Among the many markers of progress in our field, facilitating safe and successful pregnancies among an increasing number of heart transplant (HT) recipients may be the most encouraging. As noted in Thursday’s session by Francesca Macera, MD, of Hôpital Erasme in Brussels, Belgium, the pertinent question is not “whether to encourage or discourage pregnancy” but “what to do if the patient decides to become pregnant” after individualized counseling on the risks involved. She and other presenters in the Sunrise Session answered this question along many dimensions—from prenatal counseling through management of perinatal complications—while also highlighting the remaining unknowns.

The complex immunologic changes that occur during pregnancy present an array of potential challenges, as expertly summarized by Ersilia DeFilippis, MD, of Columbia University Medical Center in New York, NY USA. Increased complement activation, the induction of a regulatory T cell response, and sensitization to fetal antigens all threaten to disrupt graft tolerance – thus close monitoring for rejection is warranted. In her talk Surveillance and Management of Rejection During Pregnancy, Dr. DeFilippis detailed concrete recommendations, including monthly ECGs and echocardiograms during pregnancy, weekly therapeutic drug monitoring during the first month post-partum, and an assessment for donor specific antibodies shortly thereafter. However, more invasive measures (endomyocardial biopsy, imaging) need only be performed “for cause” given the procedural risks and radiation exposure involved. When it comes to the management of acute rejection, the ongoing consensus is that corticosteroids are the safest option; ATG and IVIG may also prove to be safe, though experience is limited.

Dr. Macera elaborated on the hormonal and metabolic changes during pregnancy that might pose particular risk to the transplant recipient in her talk Outcomes of Pregnancies Involving a Solid Organ Recipient. For instance, upregulation of cortisol, progesterone, and prolactin during pregnancy compound the already elevated risk of new-onset diabetes in the HT recipient and its associated complications (e.g. preeclampsia, preterm birth, macrosomia). Pregnancy-induced hemodilution and changes in intestinal motility and cytochrome P450 activity could reduce the effective dose of immunosuppressants—a point further elaborated on by Lilibeth Carlos, PharmD, of St. Vincent's Hospital in Sydney, Australia during her talk Pharmacologic Considerations with Pregnancy: Effects on Immunosuppression.

Exactly how this complex physiology affects broader neonatal and maternal outcomes is not precisely understood—due in part to the absence of pregnancy-related data in large-scale nationwide registries. As summarized by Dr. Macera, the largest case series to date (including 157 pregnancies among 91 heart transplant recipients; Punnoose et al, 2020) reports the following:

• Complications during pregnancy included pre-eclampsia (23%) and infections (14%).
• Rejection was reported during 9% of pregnancies and within 3 months postpartum in 7%.
• Livebirths occurred in 69%, miscarriages in 26% (half of which had MPA exposure), with no neonatal deaths.
• At last follow-up, 30 recipients had died, an average of 9.4 ± 6.2 years after pregnancy, most commonly due to allograft vasculopathy and rejection.

Synthesizing this data to enable informed decision making by patients is a key component of pre-natal counseling, as detailed by Tara Miller, NP, of Duke University in Durham, NC USA in her talk Prenatal Counseling: Aiming for a Successful Pregnancy; and further illustrated in case presentations by Patricia Chavez, MD, of Montefiore Medical Center in New York, NY USA as she discussed case presentations in her talk, Evaluating Patients in a Cardio Obstetrics Program.
   

Pets, Plants, Palatables, and “People”

“Our transplant recipients don’t want to be patients; they want to be people.” This simple yet astute observation, by Cedric Spak, MD, of Baylor University Medical Center in Dallas, TX USA, was echoed throughout the Thursday morning symposium Pets, Plants, & Palatables: When Living Life After Transplant Comes at a Cost.

His observation is best illustrated by the patient cases presented during the session. For instance, in Just Fly Away: Management of Bird-Related Pathogens, Dr. Spak presented the case of a 61-year-old male lung transplant recipient who presented with 30 pound weight loss and other “B symptoms.” He was not an owner of exotic pets, a recent world traveler, or a partaker in hobbies involving caves, dense forests, or anything else that might form the stem of a Board exam question. Only after bronchoscopy culture and urine antigen tests was the answer clearly “D. disseminated histoplasmosis.” Dr. Spak suspects that bird droppings were the culprit—the patient’s work site neighbored a rookery. This detail was apparent only after the fact—but even if bird droppings had been mentioned up front, Dr. Spak admits that it probably would not have prompted azole prophylaxis or major lifestyle changes.

So when the list of environmental, occupational, and dietary exposures that pose potential infectious risk is overwhelmingly long and often unforeseeable, how should we counsel our patients? “Keep it simple,” recommends Nicolas Mueller, MD, of University Hospital Zurich in Zurich, Switzerland. In Forbidden Fruit: Food-Borne Illnesses Following Transplant, he presented data from a Swiss cohort of 4,405 solid organ recipients. The cumulative incidence of food-borne infection (4% over a median 4.2 years follow-up) was higher than in the general population, but largely unremarkable in its etiology and symptoms (e.g. 88% of cases due to campylobacter, nearly all with typical GI symptoms); “exotic” pathogens were rare. Accordingly, Dr. Mueller focuses patient counseling on the “3 Cs” of “clean” (i.e., separate raw food from cooked food when preparing and storing), “cook” (i.e., avoid raw meat, eggs, seafood, and unpasteurized dairy), and “chill” (i.e., refrigerate food before/after cooking).

When it comes to plants and animals, other presenters echoed this emphasis on basic “common sense” (yet easy to overlook) measures over a laundry list of restrictions. Some useful pearls:

• In Cat’s in the Cradle: Prevention, Diagnosis, and Treatment of Toxoplasma and Bartonella, Tara Veasey, PharmD, BCPS, of Allegheny General Hospital in Pittsburgh, PA USA advised that cat owners avoid bites and scratches, have someone else change the litter box, and avoid adopting stray cats.
• In Old McDonald Had a Farm: Overview of Farm Animal-Related Infectious Risks, Elena Seminari, MD, of Fondazione IRCCS Policlinico San Matteo in Pavia, Italy, reminded us that transplant patients should avoiding handling their dogs shortly after they receive the modified live Bordetella (“kennel cough”) vaccine.
• Noting their high prevalence of Salmonella infection (83%), Orla Morrissey, MD, of The Alfred Hospital in Melbourne, Australia, advised strongly against reptile ownership among transplant recipients in her talk Slither: Creepy Crawly Concerns Carried by Reptiles. However, she ended on a positive note, highlighting the association of pet ownership with better quality of life measures in transplant recipients.
• Gardeners need not abandon their hobby—simple hand washing and wearing gloves will substantially reduce their risk. But transplant clinicians should be aware of their region’s endemic fungal pathogens, as noted by Maricar Malinis, MD, of Yale University School of Medicine in New Haven, CT USA, in her talk Every Rose Has Its Thorn: Uncommon Fungal Pathogens Associated with Plants and Soil.

The above “pearls” are hardly exhaustive, and recommendations must be tailored to regional and cultural sensibilities. For example, Dr. Mueller supplements his “3 C’s” with specific advice to avoid eating raw wild boar liver (a favored delicacy in Switzerland). Tomoko Kato, MD, PhD, of International University of Health and Welfare in Tokyo, Japan, who co-chaired the symposium, acknowledged that “our patients cannot live without sushi...so we just recommend going to a 5-star restaurant.” Dr. Spak noted that “in my home country of Texas, patients do what patients do”; accordingly, he finds that keeping restrictions focused and few in number offers the best chance of adherence. While joking in tone, these concluding remarks highlight the importance of seeing patients as “people first” when advising lifestyle restrictions.
   

The Right Match, at the Right Time

There is no substitute for clinical instincts and experience in the care of advanced heart failure patients. However, even the most seasoned of us would acknowledge that clinical decision-making for such patients has become increasingly complex over time, thanks to a growing array of diagnostic and therapeutic options. When should we list a given patient for transplant? And after listing, should we pursue transplant as soon as possible—or wait for the best possible match? Such questions are particularly tough in the pediatric setting—with its highly heterogenous population following an unpredictable clinical course - and the number of variables involved can overwhelm the mind.

Enter mathematics, decision-analytic modeling, and an expert financial economist. For a math nerd like me, all were unexpected but welcome highlights of Thursday’s Symposium 34, Real Options in Pediatric Heart Transplant: Small Infants, HLA Sensitization, and Non-invasive Rejection Screening.

Said expert was Laura Delaney, PhD, of Kings College London, who presented A Tough Calculation: Determining the Optimal Transplant Listing Window for Patients with Fontan Physiology. She presented a mathematical model adapted from the financial discipline of real options analysis, which weighs the value of waiting to list for transplant against the value of listing now. While mathematically complex, the model features parameters that are familiar to any transplant clinician, namely, the patient’s risk factors and their severity (θ), which factor into their rate of clinical decline (μ) and life expectancy without transplant (Lnt). In collaboration with a team from Freeman Hospital (Newcastle upon Tyne, UK), her ongoing work will refine the model using retrospective data before deploying it as a decision-support tool for pediatric cardiologists.

Brian Feingold, MD, MS, of Children's Hospital of Pittsburgh, who presented Heart Acceptance Strategies for the Highly Sensitized Candidate: Wait for the Ideal Match or Accept a Positive Crossmatch and Deal with the Consequences. His analysis applied a decision-analytic Markov model to compare the two strategies (i.e., “wait” or “accept”); the answer to this complex question, as one might expect, is “it depends.” Rather than advocate for a specific strategy, he presented his model as a framework to discuss the evolving considerations involved. For example, emerging treatment options for desensitization may tip the balance towards “accept” in many cases, and newer solid phase-based cross-matching assays could allow us to better characterize the risk of “accept.”

A growing array of diagnostic options has also “complicated” rejection surveillance post-transplant—with the potential to significantly reduce procedural morbidity and costs. These options were detailed by Justin Godown, MD, of Vanderbilt University Medical Center in Nashville, TN USA in his talk Don’t Go Breaking My Heart: Cell-Free DNA, MRI, and Non-Invasive Imaging as Alternatives to Endomyocardial Biopsy after Pediatric Heart Transplant.

Other presenters during the session tackled the unique challenges posed by dilated cardiomyopathy (DCM) in small infants. These included Aamir Jeewa, MD, of Hospital for Sick Children in Toronto, ON Canada who discussed DCM in Small Infants: Medical Heart Failure Management, and Emma Simpson, BMBS, MMedSci, MRCPCH, of Freeman Hospital in Newcastle upon Tyne, UK, who discussed DCM in Small Infants: PA Band or LVAD Therapy.
   

Impact of 2018 UNOS Heart Allocation policy change on post-transplant Outcomes: Intermediate Term Analysis
Eugene C. DePasquale, MD, University of Southern California, Los Angeles, CA USA
The UNOS heart allocation policy underwent a change in 2018 with the goal of prioritizing recipients of highest acuity in addition to broader geographic sharing. Therefore, 3 tiers were expanded to 6 tiers to account for this heterogenous population. DePasqale et al sought to assess the intermediate-term impact of this change on post-transplant outcomes in the highest urgency statuses. Around 7,710 heart transplant recipients were identified from UNOS/OPTN registry. These recipients were more than 18 years of age who were listed status 1A (per prior allocation criteria) or status 1-3 (per current policy) and who were transplanted during a 2-year period immediately prior & following the allocation policy change were included.

This cohort was stratified per policy change into Pre-policy (n=3764) and post policy change(n=3946). The survival was censored at 12 months. Multivariate Cox proportional hazard regression analysis was adjusted for age, sex, diabetes, race, ischemic time, dialysis, life support, wait time and HLA mismatch. It was observed that there was more use of devices (especially intra-aortic balloon pumps (IABPs). Fewer patients with durable left ventricular assist devices (LVAD)s were transplanted with the new policy. Status 2 patients per new policy had maximum transplants.

With this analysis, it was concluded that the current heart allocation policy didn’t adversely affect post-transplant outcomes in the intermediate analysis with a reduction in waiting list time for the higher acuity statuses. Nevertheless, the demographic is changing with increased use of temporary MCS (notably IABPs) with a reduction in LVAD patients moving forward with transplant. Further analyses are warranted to better understand these shifting demographics.

Influence of the 2018 Heart Allocation System Change on Patients With a Durable Left Ventricular Assist Device (LVAD) as a Bridge to Transplantation: A UNOS Registry Analysis
Nicholas R. Hess, MD, University of Pittsburgh Medical Center, Pittsburgh, PA USA
The United States 2018 heart allocation change has brought differential priority for those on various mechanical circulatory support devices—higher priority for temporary, non-dischargeable devices, and decreased priority for durable, dischargeable devices. On preliminary analysis of durable LVAD bridged patients, waitlist mortality has decreased but possibly lesser chances of transplant, and possibly worse post-transplant survival. Hess et al compared outcomes of waitlisted patients with durable LVAD from the time of waitlisting, before and after the 2018 heart allocation policy change.

