Jenna Aziz MD, Kukbin Choi MD
The Ohio State University Wexner Medical Center
August 31st, 2024
Abbreviations and Definitions
AF – Atrial fibrillation
BMI – Body mass index
BNP – Brain natriuretic peptide
CAD – Coronary artery disease
CAV – Cardiac allograft vasculopathy
DBD – Donation after brain death
DCD – Donation after circulatory death
DPP – Direct procurement and perfusion
EF – Ejection fraction
GDMT – Guideline-directed medical therapy
HBV – Hepatitis B virus
HCV – Hepatitis C virus
HF – Heart failure
HIT – Heparin-induced thrombocytopenia
HIV – Human immunodeficiency virus
ISHLT – International Society for Heart & Lung Transplantation
LVAD – Left ventricular assist device
LVAD/IABP – Left ventricular assist device/intra-aortic balloon pump
LVH – Left ventricular hypertrophy
MCS-D – Mechanical circulatory support devices
MMF – Mycophenolate mofetil (immunosuppressive agent)
NRP – Normothermic regional perfusion
NT-pro-BNP – N-terminal pro-B-type natriuretic peptide
NYHA – New York Heart Association
OCS – TransMedics Organ Care System Heart System
PVR – Pulmonary vascular resistance
RA – Right atrium/right atrial
rATGG – Concentrated anti-human T-lymphocyte immunoglobulin preparation derived from rabbits
TA-NRP – Thoracoabdominal normothermic regional perfusion
TPG – Transpulmonary gradient
UNOS – United Network for Organ Sharing (United States)
VA-ECMO – Venovenous-arterial extracorporeal membrane oxygenation
VAD – Ventricular assist device
WIT – Warm ischemic time
Indications & Guidelines for Management
Since Christiaan Barnard performed the first cardiac transplant on December 3rd, 1967, in Cape Town, South Africa, the field of cardiac transplantation has rapidly evolved. The current North American/United States guidelines for cardiac transplantation were published in August 2024 by the International Society for Heart & Lung Transplantation (ISHLT). The ISHLT Guidelines for the Evaluation and Care of Cardiac Transplant Candidates provide updates to the Society’s previous publications: Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates—2006 and the 2016 International Society for Heart Lung Transplantation Listing Criteria for Heart Transplantation: A 10-year Update. ISHLT states this document “aims to provide tools to help integrate the numerous variables involved in evaluating patients for transplantation, emphasizing updating the collaborative treatment while waiting for a transplant, to improve the quality of care for heart transplant candidates” and highlights significant practice-changing developments concerning patient selection criteria, care of selected patient populations, and durable mechanical circulatory support (MCS).1
The updated guidelines emphasize an individualistic approach to selecting potential cardiac transplant candidates instead of relying on absolute contraindications. A psychosocial workup, a multidisciplinary team approach, and the roles of goal-directed medical therapy, temporary MCS, and durable MCS provide crucial insight into the existing indications for advanced heart failure (HF) interventions.1
In both chronic and acute settings, patients who exhibit clinical signs or symptoms of advanced HF should receive timely consideration for advanced HF therapies, including cardiac transplantation. The clinical markers that may suggest the development of advanced HF can be remembered by the mnemonic ‘I NEED HELP’, adapted from Baumwol 2017:2
- Inotropes
- NYHA III or IV and/or persistently high BNP or NT-pro-BNP
- End-organ dysfunction
- Ejection fraction <20%
- Defibrillator shocks – recurrent and appropriate shocks
- Hospitalizations – more than 1 in the last month
- Edema/escalating diuretics – persistent fluid overload and/or increasing diuretic requirement
- Low blood pressure – consistent systolic <90-100 mmHg
- Prognostic medication – uptitrated GDMT
Heart transplantation is typically considered for individuals with end-stage HF due to various causes, such as cardiomyopathy, or recurrent life-threatening arrhythmias that are unresponsive to conventional medical and surgical therapies. Objective indications for heart transplant criteria are noted in Table 1.1,3,4
Table 1: Objective Indications for Heart Transplant.
