction, transplant coronary artery disease, and malignancies, because of immunosuppression and the donor heart. Regular hospital surveillance and readmissions are common, particularly after the sixth year post-transplantation[67-69]. Factors such as less education, a longer time since transplant, and fewer barriers to health-promoting behaviors are associated with better perceptions of quality of life[70].

NEW INNOVATIONS IN HTX

Artificial hearts and MCS

Cardiac transplantation has advanced with the development and refinement of artificial heart and MCS devices. These innovations, including left ventricular assist devices (LVADs), right ventricular assist devices (RVADs), and total artificial hearts (TAHs), help in managing end-stage heart failure and cardiac emergencies. An overview of the MCS devices is presented in Table 3[71-92]. Initially, LVADs used pulsatile flow technology, but the latest models (such as the HeartMate series) used continuous-flow technology. This shift has led to better survival rates and fewer complications[93]. RVADs, such as the Impella RP and TandemHeart, are essential for patients experiencing right ventricular failure, especially after LVAD implantation[93]. TAHs are less commonly used than LVADs and RVADs but provide an option for patients with biventricular failure. They can act as a bridge to transplantation or as destination therapy for those who cannot receive an HT. AbioCor TAH was approved by the Food and Drug Administration in 2006 and stands out because it is self-contained and does not require external tubes or wires[94]. It consists of four main components: An electronic controller, a thoracic unit, a lithium battery, and a transcutaneous energy transmission device[95]. The hydraulic pump in AbioCor mimics a natural heartbeat and is powered by a battery system that recharges through the transcutaneous energy transmission. The internal battery lasts up to 30 minutes, whereas the external battery provides up to 4 hours of power[96]. Ventricular assist devices have been implanted in more than 22000 patients and were initially intended as a bridge to HTx. However, they are now used as long-term solutions due to better outcomes with newer models[97]. Despite these advancements, MCS devices face challenges. Issues such as pump thrombosis, infection, and device malfunction remain significant risks, highlighting the need for continued research and development[97].

Table 3 Overview of mechanical circulatory support devices, indications, complications, and contraindications.

Category	Device	Description	Indications	Complications	Contraindications
Left ventricular support	IABP	Uses counter pulsations of a balloon in the descending aorta to improve coronary perfusion and cardiac output	AMI with cardiogenic shock, high-risk PCI	Vascular complications (stroke, limb ischemia), thrombocytopenia, infection	Severe aortic regurgitation, aortic aneurysm, aortic dissection, peripheral vascular disease
	Impella (2.5, CP, 5.5)	Nonpulsatile micro axial flow pumps providing up to 5 L/minute support. Available in various models for different levels of LV support	Cardiogenic shock, high-risk PCI	Bleeding, vascular injury, infection, hemolysis, pump migration	Severe peripheral vascular disease, severe aortic stenosis, LV thrombus, mechanical aortic valves
	HeartMate percutaneous heart pump	Microaxial three-blade impeller pump providing flows up to 5 L/minute	High-risk PCI	Device malfunction, bleeding, thromboembolism	Severe peripheral vascular disease, LV thrombus, mechanical aortic valves
Right ventricular support	Impella RP	Minimally invasive microaxial flow pump providing up to 4 L/minute support for RV	Right ventricular failure, postcardiac surgery	Similar to other Impella devices	Tricuspid regurgitation, pulmonary regurgitation
	TandemHeart	Centrifugal continuous flow pump providing 3.5-5 L/minute support, placed via femoral artery and left atrium	Acute RV failure, especially in postcardiac surgery	Bleeding, thromboembolism, limb ischemia	Aortic regurgitation, peripheral vascular disease
	Protek Duo	Dual-lumen cannula with centrifugal pump for RV support	RV failure, often after LVAD implantation	Similar to other centrifugal devices	Similar to other centrifugal devices
	CentriMag and Rotaflow	Magnetically levitated centrifugal flow pumps providing up to 10 L/minute	Short-term support in severe cases, including postcardiotomy	Bleeding, infection, device failure	Specific contraindications not detailed
	Short-term MCS in structural heart valve interventions	IABP	Used to support patients undergoing valve interventions, but may worsen aortic regurgitation	Structural heart disease, transcatheter valve implantation	Worsening aortic regurgitation
	Impella	Used for aortic stenosis with LV dysfunction, but may worsen stenosis	Aortic stenosis, LV dysfunction	Narrowing of valve orifice, embolic events	Severe aortic stenosis
	TandemHeart	Limited due to transseptal puncture requirements and increased support time	Aortic stenosis, high-risk interventions	Complications of transseptal puncture	Severe aortic stenosis
	ECMO	Provides both cardiac and pulmonary support, can be used in various emergent situations	Cardiopulmonary failure, CPR assistance	Harlequin syndrome, bleeding, infection	Multiorgan failure, severe aortic regurgitation
Long-term mechanical circulatory support	Durable MCS devices	Includes continuous flow devices (axial and centrifugal) and pulsatile devices	End-stage heart failure	Device-related complications and failure	Patient-specific conditions, generally no broad contraindications
	INCOR®	Berlin Heart. First implant 2002, CE mark 2003	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	HVAD®	Medtronic. CE mark 2008, FDA approval BTT 2012, FDA approval lateral implantation 2015	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	HeartMate II®	Abbott Laboratories. First implant 2003, FDA approval BTT 2008, DT 2010	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	HeartMate 3®	Abbott Laboratories. First implant 2014, CE mark 2015	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	EVAHEART 2®	Evaheart Inc. First implants 2005 in Japan, IDE approval by FDA, BTT trial ongoing	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	Jarvik 2000®	Jarvik Heart. First implant 2000, CE mark 2005, FDA approval BTT 2005, DT trial ongoing	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	Heart Assist 5®	Reliant Heart Inc. First implant 1998, CE mark 2001, BTT trial ongoing	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	EXCOR®	Berlin Heart. First implant 1990, CE mark 1996	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	SynCardia total artificial hearts®	SynCardia. First implant 1986, FDA approval BTT 2004	End-stage heart failure	Device-related complications and failure	Patient-specific conditions
	Carmat total artificial hearts®	Carmat SA. First implant 2013, investigational device	End-stage heart failure	Device-related complications and failure	Patient-specific conditions