This was a retrospective review of the UNOS registry. Adult heart transplant recipients who were bridged with isolated, durable LVAD device at listing were included. The study cohorts were stratified into patients listed from two equal-length time periods before and after 10/18/2018—old policy era and new policy era. The primary outcome included: survival from time of initial waitlisting, composite outcome waitlist mortality, post-transplant mortality if transplanted, or if removed from waitlist due to being “clinically ill for transplantation.” It was observed there was higher incidence of death or delisting under the new policy for patients with durable LVAD. The secondary outcomes were: waitlist mortality and/or de-listing due to clinical decline, cumulative incidence of transplantation, and post-transplant survival of those transplanted.

With this analysis, it was concluded that from the initial timepoint of waitlisting, patients bridged with durable LVAD are more likely to die (with or without transplant) or become too ill for transplantation under the new system. These differences in outcomes were primarily driven by increased post-transplant mortality rather than waitlist mortality.

Impact of Donation After Circulatory Death Heart Transplantation on Waitlist Outcomes and Transplantation Activity
Marian Urban, MD, PhD, University of Nebraska Medical Center, Omaha, NE USA
Urban et al aimed to evaluate the impact of DCD heart transplantation on the waitlist activity and transplantation volumes. Of 48 transplants from January to December 2021, 36 were donations after brain death and 12 were DCD. Of the 12 DCDs, 8 used thoraco-abdominal normothermic regional perfusion (TA-NRP) and 4 were Organ Care System (OCS). When compared to year 2020, median time in days to transplant was decreased.

So, more patients were added/removed from the heart transplantation waiting list. Decrease in median time from the registration on waiting list to transplant. Increase in transplantation rates of low acuity (status 6) candidates was noted. There was no change in pre-transplant/after listing mortality.

Heart Transplant Outcomes with Donation After Cardiac Death: UNOS Registry Analysis
Eugene C. DePasquale, MD, University of Southern California, Los Angeles, CA USA

Limitations in organ donation have led to approaches to expand the existing donor pool. DCD has continued to increase after efforts led by the UK and Australia. Results of the DCD trial utilizing OCS are forthcoming. DePasquale et al sought to describe the United States experience thus far. Adult heart transplant recipients from January 2019 to June 2021 were identified from the UNOS/OPTN registry. The cohort was stratified by donation status: donation after brain death and after cardiac death. The survival was censored at 12 months. Multivariate Cox proportional hazard regression analysis was adjusted for age, sex, diabetes, race, ischemic time, dialysis, life support, wait time, and HLA mismatch. Of 5,153 heart transplant patients, 229 (4.4%) were DCD donors and 4,924 (95.6%) were DBD donors.

It was concluded that short term survival of heart transplant recipients was similar regardless of donor type. (DCD vs DBD) Transplant rates increased in VAD recipients and patients in the lower priority statuses. Use of DCD hearts has the potential to increase the donor pool, however, additional study is warranted as the recipient population expands for this donor type.

Results of Heart Transplants from Donation After Circulatory Death (DCD) Donors Using Thoraco- Abdominal Normothermic Regional Perfusion (TA-NRP) Compared to Donation After Brain Death (DBD)
Claudia G. Gidea, MD, NYU Langone Medical Center, New York, NY USA
Heart transplantation is the definitive therapy for eligible patients with advanced heart failure. Increasing the donor pool can be achieved by accepting longer ischemic times using Organ Care System technology, CAD, improved LV dysfunction, high risk donors (Hep B/HepC), moderate to severe LVH, and to use DCD. TA-NRP DCD is being increasingly used to expand donor pool and decrease waitlist mortality.

Gidea et al presented their experience of DCD transplant using TA-NRP protocol and compared the results to a cohort concomitantly transplanted from standard DBD donation. Of 95 transplants over 2 years, 15 received TA-NRP DCD heart transplant and 80 recipients received DBD heart transplant. Same standardized protocols for post-transplant management and immunosuppression were followed. Survival was the primary outcome and secondary outcomes included rejection, graft function, coronary allograft vasculopathy and primary graft dysfunction.

Over a 2 year period, 19% more recipients received heart transplantation through TA-NRP DCD donation. Majority of DCD recipients were listed at a lower UNOS status. Short term results suggest that transplant outcomes from DCD TA-NRP are comparable to recipients from DBD. Expanding donor pool by using DCD is a viable option and wide adoption should be considered.

Outcomes of Mechanical Circulatory Support for Severe Primary Graft Dysfunction After DBD vs DCD Heart Transplantation
Vasudev B. Pai, MCh, FRCS, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
Severe primary graft dysfunction is defined by need for mechanical circulatory support (MCS) after heart transplantation. It is associated with increased short-term mortality but reported outcomes vary widely. Mechanism of PGD may differ for DBD and DCD hearts. Pai et al sought to determine whether there were differences in PGD outcomes between DBD and DCD heart transplants.

This was an observational study of all heart transplants from Feb 2015 to June 2021. Baseline donor and recipient characteristics were recorded. Outcome measures included- duration of MCS, length of ICU stay, length of hospital stay, 90-day mortality. Of 280 transplants, 88 were DCD and 192 were DBD. Of total 33 patients with severe PGD, 12 were DCD and 21 were DBD. It was noted that there was no significant difference in PGD incidence or outcomes between DBD and DCD heart transplant recipients. Though not statistically significant, the potential lower-90 day mortality in the DCD group may suggest that the natural history of PGD after DCD heart transplantation is more favorable compared with PGD seen after DBD heart transplantation. So further studies are warranted.
   

Outcomes of Patients Bridged to Heart Transplantation with ECMO Following the UNOS Allocation Policy Change
Sagar Patel, MD, University of Southern California, Los Angeles, CA USA
Short-term outcomes of patients bridged with ECMO to transplant have improved post 2018 heart allocation policy change. The purpose of this study was to assess long-term outcomes in patients bridged with ECMO to heart transplant. Adult heart transplant recipients with ECMO use preceding heart transplant from 2016 to 2020 were identified from the UNOS registry. This cohort was stratified per policy change into pre-policy (n=36) and post-policy change (n=266). Survival was censored at 12 months. Cox-proportional hazard regression analysis was adjusted for age, sex, diabetes, race, ischemic timer, dialysis, life support, waiting time, and HLA mismatch.

Patel et al concluded that following heart allocation policy changes, heart transplant survival has improved in recipients bridged with ECMO with associated reduction in waitlist time. ECMO utilization has significantly increased since policy implementation. Further studies are warranted to better understand the contributing factors.

UNOS Listing Status-Related Changes in Mechanical Circulatory Support Utilization and Outcomes in Congenital Heart Disease Patients
Alice L. Zhou, BA, MS, Johns Hopkins University School of Medicine, Baltimore, MD USA
Adult congenital heart disease (ACHD) population now outnumbers pediatric congenital heart disease population. Rapidly growing population of ACHD patients requiring heart failure therapies, including MCS. The role of MCS as a bridge to transplant and effects of the 2018 allocation policy revision is unclear. Zhou et al investigated the impact of the new UNOS listing criteria on MCS utilization in ACHD patients and investigated the outcomes in ACHD patients bridged with MCS.

Using SRTR database, they identified 12,723 adult heart transplant recipients, of which 535 had ACHD and 12,188 were non-ACHD. Stratified per allocation policy change, 242 patients received transplant in historical era (7 March 2017 to 17 October 2018), and 293 patients in recent era (18 October 2018 to 30 May 2020).

It was observed that ACHD candidates were younger at listing, had similar times on waitlist, were less likely to have MCS support, and were a higher proportion of females. When stratified per policy change, it was noted that temporary MCS use in ACHD patients increased after policy change. Recent ACHD patients spent less time on waitlist compared to historical ACHD patients with no adverse impact on post-transplant outcomes. Nonetheless, there was no change in durable LVAD utilization in ACHD population after policy change.

Cystatin C vs Creatinine-Based Assessment of Kidney Function in Advanced Heart Failure: Insights from REVIVAL
Alberto Pinsino, MD, Columbia University Medical Center, New York, NY USA
Renal dysfunction is one of the manifestations of advanced heart failure. Patient selection for advanced therapies relies heavily on appropriate renal function. We are aware that durable VAD are associated with worse outcomes in patients with severe renal dysfunction or hemodialysis. Advanced heart failure (HF) patients with severe renal dysfunction are listed for combined heart-kidney transplants. Serum creatinine, the traditional marker of renal function is affected by muscle mass. Advanced HF is associated with sarcopenia and therefore using serum creatinine as a marker of renal function may lead to overestimation of kidney function in patients with advanced disease.

Cystatin C is a marker of glomerular filtration which is not affected by age, sex, race, or muscle mass, thereby is more accurate and has a higher prognostic value compared to creatinine. Among 400 patients enrolled in Registry Evaluation of Vital Information for VAD in Ambulatory Life (REVIVAL), 270 patients had concomitant CysC & sCr measured. It was observed that eGFRcysC reclassified 57% of patients. Cystatin C improved risk stratification for CV outcomes, mortality, and hyperkalemia. It also strengthens the association between kidney function and a composite of death, urgent heart transplant, or durable LVAD. Lower handgrip strength, reduced functional capacity, and frailty are associated with a widened difference between eGFRCysC and eGFRsCr. Further studies are warranted to determine accuracy and prognostic implications of different estimates of kidney function in advanced HF patients.

Circulating Proteomic Analysis Identifies Reduced Inflammation After Initiation of Hemodynamic Support with Either Veno-Arterial Extracorporeal Membrane Oxygenation or Impella in Patients with Cardiogenic Shock
Nikolaos Diakos, MD, PhD, Tufts Medical Center, Boston, MA USA
The use of MCS for CS is growing, but the mortality remains high. There are various hemodynamic and metabolic variables, but we lack the molecular data. Along with the clinical, hemodynamic, and echocardiographic data, Diakos et al collected serum of 11 patients presenting with CS before and 72 hours after MCS (Impella & ECMO). Aptamer based proteomics were used, that is single stranded DNA aptamers that can measure >1,300 proteins using 75microLitre of human sample with high reproducibility. It can also capture low abundance proteins with high sensitivity and specificity.

It was observed that different proteins were upregulated and downregulated with different MCS. Impella support reduced adhesion and migration of monocytes, while ECMO inhibited monocyte activation. Both ECMO & Impella support in patients with refractory CS are associated with reduction in inflammation. Both appear to affect similar biologic functions while acting through different cellular signaling pathways. Circulating proteins may serve as a novel targets of therapy or novel biomarkers to tailor MCS device use and improve patient outcomes.

Five-Year Outcome of Hybrid Transcatheter and Minimally Invasive Left Ventricular (LV) Reconstruction for Ischemic Heart Failure
Romy RMJJ Hegeman, MD, St. Antonius Hospital, Nieuwegein, Netherlands
Left ventricular remodeling after MI can cause LV dilation, shape alteration and heart failure with reduced ejection fraction (HFrEF). Surgical ventricular reconstruction has been proven to be effective in restoring LV shape and size. Hybrid LV reconstruction involves no sternotomy, no cardioplegic arrest, no ventriculotomy.

Hegeman et al presented a single center retrospective analysis of 30 patients from 2016-2021. They included symptomatic HF patients with NYHA class > 2, LVEF < 40% after acute myocardial infarction, with dilated left ventricle with akinetic or dyskinetic scar, and > 50% trans-murality of scar tissue. Operative technique based on micro-anchoring technology. The scar-based reconstruction technique includes Hybrid RV-LV for anteroseptal scar or external LV-LV double purse string for apical aneurysm).

They observed improvement in left ventricular end diastolic and end systolic volume index, LVEF, & NYHA class. 5 year survival was 86.7%. They concluded that in selected patients, hybrid left ventricular reconstruction for ischemic HFrEF is a safe off-pump alternative, associated with significant improvement in left ventricular performance and achieves a significant long term symptomatic improvement with excellent 5-year survival.

Clonal Hematopoiesis Common Within the Advanced Heart Failure (HF) Population and is Associated With Improved Heart Transplant Outcomes
Lakshmi Ravali Gokanapudy Hahn, MD, Washington University in St Louis, St Louis, MO USA
Clonal hematopoiesis (CH) is a phenomenon found in healthy older individuals as well as in children and younger adults with chronic diseases. It occurs when hematopoietic progenitor cells acquire mutations that confer a fitness advantage relative to background population. Mutant progenitor cells subsequently expand giving rise to substantial portion of peripheral blood cells. Certain CH mutations are associated with cardiovascular mortality. Mutations in TET2 and DNMT3A have been shown to have the strongest association with cardiovascular mortality and are prevalent in HF populations.

Hahn et al sought to measure the prevalence of CH across age in advanced HF population and delineate the impact of CH on heart transplant outcomes. They established pediatric and adult advanced HF registries with comprehensive clinical phenotyping. Blood samples of 40 pediatric and 120 adult advanced HF patients were processed for DNA sequencing, single cell RNA sequencing, flow cytometry and functional studies. CH was measured using a custom next generation sequencing pipeline with 500x-4000x coverage of 76 genes. They detected CH in 20% of patients (25% adults and 5.5% pediatric).