| Persistent NYHA class IV symptoms despite optimal therapy Peak VO2 ≤12 (with beta-blocker) or 14 mL/min (without beta-blocker), VE/VCO2 slope >35, or peak VO2 ≤50% predicted in women or patients ≤50 or ≥70 years Intractable life-threatening arrhythmias unresponsive to therapy Select patients with restrictive and hypertrophic cardiomyopathies Arrhythmogenic RV cardiomyopathy, LV non-compaction Corrected or non-corrected symptomatic congenital heart disease not amenable to palliative or corrective surgery History of prior cardiac transplant with developing cardiac allograft vasculopathy or symptomatic graft dysfunction without evidence of active rejection. |
|---|
Potential Contraindications: An Individualistic Approach Rather Than Absolutes
Outcomes in heart transplantation depend on many factors, including donor and recipient selection, organ preservation techniques, immunosuppression protocols, and medical center experience. The field of cardiac transplantation has evolved, with the 2024 guidelines suggesting the potential expansion of candidate criteria. A more individualistic and holistic approach to candidate selection has emerged. Previous firm contraindications to cardiac transplantation are now carefully reassessed as potential contraindications, including individuals with additional comorbidities such as older age, higher body mass index, diabetes, renal replacement therapy, a history of malignancy, prior cardiac surgeries, and greater rates of allosensitization. For example, “although elevations in pulmonary artery systolic pressure (PASP), transpulmonary gradient (TPG), and pulmonary vascular resistance (PVR) above certain thresholds have been proposed as contraindications to listing, the risk associated with each parameter is continuous from low to high values and absolute cutoffs do not exist.”1 These changes in transplant candidate selection underscore the dynamic nature of the cardiac transplantation field and the need for continuous learning and adaptation.
The updated guidelines emphasize the crucial role of extensive multidisciplinary teams in evaluating the interplay of extracardiac conditions, comorbidities, and their impact on mortality risk. This comprehensive evaluation provides critical insight into determining the expected survival benefit of transplant, post-transplant quality of life, and the maintenance of immunosuppression. It highlights each professional’s contribution in assessing patients with advanced HF as potential heart transplant candidates.1
UNOS Listing Status and Criteria
In 2018, the current United Network for Organ Sharing (UNOS) allocation policy was enacted, stratifying potential recipients into six categories (as opposed to the three categories from 2006) to mediate an inequitable geographic distribution of organs, accommodate the increased use of MCS-D devices, and address the high number of exceptions from the prior allocation guidelines. With the new allocation policy, most status 1 and 2 patients remain inpatient, while status 3-6 tend to stay outpatient (Table 2).6,7,8,9
Table 2: UNOS Listing Status.
| Status 1 | VA-ECMO Non-dischargeable, surgically implanted biventricular support device MCS-D with life-threatening ventricular arrhythmia |
|---|---|
| Status 2 | Non-dischargeable, surgically implanted non-endovascular LVAD-IABP VT/VF – MCS not required MCS-D with device malfunction/mechanical failure TAH, BiVAD, RVAD, or VAD for single-ventricle patients Percutaneous endovascular MCS-D |
| Status 3 | Dischargeable LVAD for discretionary 30 days Multiple inotropes or a single dose inotrope with continuous hemodynamic monitoring VA-ECMO after 7 days: Percutaneous endovascular circulatory support device or IABP after 14 days MCS-D with device infection, hemolysis, pump thrombosis, right-sided HF, mucosal bleeding, or aortic insufficiency |
| Status 4 | Dischargeable LVAD without discretionary 30 days Inotropes administered without hemodynamic monitoring Re-transplantation Diagnosis of one or more of the following: congenital heart disease, ischemic heart disease with intractable angina, hypertrophic cardiomyopathy, and amyloidosis |
| Status 5 | On the waitlist for at least one additional organ at the same hospital |
| Status 6 | All active candidates remaining |
Donor Considerations
Donor-recipient height, weight, and predicted heart mass ratios must be utilized for donor-recipient matching. Several etiologies may affect a thoracic organ donor, such as trauma, cerebrovascular accidents, asphyxia, drug intoxication, and malignancy. Various criteria exist for acceptable heart donors. These include an age <55, echocardiogram findings indicating a normal ejection fraction (EF) (i.e., 55-65%), posterior left ventricular and septal wall thickness ≤13 mm, absence of valvular disease, and lack of wall motion abnormalities, no or mild coronary disease on left heart catheterization (for those aged 45 or greater, cocaine use history, or other indications), donor-recipient weight matching (a mismatch of <20% is acceptable, though it may be center-specific), and gender matching (female donor hearts are smaller than male; therefore, the female should be ≥10% larger in height and weight).1,5,6,7,8 Understanding these factors is crucial for successful donor-recipient matching and can significantly impact the success of the transplantation process (Table 3).