IABP: Intra-aortic balloon pump; AMI: Acute myocardial infarction; MCS: Mechanical circulatory support; ECMO: Extracorporeal membrane oxygenation; FDA: Food and Drug Administration; PCI: Percutaneous coronary Intervention; LV: Left ventricle; RV: Right ventricle; BTT: Bridge to transplantation; DT: Destination therapy; IDE: Investigational device exemption; LVAD: Left ventricular assist device; CPR: Cardiopulmonary resuscitation.

XTX

XTx is a promising avenue for addressing the critical shortage of human organs available for transplantation[98]. This technique involves the transplantation of organs, tissues, or cells from one species to another, with pigs emerging as the most common source animal owing to their physiological and anatomical similarities to humans, as well as their rapid growth and reproductive advantages[99]. Recent advances in pig-to-human organ transplants have focused on genetic modifications, such as the elimination of porcine antigens and the expression of human coagulation regulatory proteins, to improve outcomes. The incorporation of human thrombomodulin[100] and endothelial cell protein C receptor[101] into transgenic pigs has demonstrated potential in prolonging graft survival and mitigating thrombotic issues. Furthermore, the expression of human CD39 in transgenic pigs has been shown to alleviate early posttransplant dysfunction and improve overall graft function[102]. A pig-to-human HT performed in January 2022 utilized a 10-gene-edited pig and showed extended graft survival of up to two months[103].

The primary challenges in XTx include immunologic, coagulation, and infectious barriers. Immunologically, the human immune system can recognize and attack xenografts because of the presence of non-self-antigens on the donor tissues. The recipient’s clotting system interacts poorly with the donor’s coagulation pathways, leading to complications such as disseminated coagulation and thrombotic microangiopathy. There are also concerns about the potential transmission of zoonotic infections from pigs to humans[104]. Ethical considerations further complicate XTx. Issues such as organ access through purchase and the impact on fair allocation systems for human HTs are critical concerns. Currently, there are no established guidelines regulating pig-to-human heart XTx, and achieving uniform social acceptance remains a challenge due to diverse cultural and religious beliefs. Another issue involves animal rights and the anthropocentric perspective of prioritizing human needs over those of other species[105]. Defining the welfare standards for laboratory-bred animals, whose living conditions often differ markedly from those of their natural environments, is essential[106]. While XTx research has made substantial progress, the path to clinical application involves careful patient selection. Ideal candidates for early human trials will likely be those with advanced heart failure who are also candidates for cardiac allotransplantation or durable LVADs[104].