As expected, CH was more prevalent in older age groups with some patients having multiple mutations. Among patients who underwent heart transplant, the composite outcome of CV mortality, grade 2R cellular rejection, antibody mediated rejection, and primary graft dysfunction was significantly reduced in individuals with CH. Therefore, it was noted that CH is present across a spectrum of age in the advanced heart failure population and is associated with improved clinical outcomes post heart transplantation. Future studies are required to externally replicate these findings and uncover underlying mechanisms.
   

This oral abstract session included studies focused on waitlist survival and transplant outcomes in association with expanded donor pool and revised heart allocation system.

Donor Utilization in the Recent Era: Effect of Sex, Drugs and Increased Risk David A. Baran, MD, Sentara Heart Hospital, Norfolk, VA USA
The investigators sought to examine whether the increase in organ donors and heart transplants has resulted in an increase in the percentage of offered donors utilized as well as the effects of increased risk status and drug use on donor acceptance. They queried the UNOS registry for all transplants between 1 January, 2007 and 31 December, 2017 and compared donor hearts utilized for transplant with those that were rejected. The groups were compared for demographics, hepatitis C serology (HCV), Public Health Service Increased Risk (PHSIR) designation, as well as history of drug use and positive toxicology. They calculated a UNOS Tox Score (UTS), which was the sum of positive historical drug use variables in the UNOS registry, and a Measured Tox Score (MTS), which was the sum of positive donor toxicology categories. Strongest predictors of donor non-use were older donor age, female gender, blood type, HCV, and left ventricular hypertrophy. HCV heart utilization increased minimally from 1% to 3.5% over the study duration.

Heart Transplant Outcomes by Donor HCV NAT Status: Intermediate Analysis
Meghana Yanamandra, MD, MSc, University of Southern California, Los Angeles, CA USA
The investigators sought to compare post-heart transplant outcomes of patients who received hearts from either HCV NAT positive or negative donors. They stratified recipients from the UNOS registry by donor HCV NAT status and compared the groups using standard statistical methods. They also performed adjusted and non-adjusted survival analyses. Of 18,828 recipients, 849 and 17,979 received HCV NAT positive (HCV+) and HCV NAT negative (HCV-) donors, respectively. HCV+ recipients were older, male, Caucasian, with a high incidence of pre-transplant cardiac surgery, life support use, had older donors, longer ischemic times, and worse renal function. There were no differences in waitlist times, all-cause, cardiovascular, or non-cardiovascular mortality between the groups. The authors concluded that utilization of HCV NAT + donors was a safe and effective way to expand the donor pool.

The Regional Impact of the 2018 United States Heart Allocation System Change
Amit Iyengar, MD, MS, University of Pennsylvania, Philadelphia, PA USA
The investigators sought to examine changes in waitlist/transplant outcomes across the United States from the policy change, stratified by geographic region. They performed a retrospective analysis of all patients listed for heart transplant between January 2016 and July 2021 and grouped them by pre- and post-new UNOS allocation system era as well as by OPTN region. They performed competing risk regression for waitlist death, transplant, or delisting with their model censored at 3 years. Key findings were: 1) IABP and ECMO usage amongst waitlist patients increased in Era 2 across all regions; 2) Waitlist mortality improved in all regions except the South (Region 3 and 4) and Northwest (Regions 6-8, p>0.10); 3) Odds of transplantation increased in all regions to varying degrees; 4) In those transplanted, organ procurement distance increased by >80 mi in all regions except Region 1 (Northeast), with increases in ischemic time in all regions except Region 1 (p=0.358).

Adaptive Changes and Estimated Long-Term Survival After Updated Donor Heart Allocation Policy: A UNOS Database Analysis
Takuma Miyamoto, MD, PhD, Thomas Jefferson University Hospital, Philadelphia, PA USA
The investigators sought to characterize adaptive changes to the revised UNOS heart allocation policy, and estimate long-term survival changes on the waitlist and after heart transplantation (HTx). This was also an analysis of the UNOS database. Patients transplanted after implementation of new allocation policy as well as from the preceding 5 years were analyzed. Sub-analyses were performed for extracorporeal membranous oxygenator (ECMO), durable left ventricular assist device (LVAD), intra-aortic balloon pump (IABP), microaxial support (Impella), and no mechanical support (non-MCS). For survival analysis, they used a parametric distribution model and extrapolated based on this. The authors found that since the implementation of the new allocation policy more patients were listed on ECMO and Impella while fewer patients underwent LVAD implant or were transplanted with non-MCS. Most transplants were also performed off ECMO ,IABP, Impella, and less off LVAD and non-MCS. Overall, waitlist survival improved in contrast to worsened post-HTx survival.

Improved Survival Benefit After Implementation of the New Heart Allocation System Amongst Highest Priority Candidates Undergoing Heart Transplant
Stratton Tolmie, BA, University of Chicago, Chicago, IL USA
The authors sought to examine if the highest priority candidates under the new UNOS allocation system had higher survival benefit from transplantation compared with the highest priority candidates in the prior policy. They collected Scientific Registry of Transplant Recipients data on all adult heart transplant candidates listed in seasonally matched pre (2016-2017) and post-new policy (2018-2019) cohorts. Using a cox-proportional hazards model they estimated 1-year survival curves with and without transplantation using these hazard ratios and a non-parametric Nelson-Aalen estimate of the baseline hazard. They found that status 1 recipients under the new policy experience greater survival benefit from transplantation than Status 1A recipients in the previous policy. Their conclusion was that the policy change has resulted in more medically urgent patients being listed as highest priority status, without significantly compromising post-transplant survival.

Waitlist Outcomes in Candidates with Hypertrophic or Restrictive Cardiomyopathy and Congenital Heart Disease After Implementation of the New French Heart Allocation System
Guillaume Coutance, MD, Hôpitaux Universitaires Pitié Salpêtrière, Paris, France
The French heart allocation system launched on January 2018 is based on a national score ranking all candidates. The authors sought to examine the waitlist outcomes in candidates with hypertrophic (HCM) or restrictive (RCM) cardiomyopathy and congenital heart disease (CHD) after implementation of the current French heart allocation system. Twelve-month cumulative incidence of transplantation and waitlist mortality or delisting for worsening medical condition was compared among patients with HCM (n=92), RCM (n=55) or CHD (n=67) and those with other transplant indication (n=1531). They found that the new French heart allocation system offers equitable access to transplantation throughout all transplant indications.
   

This mini oral abstract session included research focused on exploring factors associated with heart transplant outcomes as well as their predictive value.

Outcomes of Heart Re-Transplantation with Combined Kidney Transplant
Qiudong Chen, MD, Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA USA
This study evaluated outcomes of those patients undergoing redo heart transplantation (HTx) who also required a simultaneous kidney transplant. Twenty-two patients undergoing redo HTx with kidney transplantation were compared to 55 patients undergoing redo HTx alone. The authors found that patients undergoing redo HTx with combined kidney transplant had higher incidence of post-operative dialysis and longer hospital length of stay. However, one year survival, non-fatal MACE, and freedom from CAV and any rejection, were similar between the groups.

Induction Therapy in Heart Transplantation: A Systematic Review and Network Meta-Analysis
Lakshmi Kugathasan, PhD, Toronto General Hospital, Toronto, ON Canada
The investigators performed a systematic review and network meta-analysis (NMA) to examine the safety and efficacy of post-heart transplant (HTx) immunosuppressive induction therapy (IT) and evaluated outcomes at 1-year post HTx. Seven randomized controlled trials (RCTs) and three observational studies with adjusted analyses were included. Results of the NMA suggested that the use of IT did not confer mortality benefit at one year after heart transplantation. Risk of rejection, however, appeared to be reduced by ATG compared to no IT or basiliximab, although this was not statistically significant when only evaluating data from RCTs, likely due to the small number of events and insufficient power.

Cross-Organ Survival in Patients Undergoing Multi-Organ Cardiac Transplantation
Umar A. Siddiqi, University of Chicago Medicine, Chicago, IL USA,br /> Using the UNOS database, the investigators compared survival outcomes between three of the most prevalent multi-organ procedures: heart-lung, heart-kidney, and heart-liver transplantation. A total of 80,058 patients were included in this study. Heart-lung transplant recipients experienced significantly worse survival compared to those receiving heart-kidney, heart-liver, or heart-only transplants (p <0.0001). On the other hand, heart-liver and heart-kidney transplants displayed improved rates of survival relative to heart-only transplants.

Predicting One Year Mortality Using Machine Learning After Pediatric Heart Transplantation: Analysis of the United Network of Organ Sharing (UNOS) Database
Awais Ashfaq, MD, Johns Hopkins All Children’s Hospital, St. Petersburg, FL USA
The investigators used machine learning algorithms to help select clinically relevant identifiers that could predict one-year mortality after pediatric heart transplant (HTx). UNOS Database for years 2010-2020 was used. Pediatric patients receiving their first transplant were included (N=4,150). Their key findings included: 1) risk factors for mortality one year post HTx varied based on the pre HTx diagnosis; 2) machine learning modelling effectively predicted the risk of mortality in patients listed for pediatric HTx.

Sex Differences in Clinical Characteristics and Outcomes in Patients Undergoing Heart Transplantation
Christoph Kondziella, MD, University Heart and Vascular Center, Hamburg, Germany
The investigators examined sex differences in heart transplant (HTx) listing and post HTX outcomes. OPTN data was used and 49,200 HTx recipients, including 24.6% females, were assessed. Multivariable Cox regression was used to identify predictors for sex-specific differences in all-cause mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. Pre-HTx, ischemic cardiomyopathy was common in males while dilated cardiomyopathy was common in females. At HTx, males were older than females. Sex differences in CAV and malignancy (more common in males than females) were seen in both univariate and multivariate analyses.

The New UNOS Heart Transplant Statuses: Upgrades, Transplant Rate and Survival
Jaimin R. Trivedi, MBBS, MPH, FACC, University of Louisville, Louisville, KY USA
The investigators sought to evaluate the distribution of patients listed and transplanted based on new UNOS priority status and their waitlist and post-transplant outcome. Their key findings included:

1. Over 60% of patients under new UNOS policy were listed as Status 4, 5 or 6 whereas more than 50% of patients transplanted are Status 1 and 2;
2. Over 33% patients from status 4 and 6 were upgraded to higher statuses before transplant;
3. Status 1 and 2 patients had higher rate of transplant within 30 days of listing;
4. Status 1 patients had worst post-transplant survival.

When asked, the authors added that a significant proportion of patients were transplanted with an exception status, although this data was not included in their presentation.

Instrumental Variable Estimation of the Effect of Increased Donor Heart Ischemic Time on Post-Transplant Survival
Gege Ran, BA, University of Chicago Pritzker School of Medicine, Chicago, IL USA
Under the new UNOS allocation policy, transplant programs are more likely to accept organs with longer ischemic time for more urgent candidates with higher risks of mortality post-transplant. The investigators assessed the isolated impact of ischemic time on post-transplant survival. An instrumental variable (IV) model was constructed to address bias from unobserved confounders in the relationship between the receipt of ischemic organ and mortality post-transplant, while controlling for observed candidate and donor characteristics.

In heart transplant recipients who were “randomized” a graft with > 4 hours of ischemic time by changes in heart allocation policy, no effect on survival within the first-year of transplantation was noted.

Mitigation of Post-Transplant Mortality Risk by Appropriate Donor-to-Recipient Size Matching Using Predicted Heart Mass
Ran Tao, MD, University of Wisconsin Hospital and Clinics, Madison, WI USA
Pretransplant obesity continues to be a risk factor for death post-transplant. The authors investigated whether size matching of donor-to-recipient using predicted heart mass (PHM) can mitigate some of the risk associated with pretransplant obesity. Using UNOS database, the authors created 6 categories of recipients based on their BMI (underweight, normal, overweight, obese, morbidly obese, severely obese). The found that appropriate size matching for donor hearts by PHM could lower the risk of death compared to under-matching specifically among normal and overweight recipients.

Models with Weight and Height Better Predict Mortality versus BMI After Adult Heart Transplantation
William L Baker, PharmD, University of Connecticut School of Pharmacy, Storrs Mansfield, CT USA
The investigators used SRTR database, applied a flexible weight*height interaction effect, and examined whether this improved prediction of mortality after heart transplant compared with BMI. They found that using weight and height as independent variables improved performance of models predicting mortality after HT compared with BMI.

Donor and Recipient Cytokine Profiles Predict Acute Rejection and Graft-Related Survival After Heart Transplantation
Emil Holmström, MD, University of Helsinki, Helsinki, Finland
The investigators examined donor and recipient plasma and intragraft cytokine profiles and searched for predictive markers for unfavorable outcomes. Their key findings included: 1) severe PGD was associated with a proinflammatory cytokine profile in the recipients; 2) a high immunological risk score based on donor plasma cytokines predicted acute rejection, while recipient cytokine-based risk scores predicted graft-related 1-year mortality.
   