High-risk donors (i.e., donors with active HBV or HCV) may be utilized with the understanding that a risk of transmission exists (IIA). Organs from HCV donors may be considered for HCV-negative patients who have a post-transplant treatment plan involving direct-acting anti-virals. Recipients receiving organs from high-risk donors should be monitored at 1, 3, and 12 months for HIV, HBV, and HCV.
Table 3: Criteria for Acceptable Heart Donors.
| Age <55 |
|---|
| Echocardiogram Findings Normal EF (55-65%) Posterior left ventricular and septal wall thickness ≤13 mm, absence of valvular disease, and lack of wall motion abnormalities No or mild coronary disease on left heart catheterization (for those aged ≥45, cocaine use history, or other indications) |
| Weight Matching <20% mismatch is acceptable, though it may be center-specific |
| Gender Matching Female donor hearts are smaller than male; therefore, the female should be ≥10% larger in height and weight |
Donor Procurement Strategies
In the United States, donor heart procurement strategies include Donation After Brain Death (DBD) and Donation After Cardiac Death (DCD). Advances in machine perfusion and other preservation techniques have played a crucial role in expanding the donor pool and improving outcomes. Two major DCD heart procurement techniques are direct procurement and perfusion (DPP) and normothermic regional perfusion (NRP).10,11,12 The UNOS Critical Pathway for the Organ Donor was introduced in the US in 1999. It was developed under contract with the US Department of Health and Human Services Health Resources and Services Administration to provide defined physiological goals and a consistent approach to donor management.
Table 4: Criteria for Donation After Brain Death (DBD).18
| Standard DBD criteria and evaluation to include: Age <50–60 Hemodynamic stability without high-dose inotropic support (less than 20 µg/kg/min dopamine) Evaluation/tests Past medical history and physical examination EKG Arterial blood gases Laboratory tests: (blood group, HIV, HBV, HCV) Echocardiogram Pulmonary artery catheter If indicated, cardiac catheterization |
|---|
| Absence of the following events: Prolonged cardiac arrest Prolonged severe hypotension Pre-existing cardiac disease Severe chest trauma with evidence of cardiac injury Septicemia Extra-cerebral malignancy and glioblastoma Positive serologies for HIV, HBV (active), or HCV |
| Criteria for extended DBD consideration: Age >60 Long ischemic times are likely Size mismatch LVH Positive serology (HBV inactive) Presence of CAD Valve abnormality present |
Donation After Circulatory Death (DCD)
DCD is a type of organ donation where organs are harvested from a donor after they have been declared dead based on the cessation of circulatory and respiratory functions, rather than brain death. Unlike DBD, where neurological criteria determine death, DCD involves a more gradual process of withdrawing life support, allowing for a natural cessation of circulation and respiration.13
The Maastricht Criteria
The Maastricht criteria categorize the circumstances surrounding donors in DCD. Typically, DCD cardiac donors are classified as Maastricht category III, although there are debates on uncontrolled and controlled classifications for Maastricht category IV.14 In these instances, there is a planned withdrawal of life-sustaining therapies. If asystole is achieved, a stand-down time of typically five minutes is observed before proceeding with donation. Additionally, the period between the withdrawal of care and cardiac reperfusion is referred to as warm ischemic time (WIT).15
Table 5: The Maastricht Classification of Donation after Circulatory Death.17
| Type | Category | Circumstance |
|---|---|---|
| Uncontrolled | I | Dead on arrival at the hospital |
| Uncontrolled | II | Unsuccessful resuscitation |
| Uncontrolled | V | Unexpected arrest in an ICU patient |
| Controlled | III | Awaiting cardiac arrest (in-patient, withdrawal of support) |
| Controlled | IV | Unexpected cardiac arrest in heart-beating donor |
Two techniques are used to procure DCD hearts, significantly expanding the donor pool while achieving outcomes comparable to those obtained with DBD: Direct Procurement and Perfusion (DPP) and Normothermic Regional Perfusion (NRP).