Regenerative medicine

Regenerative medicine and stem cell therapy are pioneering approaches in cardiac repair that offer solutions for heart failure. Adult mammalian cardiomyocytes can replicate DNA but do not proceed to cytokinesis owing to the permanent silencing of G2M cell cycle genes. This silencing is also observed in senescent cells, where genes responsible for cell division become condensed into transcriptionally inactive heterochromatin[107]. Recent advancements in regenerative medicine have demonstrated that disrupting heterochromatin formation and reactivating cell cycle genes can enable mature cardiac myocytes to reenter the cell cycle, thus providing a novel strategy to enhance cardiac repair[107].

Innovative bioengineering models have advanced our understanding of cardiac damage and recovery. For example, in vitro models mimicking ischemia-reperfusion injury have demonstrated that pharmacological postconditioning drugs can significantly reduce cardiomyocyte death, which is consistent with clinical findings. These human induced pluripotent stem cell-derived models offer new ways to study ischemia-reperfusion injury and test pharmacological postconditioning drug candidates[108]. These innovations offer new therapeutic avenues and enhance our ability to evaluate and repair cardiovascular function, demonstrating the potential of regenerative medicine and stem cell therapy in achieving functional cardiac repair and improving outcomes for HT recipients.

Technological advances in monitoring and follow-up

A study evaluated the safety and efficacy of transitioning HT patients to home phlebotomy and a remote monitoring protocol using gene expression profiling and donor-derived cell-free DNA. The results revealed that among 32 patients with negative results on both tests, none had a positive biopsy, whereas 12% of those with positive results on both tests did. They concluded that the remote monitoring approach was feasible and safe, accurately predicting the absence of allograft rejection without any associated hemodynamic compromise or death[109]. Future studies and refined algorithms are needed to further validate these findings and optimize remote monitoring protocols.

Cellular therapies and immune tolerance

Mesenchymal stem cells (MSCs) have shown significant promise in cardiac transplantation due to their unique immunomodulatory and reparative properties. These cells can suppress immune responses by inhibiting B-cell and T-cell proliferation, as well as modulating dendritic cells and natural killer cells, thereby reducing the risk of graft rejection. However, there is ongoing debate regarding the immunogenicity of MSCs. While many studies support their role in promoting immune tolerance, some findings indicate that MSCs can trigger T-cell responses, leading to functional memory T cells and potential graft failure[110]. Recent research has also noted that MSCs share phenotypic similarities with cardiac myofibroblasts, expressing markers like α- smooth muscle actin, vimentin, and collagen type I, which may influence their role in both immune regulation and transplantation[110].

In cardiac transplantation, MSCs offer a two-fold benefit: Immune tolerance and cardiac tissue repair. Preclinical models of heterotopic HTx have shown that MSC administration either donor or recipient derived can significantly prolong graft survival. When combined with immunosuppressive agents like mycophenolate mofetil or rapamycin, MSC therapy has achieved long-term graft acceptance. This immunosuppressive effect is closely linked to the generation of donor-specific regulatory T cells central to maintaining immune tolerance. MSCs further promote the development of tolerogenic dendritic cells, regulatory B cells, and M2 macrophages through pathways involving programmed death-ligand 1 expression and immunoregulatory molecules such as IL-35[111].

Beyond their immunomodulatory effects, MSCs also play a critical role in protecting and repairing the transplanted heart. Post-transplantation ischemic injury and fibrosis are major contributors to long-term graft dysfunction. MSCs have demonstrated the ability to reduce inflammation, inhibit fibrosis, and promote angiogenesis - qualities that are essential for improving graft survival and function. These effects are largely mediated through paracrine signaling, where MSCs secrete factors that stimulate endogenous cardiac regeneration and enhance myocardial recovery[112]. However, challenges such as poor MSC retention and survival in the ischemic environment remain significant obstacles. Strategies like delivering MSCs on tissue scaffolds, co-administering them with cardiac stem cells, or utilizing repeat dosing regimens are being explored to overcome these limitations and maximize their therapeutic impact[112,113]. Overall, MSCs represent a novel and exciting therapeutic option in cardiac transplantation. Their ability to modulate the immune system and repair damaged tissue makes them a promising adjunct therapy in cardiac transplantation. Further clinical studies are essential to refine these approaches and unlock the full potential of MSCs in cardiac transplantation. Their dual role in immune tolerance and cardiac repair positions them as a potential adjunct therapy to current immunosuppressive strategies, offering new hope for improving long-term graft survival and patient outcomes.