Pediatric Heart-Lung Transplantation Through the Decades: A Single-Center Analysis
Horacio G. Carvajal, MD, Washington University in St. Louis, St. Louis, MO USA
Pediatric heart-lung transplant is getting uncommon, and its indications have changed over time. Cavajal et al evaluated 22 patients who underwent heart-lung transplants from 1993 to 2021 and stratified them by decade. They evaluated indications, post-operative outcomes and survival and observed that 10-year survival was similar in all decades. The complexity of cases referred for HLT has increased while chronic rejection rates have decreased.

Iron Deficiency in Pediatric Dilated Cardiomyopathy is Associated with Clinical, Biochemical and Hematological Markers of Severe Disease and Adverse Outcomes
Jack C. Luxford, BA, MD, The Children’s Hospital at Westmead, Sydney, Australia
Iron deficiency (ID) is an established prognostic marker in adult heart failure, and treatment improves morbidity and mortality in acute and chronic HF. Luxford et al sought to establish prevalence of ID in a hospital cohort of dilated cardiomyopathy (DCM) and identify associations between ID and markers of DCM severity.

This was a single center retrospective chart review of all children (0-18 yrs) with DCM and full set of iron studies between 2010-2021. They observed that ID is highly prevalent in pediatric DCM (62%), but iron studies are undermeasured in this population with only 1/3 of patients with DCM in this time period had iron studies drawn. ID in DCM is associated with an increased risk of the composite adverse outcomes. Those who are iron deficient tend to be anemic, with higher NT-proBNP, lower albumin and increased incidence of inotrope/respiratory support requirement. Lower iron and transferrin saturation levels are correlated with LV dysfunction.

A Novel Approach to Pediatric Heart Failure Quality Improvement Within the ACTION Network
Justin Godown, MD, Vanderbilt University Medical Center, Nashville, TN USA
Children with HF are at high risk for mortality, prolonged length of hospitalizations, and readmissions with high resource utilization. There is wide practice variation with little standardization and there is opportunity to impact clinical care through quality improvement efforts. There are many multicenter collaborations routinely used to advance care in pediatric heart disease. Furthermore, pediatric HF is a very heterogenous population, comprising complex congenital heart disease, cardiomyopathies, metabolic heart disease, myocarditis, and acquired cardiac disease.

Godown et al identified children hospitalized with acute decompensated HF across 6 centers that participate in both ACTION network and Pediatric Health Information system (PHIS) between June 2019 to July 2020. A total of 227 patients with 309 hospitalizations were included in this pilot study. This strategy through central data abstraction supplemented with administrative data which includes outcome measures (mortality, LoS, ECMO use), process measures (medication use at discharge and discharge checklist) and resource utilization (overall cost, echo and cardiac MRI utilization) is a reliable and efficient data collection and provides a valuable platform for QI efforts.

Contemporary Care and Outcomes of Critically Ill Children with Myocarditis
David M. Peng, MD, University of Michigan, Ann Arbor, MI USA
Peng et al utilized the pediatric cardiac critical care consortium (PC4) registry to describe the contemporary characteristics, management, and outcomes of critically ill children diagnosed with myocarditis in the cardiac ICU. They included 847 patients admitted to ICU and diagnosed with myocarditis by the treating clinician from August 2014 to June 2020. They noted that myocarditis often required intensive supportive care such as vasoactive infusions, mechanical ventilation, and MCS and carries added risk of cardiac arrest, renal failure, and death. Small patient size, severe renal dysfunction at presentation, need for mechanical ventilation, and MCS were independently associated with mortality. ECMP remains the most used form of MCS in myocarditis. In critically ill patients with myocarditis in PC4 registry, higher ECMO, eCPR, and overall transplant-free survival to discharge compared with earlier reports suggesting that supportive care has improved over time.

Cardiogenic Shock in Children: Clinical Presentation and Outcomes
Kriti Puri, MBBS, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX USA
Puri et al did a retrospective single center analysis of patients hospitalized with acutely decompensated HF at a referral children’s hospital from January 2004 to December 2018. They sought to evaluate hospital mortality in patients with CS at presentation as a primary outcome using multivariable analysis by binary logistic regression using generalized estimating equations. They noted that 26% of children hospitalized with acutely decompensated HF presented in CS. It was independently associated with hospital mortality in children with mortality rate around 25%. These patients suffered greater morbidity, including mechanical ventilation, MCS and renal replacement therapy. Risk stratification of pediatric CS should be considered to optimize early use of rescue therapies and improve survival to recovery or heart transplantation.

TPN-Dependence and Paralytics Predict Post-Heart Transplant Mortality in Infants
Jason W. Greenberg, MD, The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
Infants represent a unique subgroup within the field of pediatric heart transplantation with greater organ dysfunction, ventilatory and ECMO requirements, a greater burden of congenital heart disease (CHD), and inferior one-year survival. Known predictors of post-transplant mortality in infants are presence of CHD, renal & hepatic dysfunction, ECMO requirement, and mechanical ventilation, while several other important risk factors remain understudied.

Greenberg et al aimed to characterize the effects of pre-transplant TPN-dependence and paralytics—with and without mechanical ventilation—on post-transplant outcomes. This was a retrospective, multi-institutional observational study from UNOS and Pediatric Health Information System (PHIS) infants who received heart transplant in the United States between 2003 and 2020. They noted that infants who require pre-transplant mechanical ventilation, paralytics, or TPN dependence experienced inferior early outcomes and resource utilization. They are at independent higher risk for one-year mortality. Knowledge of these modifiable risk factors can assist with risk stratification and inform expectations with pre-transplant optimization seeking to correct these modifiable risk factors prior to transplantation. Future studies are warranted to examine impact of other support modalities.

Repeat Pediatric Heart Transplantation in the United States: United Network for Organ Sharing Database Analysis
Georgina Rowe, MD, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA USA
Pediatric heart transplant mortality exceeds 25% and an additional 7% are retransplanted at 10 years. CHD is associated with worse survival following pediatric heart transplant. Rowe et al identified UNOS database to identify all children undergoing isolated heart transplant from 2000 to 2021. There were 7,678 primary transplants and 441 repeat transplants. The repeat transplants were divided into early or late sub-groups according to whether retransplant occurred within 1 year of primary procedure. Primary outcome was all cause mortality with a median follow up of 5 years. It was noted that repeat pediatric transplantation is associated with worse long-term survival compared to primary transplantation, this survival difference is particularly evident among patients with cardiomyopathy and those undergoing early repeat transplantation.

Predicted Heart Mass is Not the Optimal Metric for Size Matching in Pediatric Heart Transplantation
Zhaozhi Li, University of Chicago, Chicago, IL USA
Donor recipient size match is traditionally assessed by body weight. However, some studies suggest that hearts mismatched by weight have similar outcomes with properly matched hearts. Predicted heart mass (PHM) may be a more effective metric for donor-recipient size matching. Recent studies demonstrated that PHM was predictive of survival and primary graft dysfunction in an adult cohort. However, the predictive value of PHM in a pediatric population remains unknown. Li et al sought to assess the ability of PHM donor to recipient ratio to predict 1 year patient and graft survival after heart transplant (HT) in pediatric patients. They retrospectively reviewed 5431 pediatric patients undergoing initial isolated HT from 1/2000 to 12/2020 from the UNOS database. They noted that donor to recipient PHM ratio mismatch is not associated with reduced 1-year patient or graft survival in pediatric HT recipients. The question of the importance of donor-recipient size mismatch persists, particularly in a pediatric population as it is conventionally believed that pediatric hearts have greater adaptability.

Sudden Cardiac Arrest After Pediatric Heart Transplantation
Lynsey M. Barkoff, CPNP, Lucile Packard Children’s Hospital, Palo Alto, CA USA
Despite many advancements in the field of pediatric heart transplantation (HT) over last 30 years, long-term survival is still not adequate. Sudden cardiac arrest (SCA) continues to be an important cause of mortality but is understudied. Barkoff et al analyzed the frequency, outcomes and rsk factors of SCA at their center using retrospective data from 1/1/2009 to 9/1/2021. They noted that SCA occurred in 6% of their patients. It is fatal and occurred relatively early after pediatric HT (within 3 years). It often occurs outside the intensive care units. Transplant recipients with younger donors, rejection history, or of black race were at increased risk for SCA. Intracardiac cardioverters defibrillators and pacemakers offer limited protection in this population.

Long Term Survivors Following Pediatric Heart Transplantation: A PHTS Database Analysis
Emily Anne Hayes, MD, Nationwide Children’s Hospital, Columbus, OH USA
In a retrospective cohort study, Hayes et al evaluated patients transplanted between 1993 to 2010. Overall survival at 15 years was 53.3%. They noted increased number of long-term survivors. Aggressive coronary allograft vasculopathy and rejection were risk factors for mortality. Of modifiable risk factors, cessation of steroids may provide long-term survival benefit. Further studies on social determinants of health in this population are warranted.
   

Technical Aspects of DCD Heart Transplantation
Stephen Large, MB, MA, MS, FRCS, FRCS (CTH), Papworth Hospital, Cambridge, UK
The speaker discussed the technical aspects of DCD heart transplantation. Ethically, the transplant team will not be a part of the recognition of futile life support therapy nor of confirmation of death following withdrawal of life support. 75% of cases progress to cardio-pulmonary arrest after withdrawal of futile life support. The insult to donor heart by this process is ischemic. We probably have 30 minutes of normothermic anoxia before myocyte loss. The timeline of events involves withdrawal of life support, onset of functional warm ischemic time (FWIT), onset of death and confirmation of death 5 minutes after, 15 minutes of ischemic asystolic period, reperfusion with limited circuit, reanimation, to normothermic regional perfusion (NRP) DCD heart working.

Reperfusion of the ischemic DCD heart in ex situ reperfusion involves direct procurement and preservation using (i) Transmedics Organ care system (OCS) primed with donor blood after white cell filtration and free radical scavengers; donor heart cooled with cardioplegia @ 4C; reperfusion in non-working mode for 60 minutes. The in situ reperfusion used TA-NRP or thoracoabdominal that excluded aortic arch vessel and illiacs so isolated thoracoabdominal perfusion; perfuses heart & lungs and all abdominal viscera; did functional assessment after required DCD ischemia, and progress to removal and transportation on ice.

Problems of process include the assessment of donor heart function and selective perfusion. Problem of the device involves the perfusate, weight of the device and limited mobility, and the assessment of function/transplantability of the donor heart. Results of reperfusion of DCD heart revealed an increase in transplant activity by up to 50% (2021) probably settling at 40%. The outcomes in terms of hospital stay, 90-day, 1-, 5-, and 8-year survival was similar compared to DBD. The ischemic times as FWIT (ends with cardioplegia) and then functional cold ischemic time to a total of functional total ischemic time of order 15-30 mins. The average ischemic time in TA-NRP 16.2 minutes: no donor heart related deaths (international cohort) noted in 8 years, and 15% requirement for MCS early after surgery and 15% requirement for treated acute rejection of direct procurement protocol (DPP) and DBD. The DCD donor heart selection for transplantation rests on the pre-withdrawal of futile supportive therapy echocardiogram demonstrating acceptable cardiac function.

Comparison of Outcomes after DCD and DBD Heart Transplantation
Sarah Scheuer, MD, PhD, St. Vincent’s Hospital, Sydney NSW Australia
Prior to the recognition and legislation of brain stem death, all heart transplants were performed from DCD donors. The speaker reviewed historical and modern outcomes of DCD.

Historical outcomes:
Pediatric: Denver series—Boucek et al in 2008 reported three successful infant DCD heart transplants, all co-located and with brief standoff periods. Rajab et al in 2020 reported 10-year outcomes with 66% survival with normal graft function. In an ISHLT retrospective analysis, Kleinmahon et al 2017 reported 21 heart transplants between 2005 and 2014, with 61% survival at one year vs 91% for matched DBD with 24% of DCD recipients dying from primary graft failure. 55% of recipients were on VA ECMO pre-operatively compared with 9% DBD recipients.

Modern Outcomes:
Sydney series: Chew et al reported two-year outcomes in 2018, where 23 DCD transplants had 95% one-year survival vs 88% in DBD. No significant difference in rejection rates was noted. There were relatively high rates of severe PGD, with 35% early VA ECMO support. The Sydney series reported their current outcomes in this meeting. In 74 DCD heart transplants: 94% one-year survival and 88% five-year survival, compared to 87% and 81% one- and five-year survival with DBD. Significant reduction in severe PGD, 16% VA ECMO requirement overall was 8% compared to 35% published from the original cohort. Most significant predictor of sPGD was aWIT greater than 15 minutes.