Direct Procurement and Perfusion
DPP utilizes ex vivo reperfusion with either normothermic or hypothermic perfusion. Standard explantation is performed with 1.5 L of donor blood collected to prime the ex vivo organ perfusion system in this method. Once the aorta and pulmonary artery are explanted, they are cannulated before reperfusion. The vena cavae are closed to allow blood to circulate through the tricuspid valve and be directed into the pulmonary artery. In normothermic perfusion, warm oxygenated donor blood is pumped into the aorta for coronary artery perfusion; in hypothermic perfusion, cold oxygenated cardioplegia solution is used to perfuse the heart ex vivo.15,16
Normothermic Regional Perfusion
In NRP, in situ reperfusion using a standard cardiopulmonary bypass (CPB) circuit occurs in the DCD donor heart. The arch vessels are clamped to prevent cerebral circulation, and cannulation is performed through the distal aorta, the aorta, and the right atrium (RA). Thoracoabdominal normothermic regional perfusion (TA-NRP) is then initiated, resulting in spontaneous cardiac activity that allows for the functional assessment of cardiac function. If accepted, the DCD donor may be weaned off, and procurement may proceed.17
Immunosuppression
Table 6: Immunosuppression Protocol.18
| Induction | Preop | Postop |
|---|---|---|
| Induction plan determined by the team at the time of listing: Non-sensitized, renal dysfunction: Casirivimab Sensitized: rATGG | MMF 1000 mg PO Intraoperative Methylprednisolone 1 gm IV | MMF 1500 IV/PO Q12hrs Methylprednisolone 125 mg IV Q8hrs, then taper to prednisone 15–20 mg daily by 2 weeks Tacrolimus 2 mg Q12hrs starting 24–48 hrs post-surgery (target trough 10–12 for first three months) |
Summary Diagram.
Ongoing Trials/Recent Publications
DCD Cardiac Transplantation
The Proceed II was the first clinical trial (2015) to demonstrate that heart transplantation outcomes using DCD donor hearts (procured utilizing the OCS) were noninferior to outcomes in DBD transplantation.10 Additionally, three large multi-center registries in the United States, Australia, and the United Kingdom have reaffirmed similar short- and medium-term outcomes after DCD donation compared to those with DBD donation.12,13,19
Xenotransplantation
In 2022, the first case report ‘Modified Porcine-to-Human Cardiac Xenotransplantation’ detailing the utilization of a genetically modified porcine xenograft was published in the New England Journal of Medicine by Griffith et al.20
Expert Commentary
The field of heart transplantation continues to evolve. Improvements have been made in each step of the transplantation process. Barriers within the field of transplantation include allograft tolerance and a perennial shortage of donor organs. Developments in the use of DCD hearts, the possibilities of xenotransplantation, and new iterations of total artificial hearts show promise in the concept of cardiac replacement therapies to mitigate these challenges.
Sources
- Peled, Yael, et al. “International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates—2024.” The Journal of Heart and Lung Transplantation 43.10 (2024): 1529-1628.
- Baumwol, Jay. “”I Need Help”-A mnemonic to aid timely referral in advanced heart failure.” The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation vol. 36,5 (2017): 593-594. doi:10.1016/j.healun.2017.02.010
- Heidenreich, Paul A., et al. “2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.” Journal of the American College of Cardiology 79.17 (2022): e263-e421.
- Givertz, Michael M., et al. “Advanced heart failure therapies for adults with congenital heart disease: JACC state-of-the-art review.” Journal of the American College of Cardiology 74.18 (2019): 2295-2312.
- Costanzo, Maria Rosa, et al. “The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.” The Journal of heart and lung transplantation 29.8 (2010): 914-956.