CHALLENGES AND FUTURE DIRECTIONS

Ethical and legal considerations

Cardiac transplantation is fraught with ethical and legal considerations that need to be addressed. The criteria for recipient selection can vary across different institutes and regions, and fairness and equity are needed, especially given the many waiting lists for recipients and the insufficient number of donors. This issue was highlighted when the state of Maryland in the USA allowed drivers to have a donor card on their driver’s license, but only 1.5% of all eligible drivers agreed to be donors[114]. Currently, many global organizations and initiatives are aiming to increase awareness of the importance of organ donation, such as the World Health Organization’s Global Initiative on Organ Donation and Transplantation, which seeks to increase awareness of the life-saving potential of organ donation and address challenges such as organ shortages and inequities in access to transplants[115]. Another ethical consideration is obtaining consent from the donor, especially in cases of presumed consent, which requires ongoing scrutiny to ensure respect for donor autonomy. The rise in organ transplant tourism, where patients travel to another country for transplantation, has raised concerns regarding the exploitation of vulnerable populations and the legality of organ donation under these circumstances[116].

Overcoming organ shortage

One of the most pressing challenges in cardiac transplantation is the severe shortage of donor hearts. The demand for transplants far exceeds the available supply, leading to prolonged waiting lists that can extend beyond a year[117]. This significant delay often results in patient mortality before a suitable organ becomes available. To address this critical issue, normothermic machine perfusion has emerged as a promising technique. Normothermic machine perfusion enhances the quality of donor hearts by maintaining them in a state that closely mimics physiological conditions[118]. Additionally, HTx from circulatory-determined death donors is now being utilized as a strategy to expand the donor pool. While this approach is currently considered safer and more effective than in the past, further research and development are needed to optimize outcomes[119].

XTx, which involves the use of nonhuman cells, tissues, or organs for human transplantation, is another innovative avenue. Recently, a genetically modified pig heart was successfully transplanted into a brain-dead patient[120]. Although this technique holds promise for alleviating organ shortages, significant ethical and immunological challenges remain obstacles that must be overcome. Another exciting direction for the future is the development of bioengineered hearts created through the combination of stem cells and scaffolding technology. However, the long-term viability of these bioengineered organs is currently unknown, and there are concerns about the potential for tumor development when induced pluripotent stem cells are used. Moreover, even if the bioengineering of hearts becomes technically feasible, the financial feasibility of using these constructs for transplantation remains uncertain[121].

Research and clinical trials

Research and clinical trials are critical to the ongoing development of cardiac transplantation. Current research is focused on several key areas, such as immunosuppressive therapy, which is essential for preventing organ rejection and other immunological side effects associated with HTs. New immunosuppressive therapies and protocols are being tested to reduce risks while maintaining effective prevention of rejection[122]. Additionally, some research has focused on developing biomarkers to predict and monitor rejection, which will offer a more personalized approach and improve outcomes. Clinical trials are also exploring regenerative medicine techniques, such as stem cell therapy, which help regenerate damaged myocardium in transplant patients. This approach could reduce the need for lifelong immunosuppression[123]. Moreover, gene therapy is being investigated as a means to find more compatible matches between donors and recipients, thereby reducing the risk of rejection.

CONCLUSION

In conclusion, major improvements in surgery, medication, and donor selection have been made in HTx. Techniques such as minimally invasive and robotic-assisted surgeries, along with the use of ECDs, have greatly affected patient recovery and outcomes. However, we still face significant challenges, such as a shortage of donor organs and ethical concerns. New technologies, including artificial hearts and potential advances in XTx and regenerative medicine, offer hope for addressing these issues. Continued research and a collaborative approach are key to tackling these challenges, improving patient survival, and meeting the growing demand for HTs.

At present, HTx remains the only definitive treatment for end-stage heart failure, while artificial hearts and mechanical devices are primarily used as temporary solutions until a transplant can be performed. Advancements in technology including the improved durability and functionality of TAHs have led some patients to consider TAHs as a long-term destination therapy. Although researchers have faced challenges in creating a TAH that can fully and permanently replace a natural heart, ongoing progress in this field offers hope in the future.