Papworth series since 2015 (with mix of DPP and TA-NRP): Messer et al reported five-year outcome data on a retrospective, matched, observational cohort study comparing outcomes of DCD to DBD, and noted one-year survival 91% vs 89% for DCD and DBD respectively. They also noted that requirement for post-transplant MCS was 34% for DCD, vs 23% for DBD. VA ECMO or temporary MCS was used in 19% DCD, vs 9% for DBD. Amongst these, 57 were DPP, 22 TA-NRP, survival was 100% for TA-NRP group with no difference in requirement for post-op MCS.

USA experience, Vanderbilt series: Hoffman et al presented 15 TA-NRP/CS DCD transplants, donor age was < 35 yrs, anticipated transport time < 240 mins. Average ischemic was 183 +/- 31 min; no sPGD-LV with 100% 30-day survival. NYU series: Smith et al presented 8 DCD TA-NRP/CS heart transplants, with relocation of donor to recipient hospital. Cold preservation following TA-NRP assessment. 30-day survival was 100% with only one case (13%) requiring VA ECMO.

Provisional results of OCS DCD Heart Trial were announced in November 2021. It was a multicenter RCT with 3:1 randomization of recipients to DBD with CS or DCD with DPP. Six-month survival was 95% for DCD vs 89% for DBD.

There is a growing body of evidence that DCD heart transplantation is as effective as DBD with comparable short-term survival. Higher rates of sPGD were reported in some programs, but appears to be reducing with increasing experience. Rapid uptake of DCD heart transplant throughout USA over last two years leading to significant increases in transplant volume. Future directions include optimizing ex situ management, ex situ regeneration of organs, novel biomarkers for assessment of organs during ex situ perfusion, and more studies comparing outcomes of DPP vs TA-NRP.

Heart in a Box as a Platform for Molecular and Cellular Research
Niels van der Kaaij, MD, PhD, UMC Utrecht, Utrecht, Netherlands
Kaaj et al discussed ex situ treatment of the heart in a bioreactor and described this as a gift box. We are aware that there is a major shortage of organs. In Dutch experience, only a minority of patients with advanced heart failure get accepted for the transplant waiting list. On top of it, 19% of these are removed from the list due to mortality or clinical worsening. DCD transplants are increasing in number. In comparison to UK or Austria where DBD: DCD is 50:50 or 92:8 respectively, this ratio is 40:60 in the Netherlands.

From 21 March to present, 35 donors were attended of which 29 DCD hearts were transplanted (the rest failed to arrest or were declined). Survival after one year was 96.6% with 3.4% mortality. Ex situ heart perfusion to prevent or minimize additional injury by ischemia and reperfusion injury. Advanced HF treatment options include transplantation, LVAD, or a total artificial heart. Both LVAD and artificial heart have high risk of complications like driveline infection, stroke, technical failure, pump thrombosis, and lack of right ventricular support in LVAD. The ultimate goal is to treat a patient with HF by preserving, regenerating, and possibly testing the heart in a bioreactor without any side effects.

The advantages of this heart would be no immunosuppression requirements, no organ donation requirement, no VAD related complications, and less therapeutic side effects. On our way, we might be able to discover newer technologies that will be applicable for in situ treatment. Over requirements for this cardiovascular moonshot would be bioreactors with perfusion approach for heart survival; extra-corporeal circulatory life support system for patient survival; regeneration would include improvement in cardiac contractility, valvular disease and atherosclerosis, conduction system; and testing would include functional assessment before re-implantation.

Many cardiovascular functions are regulated by the circadian clock. The amount of acute adverse cardiovascular events shows circadian rhythmicity. To study a circadian rhythm, one needs multiple biopsies during 24-48 hrs. Heart box gives the opportunity to study the peripheral heart clock in an isolated organ. Thus, this heart box can be used for DCD heart preservation, modulation & testing. It also gives optimal access for research and sequential analysis and can be used to apply treatment strategies for ex-situ regeneration and repair.

Tips and tricks to set up a DCD Heart Transplantation Program
Kumud Dhital, BM.BCh, FRCS-CTh, FRACS, PhD, Sparsh Hospital, Bangalore, India
There is a big unmet need when it comes to heart transplantation. Using DCD can increase the donor pool. The strategy for this DCD program included laboratory validation, unutilized human hearts, marginal DBD hearts, and DCD hearts.

Recipient protective donor would be Maastricht Category III donors, with Age < 40 years, no history of any cardiac disease, no prior cardiac surgery or trauma, requiring low dose inotropy/vasopressor with stable hemodynamics (MAP > 60, CVP< 10 mm Hg), maximum warm ischemic time ~ 30 minutes, pre-donation echo, and antemortem heparin. If donor age < 40 years, then the process is 30 minutes withdrawal to cardioplegia. But if donor age < 55 years, we opt for 30 minutes SBP < 90 mm Hg to cardioplegia.

The Law and in situ reanimation: In Australia, death definition is irreversible cessation of all functions of the brain of the person or irreversible cessation of the circulation of blood in the body of the person. An analysis of heart donation after circulatory determination of death showed that only death criteria based on permanency are compatible with the DDR under two conditions:

1. a minimum standoff period of 5 minutes to ensure that autoresuscitation is impossible & all brain functions are lost
2. no medical intervention is undertaken that might resume bodily or brain circulation

The Australia heart DCD program respects the DDR when the criteria of death is permanency. A proposed method of organ retrieval that uses what has been called normothermic regional perfusion (NRP) with controlled donation after circulatory determination of death (cDCD)- referred to as “NRP-cDCD”.

There is an urgent need to relax rules and define marginality. There is an overwhelming need for multidisciplinary teamwork in this regard. To evolve this practice of DCD, we need the following measures:

• To improve DCD legislation, standardizing DCD certification. Antemortem interventions, location of WLST.
• Increasing tolerance to WIT, bank blood vs donor blood collection, better markers of cerebral & myocardial injury, more metrics of physiological assessment, portable or static (+/- cold perfusion) + functional evaluation
• Surgical repair, gene therapy, immunomodulation

   

This sunrise session presented the proposed updates to the 2010 ISHLT heart transplant guidelines.

Overview of the Guideline Process
Angela W. Velleca, RN, BSN, MHDS, CCTC, Cedars-Sinai Heart Institute, Los Angeles, CA USA
This presentation introduced the members of the writing group and chairs and co-chairs of task forces 1 through 4. Members of the writing group were 54% North American; 56% were female, and 18% were junior faculty. A 75% agreement was needed to achieve recommendation consensus. Class of recommendation and level of evidence was applied using the ACC/AHA recommendation system from 2015. The COVID-19 pandemic prolonged the guideline update writing process, and resulted in inclusion of topics addressing emerging pathogens and pandemic considerations for heart transplant recipients. The documented has completed an expert review and review by the Advanced Heart Failure and Transplantation Interdisciplinary Network and, as of the time of the meeting, was expected to be reviewed by the ISHLT Board soon.

Task Force 1 - Peri-Operative Care of the Heart Transplant Recipient: What’s New?
Estela Azeka, MD, University of Sao Paolo, Sao Paolo, Brazil
Task force 1 has put forth new recommendations pertaining to pre-transplant optimization and considerations in patients bridged with mechanical circulatory support. Updates to pre-transplant optimization will focus on frailty/pre-habilitation, vaccinations, and hemodynamic optimization. Task force 1 expansions will include: incorporation of recommendations from the donor consensus statement; primary graft dysfunction; peri-post-operative management of multiorgan transplant; vasoplegia; and care of recipients with congenital heart disease.

Task Force 2 - Immunosuppression and Rejection: What’s New?
Michael Shullo, PharmD, University of West Virginia, Morgantown, WV USA
Task force 2 compiled expansions to topics including rejection surveillance; emerging areas in non-invasive surveillance (molecular microscope, micro-RNA, cell free DNA, MRI); immunosuppressive regimens; antibody-mediated rejection (AMR) therapies; and late AMR.

Task Force 3 - Heart Transplant Long-Term Care Complication Management: What’s New?
Kyung-Hee Kim, MD, PhD, Sejong General Hospital, Seoul, Korea
Task force 3 addressed new topics including arrythmias, anticoagulation after heart transplant, and monitoring recipients of organs from donors at high risk of infectious diseases. They also proposed expansions to topics including imaging modalities and immunosuppression minimization.

Task Force 4 - Heart Transplant Long-Term Care Prevention and Prophylaxis: What’s New?
Howard Eisen, MD, Penn State Hershey Medical Center, Hershey, PA USA
Task force 4 addressed four new topics including substance use and abuse, family screening, travelling after heart transplant, and emerging pathogens, epidemics, and pandemic considerations for heart transplant recipients. They also composed expansions to topics including nutrition and weight management, intercurrent surgery updates, and psychosocial and psychologic issues.
   

Cancer and heart transplantation: once estranged, now commonly kin

The improving safety profile of VAD and heart transplant has allowed us to extend consideration for these therapies to an older, more complex patient population. As palpable evidence of this, consider the opening “one-liner” for the last patient presented at your heart transplant or VAD selection committee meeting. Chances are, it was sufficiently long that only a few salient words stick in your mind. But if “cancer” was mentioned—as is increasingly common—I suspect it was memorable and colored your overall impression of the patient.

Should mention of “cancer” carry such salience in the pre-transplant period? Sometimes yes, but often maybe not; this was my overall impression from today’s symposium Cancer, Advanced Heart Failure, and Heart Transplant: Do Any of My Cells Work Properly? Indeed, the observational data links pre-transplant history of malignancy with higher risk of post-transplant malignancy and (in some studies) reduced survival. But the list of potential confounders is long, and the same could be said for age and many other pre-transplant comorbidities. Nuanced consideration—weighing the type of malignancy and recurrence risk—is clearly warranted, as concluded by Neha Bansal, MD, of Children's Hospital at Montefiore in Bronx, NY USA during her talk Heart Transplantation and Cancer: What is the Risk?. “Blanket” policies (e.g., requiring at least five years of remission before heart transplant (HT) in candidates with any cancer history) should be reconsidered.

That said, the risk of malignancy—both recurrent and de novo—is perhaps unduly overlooked in the several years after transplant. To this point, Dr. Bansal presented data showing that risk of malignancy and associated mortality increases sharply at five years post-HT and beyond—a period when most other causes of mortality are in decline. By 10 years post-HT, the cumulative incidence of cancer reaches 20%, with non-melanoma skin cancers comprising the majority of cases. To some extent, this is an inevitable consequence of the mutagenic effects of aging and chronic immunosuppression. But Dr. Bansal suggests there’s a lot we could do to potentially reduce this risk. For instance, we might exploit the antiproliferative effects of mTOR inhibitors; their substitution (in place of calcineurin inhibitors) is associated with markedly reduced risk of post-HT malignancy. Avoiding induction therapy in those at risk of malignancy is another plausible strategy, though data bearing out the benefits of this approach are limited. When cancer prompts treatment with immune checkpoint inhibitors (ICIs), it should be at the forefront of the transplant clinician’s mind. This was emphasized by Jayant Raikhelkar, MD, of Columbia University Medical Center in New York, NY USA during his presentation Immunotherapy: What Do Transplant Providers Need to Know? While uncommon—occurring in 1% those treated with ICI therapy—fulminant myocarditis has a 50% mortality rate in this population. Its early clinical features (e.g., elevated troponin) overlap with those often occurring in HT rejection—and thus a high index of clinical suspicion must be maintained. “Timing matters” is perhaps the most important takeaway—if ICIs are stopped and high-dose IV corticosteroid therapy is started early in the course of ICI-related myocarditis, then mortality risk drops dramatically. Distinguishing it from rejection remains challenging, but MRI and specific biopsy features can help in its diagnosis.

If active malignancy is felt to preclude consideration for heart transplant, a natural follow-up question is “What about LVAD?”. Farooq H. Sheikh, MD, of MedStar Heart and Vascular Institute in Washington, DC USA addressed this question in his presentation A Balancing Act: Unique Challenges of Cancer in MCS Patients. Reassuringly, Dr. Sheikh presented data showing that both 1) patients with anthracycline-induced cardiomyopathy and 2) patients with active malignancy have no worse adjusted survival after LVAD implant, when compared with LVAD recipients with no malignancy history. Yet he emphasized the importance of goals of care discussions for cancer patients considering LVAD: “We’ve moved well-beyond one-year survival as a marker of success after LVAD implant… it’s critical to define upfront the goals of therapy beyond prolonging survival.”

Does cancer matter in the context of donor selection? The answer remains unclear, but emerging technology may help, as discussed by Jan von der Thüsen, MD, PhD, of Erasmus Medical Center in Rotterdam, Netherlands during Leveraging Pathology and Molecular Tools to Aid in Heart Donor and Recipient Cancer Risk Assessment. Even outside the context of MCS and heart transplant, there is an increasingly broad range of considerations affecting patients with concurrent cancer and medically-treated heart failure. These were discussed in depth by Anju Nohria, MD, MSc, of Brigham and Women's Hospital in Boston, MA USA during Curing Cancer, Causing Heart Disease: Acute Cardiac Dysfunction From Cancer Treatment and by Kirsten Rose-Felker, MD, of UPMC Children's Hospital of Pittsburgh during Developing Cardiomyopathy After Cancer Treatment: A New Journey Begins.
   

What to do When the Parents of the VAD/Transplant Candidate are High Risk? Ethics of Supporting Families Facing Structural Vulnerabilities
Samantha Anthony PhD, MSW, Hospital for Sick Children, Toronto, ON Canada
Bioethics is a critical reflection on moral/ethical problems in healthcare settings. An ethical dilemma is defined as when healthcare providers encounter (i) conflicting values, beliefs, and goals; (ii) have conflicting obligations or responsibilities, (iii) are concerned about rights violations or persons not being respected, fairness & justice, something conflicting with professional code of ethics; and/or (iv) are unsure what, why and how to do it. Fairness is paramount in deciding who is eligible for a lifesaving organ.

Social determinants of health include: education access and quality, healthcare access and quality, economic stability, social and community context, and the neighborhood and built environment. A structural vulnerability is an individual or a population group’s condition of being at risk for negative health outcomes through their interface with socio-economic, political, and cultural hierarchies. Patients are structurally vulnerable when their location in their society’s multiple overlapping and mutually reinforcing power hierarchies and institutional and policy-level statuses constrain their ability to access health care and pursue healthy lifestyles.

There is immense pressure of best use of available organs, we must optimize graft survival and function, and it should benefit both quantity and quality of life. A patient’s psychological health and social support system are key to optimizing quality of life and maintaining medical adherence, thus psychosocial evaluation is very important to identify psychosocial risk factors and appropriately intervene to optimize psychological health. An evaluation of child and their parent and family is necessary. Psychosocial factors are not commonly used in pediatrics to determine eligibility for transplant. Transplant teams are motivated to identify psychosocial concerns early in the transplant process and address deficient resources and facilitate healthy change. However, there may be circumstances when the sum of the psychosocial risk factors is so great that a child should not be transplanted or should have transplant delayed.

Pre-transplant strategies to support families include screening for and addressing a child and family’s social needs by a social determinants of health/structural vulnerability assessment tool that includes the following domains:

• Financial security
• Residence
• Risk environments
• Food access
• Social network
• Legal status
• Education
• Discrimination

There should be open conversations about increased psychological support and help from other family members. Adequate information should be provided and understanding ensured regarding pros and cons of VAD and transplantation and the procedures and post-treatment management. Mentorship programs can be started.

Post-transplant strategies to support families include assessments of family’s readiness for discharge as a part of routine post-operative care; immediate post-transplant and follow up neuropsychological assessment; and interventions to promote early transplant mobility. Coordinated discharge teaching should be done tailored to the family’s needs. The ongoing communication between the transplant team, family and school should be monitored. Parent/family functioning should also be monitored as part of routine follow up. Use of telehealth technology can also be used as a monitoring tool.

Don’t Throw Away Your Shot: Vaccine Refusal in Pediatric Transplantation
Lara Danziger-Isakov, MD, MPH, Children’s Hospital Medical Center, Cincinnati, OH USA
Firstly, we demonstrate the need for vaccination. Feldman et al evaluated 6,980 pediatric patients with solid organ transplant. There were 1,092 patients with 1,471 cases of RSV or vaccine preventable illness; of these, 187 cases were during transplant hospitalization, and car=se fatality rate was 1.7%/ Of the 1,257 events outside transplant hospitalization, 213 were admitted to the ICU. It was noted that through September 2020 that there was a 26% drop in DTap vaccine administration and MMR administration, and a 16% drop in polio vaccination when compared to 2019. There were around 9 million missed vaccinations in 2020, with 40% of parents confirming that their child missed vaccination due to COVID-19. There is reduced community protection for our children and communities against measles, whooping cough, and polio.

Secondly, the issues need to be framed. Medical contraindications like age or transplant urgency, fefusal, and social/logistical reasons. A 2013 survey of 195 pediatric programs with a 71% response rate revealed inconsistencies across pediatric transplantation programs regarding how parental refusal of vaccination affects listing decisions. Logistical concerns include timing, decentralized care, and clinic-related factors like vaccine availability, clinic time/room turnover, transition to telehealth/remote care, and distraction by ongoing medical issues.

Various opportunities to tackle this include:

• Adequate education: assess underlying reasons for refusal, address risks and benefits, and provide an individualized assessment. Practice with patience, empathy, and persistence.
• Prioritization and routinization of providing the vaccine
• Ensuring Availability
• Coordination with various apps that document vaccination schedules and statuses and innovation. These apps may not be applicable to patients with accelerated schedules, presence of any contraindications, and individuals with specific risks
• Innovation: The Updated 2019 AST ID guidelines- MMR and Varicella vaccination are generally contraindicated post-transplant but may be administered in a carefully controlled setting with appropriate education and close follow up. Outstanding questions remain regarding durability and patient selection.

You Are What You Eat: BMI Considerations in Pediatric Transplant and VAD Patients
Carmel Bogle, MD, University of Maryland Medical Center, Baltimore, MD USA
The definition of obesity in pediatrics is stratified on basis of percentile, unlike adults. Class I obesity is 100-120% of 95th percentile, Class II is 121-140% of 95th percentile, and Class III is > 140% of 95th percentile. There is an increasing trend in obesity among children, and adolescents aged 2-19 years by age had worsened over the course of years (from 1960s through 2018). When adjusted with age and sex, it was noted that BMIs have increased significantly post-pandemic.

A PHTS analysis evaluated obesity and dyslipidemia to predict cardiac allograft vasculopathy and graft loss in children and adolescents post-heart transplant. They noted 10% were overweight, 11% were obese, and there was higher propensity of obesity in recipients over 10 years of age. In a survey of adult and pediatric heart, kidney, liver, and lung programs, it was noted that 59.4% pediatric heart transplant centers encountered patients with BMI> 45. 53.5% pediatric heart transplant centers noted BMI > 45 as an absolute contraindication to adult heart transplant listing.

In another analysis, Ryan et al noted that obesity class does not further stratify outcome in overweight and obese pediatric patients after heart transplantation. Patients with BMI > 85th percentile were more likely to be older, males, Black, or Hispanic with dilated cardiomyopathy, diabetic, and required MCS at both listing and transplant. Overweight and combined obese patients had lower cumulative post-transplant survival compared to normal weight patients. Pediatric patients who are obese at the time of HT and dyslipidemic at one year post-HT are at an increased risk for CAV and graft loss.

Is obesity a contraindication for VAD placement? Puri et al evaluated trends in BMI and association with outcomes in pediatric patients on continuous flow ventricular assist device support. They noted that 18% were overweight, 17% obese, BMI was increased in all categories and overweight patients carried more frequent non-VAD infections. Obese patients required longer duration on VAD support, and were less likely to be transplanted.

In another analysis by Joong et al, it was noted that 74% providers would agree to offer VAD support to an adolescent with a BMI > 35. Fitness programs are recommended to improve outcomes pre- and post-transplant. Chen et al demonstrated excellent adherence with significant improvements in cardiovascular and functional health in pediatric heart transplant recipients with a live video-supervised exercise and diet intervention is feasible.

Delays Shouldn’t Leave Me Behind: Transplantation in Patients With Neuro-Cognitive Impairment Matthew Fenton, MD, MBBS, BSc, Great Ormond Street Hospital Children’s, London, UK
We are now in an era where early mortality post-transplant is rarer. As outcomes have improved, the utility for a broader range of conditions has increased. As survival increases, the value of treatment increases as well. However, organ availability has not kept pace with increasing demand for an effective treatment. Ethical principles in rationing donor organs include:

• Utility: Allocation should maximize the net amount of good. We should balance doing good and not doing harm; determinants will be predicted years of life and wellbeing, with social worth excluded.
• Justice: Fairness in the allocation of organ for individuals and centers; all members of the public are morally entitled to fair access of its benefits; access related to social characteristics conflicts with just principles.
• Respect for person’s autonomy: A respect for right to decide, equality of access, and when considering listing those with infectious disease this is quite important
• Rule of rescue: The human desire to help when life is in danger. Utilitarian principles can appear inhumane: rescue first, evaluate effectiveness later.

Prior to the 1990s, intellectual disability was generally regarded as a contraindication for transplant. 1995 American Society of Transplant Physicians state that intellectual disability should only be a contraindication if compliance is impaired and caregivers ae not able to compensate for this. In 1996, the first patient with Down Syndrome received an organ transplant. It is unacceptable to exclude an individual from transplant listing based on disability. Evaluation was to focus on benefit, predicted survival, compliance, and availability of support. It was noted in 2004 that only 3 patients with Down Syndrome were referred for thoracic transplant over 14 years in the UK. Per Broda et al in 2018, only 2.1% of US pediatric hearts were done on patients with chromosomal abnormalities with no difference in outcomes. Patients receiving heart transplants for inherited myopathies and DiGeorge Syndrome have similar outcomes to unaffected heart transplant recipients.

In another survey of heat, kidney, liver, and lung transplantation, Wall et al noted that there are still some programs that consider genetic disease and intellectual disability as an absolute contraindication for transplant, with pediatric centers less likely to do so compared with adult centers. Categorization in general should be avoided and focus should be on individual assessment. General practice guidelines should be formulated to aid assessment.

Blanket discrimination against people with neurocognitive impairment or genetic conditions is unethical and illegal. Patients with comorbidities should be assessed for transplant listing based on their individual circumstances. Guidelines for rare conditions help provide consistency and should be created across centers. Public engagement in driving decision making reveals that perhaps the threshold for a meaningful life is lower than the medics may think. Using a limited resource does not always have to about efficiency but can also be about equality of access to transplantation.

“The Green Revolution”: What to do When Your Teenage Patient Smokes Pot?
Robert Page, PharmD, MS, University of Colorado School of Pharmacy, Aurora, CO USA
During the past year, marijuana and substance use has increased among people aged 12 years and older. Marijuana is legalized in many states now, but there are certain age restrictions varying per each state. Younger people are using marijuana mostly due to mental health issues, friends and peer pressure, and media and pop culture. Cannabis has certain neurological effects on teens, like abnormal stress responsivity, glial cell activation, desynchronization of PFC neuronal networks, excessive synaptic pruning, and dysregulation of monoaminergic pathway. Acute neurological effects include inaccurate perception of time and sounds; slower reaction time affecting driving and increasing injury risk; problems with memory and learning; as well as poor judgement, panic attacks, distrustful thoughts, and symptoms of psychosis. Chronic neurological effects include impaired learning, memory, and attention; increased risk of schizophrenia or other psychotic disorders, especially in vulnerable individuals; and addiction.

Various cardiovascular effects on teens include hypotension/bradycardia with higher doses, arrhythmia due to hyperadrenergic state, stroke due to decreased cerebral blood velocity, ischemia due to arterial vasospasm and tachycardia, thrombosis due to procoagulant state, and platelet activation and atherosclerosis due to oxidative stress/endothelial injury. Matta et al noted that recreational substances including cannabis were independently associated with a higher likelihood of premature and extremely premature ASCVD, and its use confers a greater magnitude of risk for premature ASCVD among women.

Therefore, a discussion of risks and potential of not being listed per center’s policy should be discussed, and a psychologist and social worker evaluation is a must. Teens are not invincible and cannabis use can have long term consequences.

When the Team is at Odds: Decision-Making Distress and Conflict Among the Advanced Heart and Lung Failure Teams Melissa Cousino, PhD, C.S. Mott Children’s Hospital, Ann Arbor, MI USA
Interprofessional teamwork is an interpersonal process characterized by healthcare professionals from multiple disciplines with shared objectives, decision making, responsibility, and power working together to solve patient care problems. The joint commission in 2011 noted that 65% of sentinel events in cardiac operating room are due to communication failures. Transplant medicine is high-stakes and involves end-stage decision making with a lack of predictability and multiple ethical considerations, including large teams with diverse backgrounds. Communication amongst the team is extremely important. Clinician stress and burn out is highly prevalent amongst physicians and nurses.

Group dynamics that can fuel conflicts include hierarchies, trust/rapport, and preference/style. Clinician bias includes race, socioeconomic status, and education. Our goal is to intentionally cultivate and maintain strong personal relationships, reliable and open communication methods, conflict resolution strategies, and shared professional goals to succeed in our challenging work.

Various strategies to improve rapport include clinician wellness, team building, conflict resolution, co-location, communication, and education. We must evaluate the strengths and weaknesses of our teams, realize the team goal, and identify opportunities to work on these goals, along with identifying threats that are outside of our team’s control.
   

A Blurry, Moving, and Faintly-Drawn Line

Today’s symposium Relative Contraindications to Heart Transplantation: Where is the Line? poses a simple and clear question. The answer is anything but simple; advances in our field (e.g., multi-organ transplantation, mechanical circulatory support) have allowed an increasingly broad range of patients to benefit from heart transplantation (HT); accordingly, the “line” is blurry, moving, and faintly-drawn. This is no doubt a sign of progress—but it also poses a challenge, as we must continually revise our lists of relative and absolute contraindications to HT.

A case in point: diabetes mellitus (DM) or chronic kidney disease (CKD) appeared at the top of these “lists” in the 1980s-1990s, but are exceedingly common among today’s HT recipients. In contrast, HIV infection remains an absolute contraindication to HT at some centers—even as it resembles DM and CKD in terms of its effect on life expectancy (reducing it by ~9 years). This apparent paradox was addressed by Julie Doberne, MD, PhD, of Duke University Medical Center in Durham, NC USA in her presentation HIV: Is It Time To HOPE?. Her recent study compared outcomes in HIV+ recipients with propensity-matched HIV- recipients in a nationwide cohort; HIV+ recipients had higher rates of acute rejection but equivalent overall survival. On the next frontier—made possible by the HOPE Act—are prospective studies on the use of HIV+ donors for transplant into HIV+ recipients (D+/R+). Dr. Doberne presented data from the first such studies in kidney (Durand et al 2021) and liver (Durand et al 2022) transplants, which found equivalent survival in D+/R+ and D-/R+ transplants.

Age is another HT contraindication where the “line” is blurred. While age ≥ 70 would preclude transplant in many settings, it is increasingly common in France, according to data presented by Richard Dorent, MD, of Agence de la Biomédecine in Saint-Denis, France in Happy 70th Birthday! Off You Go. In a comprehensive sample of septuagenarian transplants in France, his team found that their 10-year survival was lower (34%) than that of younger HT recipients. This may have been expected—but perhaps more noteworthy was that most deaths in these older recipients were due to either infection or cancer. Whether an “age-tailored,” lower-intensity immunosuppression strategy could have averted some of these deaths warrants further study.

The “lines” are a bit clearer when it comes to candidates with active tobacco use and alcohol abuse; per 2016 ISHLT Guidelines these are relative and absolute contraindications to HT, respectively. No explicit recommendations were given regarding recreational cannabis use, leaving transplant centers much room for discretion. Chief among the many pertinent considerations, as presented by Eileen Hsich, MD, of Cleveland Clinic in Cleveland, OH USA in VAPING, NICOTINE and CANNABIS: Going Up in Smoke? is the fact that cannabinoids (e.g., THC, CBD) inhibit the metabolism of calcineurin inhibitors (thus potentially increasing their levels) via interactions with cytochrome P450 enzymes. Accordingly, most programs mandate abstaining from cannabis use prior to HT—how long this period of abstinence should be remains open to debate. Per audience comments at this Friday session, such debates are a common occurrence in HT selection committee meetings.

Additional presentations discussed the challenges posed by HT candidates who are “difficult to match”, in terms of size and histocompatibility. These included: WEIGHT: Balancing the Scales by Johan Nilsson, MD, PhD, of Skanes University Hospital in Lund, Sweden and SENSITIZATION: Is There a Sensible Solution? by Monica Colvin, MD, of the University of Michigan in Ann Arbor, MI USA.
   

This oral abstract session highlights research focusing on expanding donor availability, including donation after circulatory death (DCD) as well donor selection and procurement during the COVID pandemic.

Heart Transplantation from Donation After Circulatory Death Donors: An Update on the Australian Experience
Yashutosh Joshi, MBBS, St. Vincent’s Hospital, Sydney, NSW Australia
The investigators presented the overall impact of DCD over the last eight years on their heart transplant program as well as their early and more contemporary outcomes with utilization of DCD donors. Inclusion criteria for DCD donors included: normal transthoracic echocardiogram, age less than 55 years, and absence of previous cardiac history. Explanted hearts were cannulated onto an ex vivo normothermic machine perfusion device where 1.2-1.5L of donor blood is circulated in a Langendorff fashion. Visual inspection and monitoring of lactate trends were used to assess for viability. Since 2014, 69 DCD heart transplants were performed.

Key findings include:

1. Overall one- and five-year survival for DCD vs BD donor heart transplant recipients was not significantly different (p=0.27).
2. The use of ECMO/mechanical support in the immediate post-op period decreased from 35% to 8.6% over the study period.
3. Donor hearts subject to an aWIT >15mins were more likely to require post-operative ECMO/mechanical support.

Expanding Heart Transplants from Donors After Circulatory Death (DCD) - Results of the First Randomized Controlled Trial Using the Organ Care System (OCS™) Heart - (OCS DCD Heart Trial)
Jacob Niall Schroder, MD, Duke University, Durham, NC USA
The purpose of this study was to evaluate the effectiveness of the OCS Heart technology to resuscitate, preserve and assess DCD hearts for transplantation. Standard donor inclusion/exclusion criteria were applied. Recipient exclusion criteria included: multi-organ transplant candidates, history of prior solid organ or bone marrow transplants, history of chronic renal failure, or unrandomized recipients. Recipients were randomized 3:1 into the DCD or the donation after brain death (DBD) groups. A total of 180 patients were randomized and transplanted in the trial (DCD n=90 and Control n=90) at 13 heart transplant centers in the United States between 2019 and 2020.

Outcomes included: patient survival at 6- and 12-months post-transplant, OCS DCD heart utilization rate, incidence of severe left or right ventricular primary graft dysfunction (PGD). A total of 101 hearts were instrumented on OCS heart technology and 90 of these were transplanted, i.e. utilization rate of 89%. DCD donors were significantly younger than DBD donors. Superior patient and graft survival was seen at 12- and 24-months post-transplant with use of DCD OCS hearts compared to DBD cold storage hearts (12 months: 93% vs 86%; 24 months: 93% vs 83%). Lower complication rate was seen with DCD OCS hearts.

Early Outcomes of Donation After Circulatory Death Heart Transplantation with Thoracoabdominal Normothermic Regional Perfusion
Marian Urban, MD, University of Nebraska Medical Center, Omaha, NE USA
The purpose of this study was to evaluate the early outcomes of DCD heart transplantation using thoracoabdominal normothermic regional perfusion (TA-NRP). This was a single-center prospective study with single arm. In addition to standard inclusion criteria, recipients listed for dual organ transplantation and patients with previous cardiac operation including durable LVAD implantation were also included. All hearts were recovered with TA-NRP after no more than 30 minutes of warm ischemia (defined as the time period commencing from SBP < 50 mmHg to in situ reperfusion) and details of their TA-NRP protocol were presented. Grafts were recovered using 2,000mL of Celsior® for cardio protection, and transported with colds storage. Eight donor hearts were procured and from each donor at least one other organ was procured.

Key findings:

1. Modality of NRP was cardiopulmonary bypass in 5 cases and VA-ECMO in the remaining three
2. Only 2 recipients required post-transplant MCS in the form of VA-ECMO, all recipients were alive at 30 days post-transplant
3. Inotrope score at 72 hours ranged from 0 to 15, ICU length of stay ranged from 4 to 74 days
4. AKI was the most common adverse event (in 4 out of 8 recipients)

Increasing Utilization of Extended Criteria Donor After Brain Death (DBD) Hearts Seldomly Used for Transplantation in the U.S. Due to Limitation of Ischemic Cold Storage - 2-Year Results of the OCS Heart EXPAND Prospective Multi-Center Trial (OCS Heart EXPAND)
Jacob Niall Schroder, MD, Duke University School of Medicine, Durham, NC USA
The purpose of this study was to evaluate the effectiveness of the OCS heart perfusion technology to preserve and assess extended criteria DBD hearts that are seldom transplanted due to limitations of ischemic cold storage. This prospective, multi-center trial targeted DBD hearts with one or more of the following risk factors: expected cross clamp time of ≥4 hours; OR expected cross-clamp time of ≥ 2 hours with one or more of the following risk factors: Older donors age 45-55 years with no coronary cath OR ≥ 55 years old; history of cardiac downtime ≥20 min with stable hemodynamics at time of offer; history of LVH with septal or posterior wall thickness between 13-16 mm; LVEF 40-50%; or history of diabetes, or carbon monoxide poisoning or non-specific angiogram irregularities with no significant CAD. Use of these criteria made randomization impractical. A total of 138 extended criteria donor hearts were perfused and assessed on the OCS Heart System between 2015 and 2020. Over the same period, 1,813 standard criteria DBD heart transplants at the same EXPAND centers served as controls.

Key findings:

1. Of the 138 hearts procured, 116 were successfully transplanted resulting in an 84% utilization rate
2. Using KM analysis, survival of EXPAND trial patients was similar to controls (85% vs 88%)

Early Single Center Experience of Heart Transplantation from Donation After Circulatory Death Donors in the United States
Mark J. Kearns, MD, UC San Diego, San Diego, CA USA
The authors presented a single-center experience with DCD heart transplant (HT) using two procurement strategies: 1) direct procurement and perfusion (DPP) protocol, and 2) thoracoabdominal normothermic regional perfusion (TA-NRP) protocol. Data was collected prospectively.

From September 2020 to October 2021, they performed 33 DCD HTs with 13 DPP and 20 TA-NRP procurements. 30-day survival was 100% among all DCD heart recipients. The incidence of primary graft dysfunction and other secondary endpoints was comparable with standard DBD HT.

Transplanting Thoracic COVID-19 Positive Donors: Overcoming the Pandemic
Emily M. Eichenberger, MD, Duke University Medical Center, Durham, NC USA
The authors presented their institutional protocol and early results for thoracic organ transplantation using COVID-19-positive donors. Ten thoracic organ transplants in nine recipients using organs from COVID-19 positive donors (9 hearts; 1 pair of lungs) were performed with patient and graft survival to date of 100% and 91%.

Per protocol:

1. Hearts were procured from donors testing positive for COVID-19 on upper and/or lower respiratory tract specimens, provided severe COVID pneumonia or myocarditis was not the cause of death, and hypercoagulable complications were absent
2. Lungs were procured only if donors were first positive >20 days prior and were PCR-negative on bronchoalveolar lavage. Cycle threshold, duration of infectivity and urgency of recipient need were considered in addition to routine evaluations.

Key findings:

1. Eight heart recipients did not acquire COVID-19
2. One heart-liver recipient required re-do HT due to massive hemorrhage followed by hypercoagulability and coronary thrombus, with an RV biopsy suspicious for SARS-CoV-2 myocyte infiltration
3. Lung recipient did not develop COVID-19

   

Should Age-Based Eligibility Thresholds Differ for Heart Re-Transplantation? Analysis of the United Network for Organ Sharing Database
Qiudong (Kevin) Chen, MD, Cedars-Sinai Medical Center, Los Angeles, CA USA
Heart re-transplantation is associated with worse unadjusted survival compared to primary transplantation. In propensity-matched patients, survival after re-transplant is comparable to that of primary heart transplantation after excluding early/acute re-transplantation.

Chen et al evaluated outcomes of heart re-transplantation in older recipients using the national UNOS database. Of 1,295 heart re-transplants, 1,083 were retransplanted at < 60 years of age and 212 after 60 years of age. Of the 212 patients, 38 were excluded due to early/acute re-transplantation. The remaining 173 patients were compared with 12,833 patients who got primary heart transplantation after 60 years of age from 2003 to 2020.

The primary outcome included post-transplant survival up to 10 years. Secondary outcomes included in-hospital complications like treated acute rejections, stroke, new dialysis requirement, or permanent pacemaker placement, and 30- and 90- day mortality. It was observed that older recipients more than 60 years undergoing re-transplantation had worse unadjusted survival compared to younger recipients, while there was no difference in survival between different age groups when recipient ages < 60 years. It was concluded that retransplanting patients greater than 60 years old is independently associated with increased risk of long-term mortality. Careful consideration of recipient candidacy is warranted in elderly patients undergoing evaluation for heart re-transplantation.

The Effect of Race on Heart Transplantation Survival by Age
Alejandro Plana, MD, University of Chicago, Chicago, IL USA
The 2021 annual ISHLT adult heart transplantation (HT) report demonstrated worse survival for 18-39 year-olds in North America following HT compared to the 40-59 and 60+ age groups. The racial demographics of North America and Europe differs greatly, with a significantly higher proportion of Black patients in North America. African American patients are more likely to be diagnosed with HF at a younger age, with a higher prevalence of non-ischemic dilated cardiomyopathy as an indication for transplant. They are more likely to receive left ventricular assist device (LVAD) later in the disease course, and are subsequently less likely to undergo HT. Furthermore, African Americans undergoing HT have higher mortality and higher rates of graft failure. There is a higher prevalence of hypertension, recipient-donor HLA mismatch, and significantly different demographic characteristics. A higher proportion of young African American recipients die due to cardiovascular causes and graft failure compared to older African American patients and social determinants of health more heavily affect African American patients.

Plana et al aimed to assess each age cohort within the UNOS database for differences in survival after HT stratified by race/ethnicity. It was concluded that African Americans had increased post-HT mortality compared to their white, age-matched counterparts. This difference was prominent in the youngest age cohort, but was mitigated with increased age. These disparities were likely driven by social determinants of health, which affected younger patients more adversely. Low socioeconomic status (SES) correlates with more frequent HF hospitalizations and increased mortality. Low SES patients have been shown to have poorer adherence to immunosuppressive medications, higher rates of rejection, and higher frequency of infections. Immunologic factors may also play a role given higher PRA and immune activation after transplant, higher rate of DSA formation, and that younger African American females tend to be highly sensitized with an increased risk of rejection. More analysis is needed to determine key drivers of these differences. Key areas of further research would be optimizing immunosuppression management and regimens especially in the first- year post-transplant for young black patients.

Survival After Heart Transplant is Poor With High Venous Pressures and Low Arterial Elastance
Komarakshi Balakrishnan, MD, MGM Hospital, Chennai, India
Increased venous pressure is associated with renal dysfunction and mortality in patients with decompensated heart failure. Impaired right ventricular function is associated with poor survival in heart failure. Heart transplant (HT) is the only option for patients with severe biventricular dysfunction who have failed medical therapy. Lowering arterial elastance with vasodilators is very effective in improving the cardiac output, and vasodilators are an important component of medical management.

Balakrishnan et al sought to evaluate the effect of high venous pressures and a low Ea after HT. They retrospectively studied 250 patients who underwent a HT between October 2012 to March 2020. Venous pressure more than 15 mm Hg was considered high and as evidence of RV dysfunction. Hospital mortality was defined as death within 90 days of the transplant.

It was observed that higher right atrial pressure was a significant risk factor for 90-day mortality. This risk was decreased with increasing arterial elastance. Lower organ perfusion pressure index (that was measured as [mean arterial pressure – right atrial pressure]/BSA) had a significant impact on 90-day mortality. The impact of high RAP and low arterial elastance persisted at medium-term follow up. Higher MELD score significantly increased hospital mortality. A value < 40 is associated with worse outcomes.

They also concluded that compared to isolated LV dysfunction, onset of biventricular dysfunction leads to higher RAP, lower cardiac output, higher arterial elastance, lower mean arterial pressure, and lower OPPI. Aggressive vasodilator therapy to improve cardiac output in the presence of high RAP can lead to increased venous return to the right heart and higher RAP and lower OPPI. This study revealed insight into why onset of RV dysfunction in HF carries an ominous prognosis. Patients with high venous pressures awaiting HT need to be carefully monitored for drop in organ perfusion pressure while on vasodilators, and addition of intra-aortic balloon pump may confer additional benefit.

Comparative Analyses of Donor-Recipient Age Differences in Adult Cardiothoracic Transplantation: An Analysis of the UNOS/OPTN Database
Hari Rajagopal, Carnegie Vanguard High School, Houston, TX USA
Broad trends towards increased thoracic organ transplantation in older recipients are well described and usage of older donor organs is well accepted by many programs. However, little is known about comparative recipient and donor age demographics, and how these may vary with time.

Rajagopal et al evaluated the UNOS/OPTN STAR file for both adult isolated heart and lung transplantation between 1988-2017. Donor organ pool, recipient waitlist pool, and transplanted patient pool were stratified with respect to age, and 30-day and 1 -year survival outcomes were reported, also stratified per age range. They observed that there was an increased percentage of heart recipients aged 60-69 and > 70 years over time. There was a decreased percentage of heart recipients aged 40-49 and 50-59 over time. No clear temporal trends were observed with respect to donor heart age demographics. Short-term survival was inversely related to recipient age.

With respect to lung transplants, they noted similar trends in recipients, but more dramatically, as the age group 60-69 years is close to majority of the recipients. No clear trends in donor age demographics were noted akin to heart transplantation. Short-term survival was inversely related to age except in the 18-29 years age group. Cardiothoracic transplantation involves a transference of organs from younger donors to older recipients but the extent of this has increased recently. Older recipients have decreased short term survival which likely translates to diminished long-term survival. These findings may have implications for organ allocation policies.

Using Hemodynamics to Define Graft Function: Do We Need It?
Marco Masetti, MD, PhD, Heart Failure and Heart Transplant Unit, Bologna, Italy
Evaluation of graft function after heart transplantation (HT) is made by echocardiography to evaluate left ventricular ejection fraction (LVEF), endomyocardial biopsy (EMB) for monitoring for rejection, and coronary angiography to assess allograft vasculopathy. The role of assessment of graft function through hemodynamics as assessed by right heart catheterization (RHC) is unknown.

Masetti et al sought to explore the correlation of RHC with histological findings and the standard methods used to evaluate graft function and its ability to stratify prognosis. Bologna’s usual protocol is EMB routinely until five years after HT, and after five years in case of concerns for rejection; echo at every EMB and clinical visit; angiography at first and every five years after HT. They included patients undergoing EMB after the first month from HT for standard monitoring or for symptoms > 5 years from HT.

The follow up was started after first abnormal RHC or, if no abnormal values were found, after the last RHC performed in the observation period. The endpoints were the interplay between RHC, LVEF and EMB; and two years MACE occurrence events. Data was collected at each EMB. The RHC groups were divided as normal (normal filling pressures and normal cardiac index); diastolic dysfunction (high filling pressures and normal cardiac index) and low cardiac index. 586 EMBs were performed in 113 patients.

They noted poor correlation between LVEF and hemodynamics, particularly cardiac output. Hemodynamics are better correlated than LVEF to histology and helps in stratifying prognosis in patients with rejection. The assessment of graft function by LVEF underestimates the risk of MACE. Assessment of diastolic dysfunction by RHC may help in suspecting AMR.
   

Considering the benefits—and costs—of two instead of one
Increasing familiarity and improving outcomes with dual-organ transplant has effectively broadened the heart transplant (HT) candidate pool to include those with accompanying end-stage kidney or liver failure. Simultaneous heart-kidney and heart-liver transplant volumes have increased accordingly. These trends are no doubt encouraging, but should be considered alongside a more sobering fact: each of these dual-organ transplants means one fewer organ available to the > 100k patients waiting (months or often years) for kidney-only or liver-only transplant.

This tension demands that we in the HT community consider ourselves in partnership with the broader solid organ transplant community, and ask the question posed by today’s aptly-titled session A Heart Partnership: When is Two Better Than One?

Maria Currie, MD, PhD, of Stanford University in Palo Alto, CA USA attempted to answer this question in the heart-liver context in her presentation Predicting Survival in Combined Heart-Liver Transplantation Compared to Heart Transplantation Alone. Specifically, her group hypothesized that candidates with higher MELD-Na score would derive greater benefit from heart-liver transplant (vs. heart transplant-only). While certainly plausible, her analysis—which compared survival in 326 simultaneous heart-liver (HLT) recipients in the nationwide UNOS database with 278 heart-only recipients in the Stanford database—showed no interaction between type of transplant (i.e., heart-liver vs. heart-only) and MELD-Na score. She concludes that MELD-Na score is not a useful metric for discerning which patients warrant simultaneous heart-liver (vs. heart-only) transplant.

An analysis by Pierre-Emmanuel Noly, MD, PhD, of the University of Michigan in Ann Arbor, MI USA posed a related question: “Might HLT outcomes differ according to the underlying heart failure etiology?” In his presentation Outcomes Following Simultaneous Heart-Liver Transplantation: An Analysis of Donor and Recipient Characteristics, he compared short- and long- term outcomes after SHLT among ischemic cardiomyopathy (ICM), non-ischemic cardiomyopathy (NICM), and adult congenital heart disease (ACHD) patients in a comprehensive US sample spanning 10 years. His findings included similar short-term survival, but better long-term survival among ACHD recipients—perhaps owing to their younger age. Of note, he presented a separate abstract (Outcomes Following Heart Transplantation in Adults with Congenital Heart Disease) comparing outcomes after HT-only by heart failure etiology. This analysis actually showed slightly worse short-term survival—but again, better long-term survival—among ACHD (vs. non-ACHD) recipients. Further work identifying which ACHD patients fare better with SHLT (vs. HT-only) could yield guidance for patient selection.

Further complicating patient selection for dual-organ transplant is the potential impact of changing allocation policy, and associated changes in the use of temporary mechanical circulatory support (tMCS), as was addressed by Arianne Clare Agdamag, MD, of the University of Minnesota in Minneapolis, MN USA during her analysis Simultaneous Heart-Kidney (SHK) Transplant Outcomes Pre- and Post-Heart Allocation System Change: Impact of Temporary Mechanical Circulatory Support. In an analysis including all US SHK recipients from 2016-2019, she found that one-year survival was actually worse after the October 2018 allocation change, but that this change could not be ascribed to the dramatic rise in tMCS use (as the tMCS and non-tMCS groups had equivalent one-year survival). This potentially alarming trend warrants our attention, along with further studies extending beyond 2019.

Last but certainly not least was Umar Siddiqi of the University of Chicago, who presented Graft Rejection and Survival in Patients Undergoing Multi-Organ Heart Transplantation. In a comprehensive cohort of US heart-only (HT-only), HLT, SHK, and heart-lung recipients dating back to 1988 (total n = 80,058), he found that heart-lung recipients had the worst (multivariate adjusted) graft survival among these groups. But intriguingly, each of the dual-organ groups had significantly lower risk of rejection than HT-only recipients.

So “two is better than one” when it comes to post-transplant rejection; but beyond this, the answer to this session’s titular question remains unclear. Kudos to these presenters for their ongoing efforts to answer it, and thus ensure that the limited supply of donor kidneys and livers goes to recipients who will benefit from them most.
   

The aim of this session was to explore the impact on anti-HLA sensitization, the donor specific crossmatch, and eplet matching on pediatric heart transplant outcomes. This session also explored how immunosuppression medications and diagnostic imaging are being used in pediatric heart transplant care.

No Association Between Early Donor Specific Antibody and Subsequent Allograft Function at 3 Years Post-Pediatric Heart Transplantation. First Results of a Prospective Multi-Institutional Study
Steven A. Webber, MBChB, Vanderbilt University School of Medicine, Nashville, TN USA
As part of a follow-up of the CTOT-04 study, the authors presented CTOT-09 study wherein they assessed the impact of ‘preformed’ (at transplant) and first-year newly detected donor specific antibody (ndDSA) on allograft function at three years. Consecutive children listed for transplant at nine centers were prospectively enrolled and the management of sensitization, immunosuppression, and rejection surveillance was standardized across centers. Donor specific antibody or DSA was defined by single antigen Luminex testing with ≥1 antibody specific towards donor HLA antigens with MFI>1000.

Key findings were:

1. The primary outcome of PCWP at 3 years was similar in transplant recipients with and without early DSA
2. Other invasive hemodynamics, ejection fraction, and BNP were also similar regardless of early DSA
3. Graft and patient survival did not differ between groups, though freedom from all acute rejection types was inferior in subjects with preformed DSA.

A Positive CDC T-cell Crossmatch is Strongly Associated with Allograft Loss and Early Rejection in Pediatric Heart Transplant Recipients
Ryan J. Williams, MD, UCLA Mattel Children’s Hospital, Los Angeles, CA USA
The investigators queried the OPTN database for all pediatric heart transplants performed between 1999 and 2019 and assessed the association of donor specific T-cell CDC and Flow XM HT with the risk of rejection and allograft loss in United States pediatric recipients.

Of 4,695 pediatric HT, there were 165 CDC+, 288 Flow+/CDC Unknown, 94 Flow+/CDC-, and 4,148 Flow- recipients. Children receiving a CDC+ XM HT were found to be at higher risk of graft loss and rejection during the first post-transplant year, suggesting higher anti-HLA antibody burden in such recipients. They concluded that the shift away from performing a CDC XM results in a loss of important prognostic information.

Eplet Matching in Pediatric Heart Transplantation
Barbara Cardoso, MD, Freeman Hospital, Newcastle-upon-Tyne, UK
The purpose of this retrospective, single-center study was to compare antigen- to molecular-level HLA matching in regard to post-heart transplant outcomes in a pediatric population. HLA typing, antigen mismatch, and eplet mismatch analysis were performed on all donor/recipient pairs. 77 patients were included.

Key findings included:

1. Number of HLA Class II DPB donor-recipient eplet mismatches was independently associated with graft loss (HR 8.14 [95% CI: 1.26 - 49], p = 0.02)
2. Neither HLA class I nor class II eplet mismatching nor HLA class I and II antigen mismatching was associated with rejection or graft loss
3. The most accurate prediction was obtained with prior heart surgery, prior ECMO, sensitization against HLA class II antigens, and number of HLA Class II DPB eplet mismatches as independent variables.

Immunosuppressant Drug Level Monitoring in Pediatric Heart Transplant Recipients: A Report from the TEAMMATE Trial
Matthew J. Bock, MD, Rady Children’s Hospital, UC San Diego, San Diego, CA USA
The investigators presented results of an analysis from the TEAMMATE trial of everolimus (EVL) with low-dose tacrolimus (LDTAC) vs. standard tacrolimus (TAC) with mycophenolate (MMF) focused on their immunosuppressant drug level monitoring experience in the trial. A total of 211 children were randomized to either EVL/LDTAC (n=107) or usual care TAC/MMF (n=104). After randomization, a therapeutic level was achieved in 94% (EVL) & 91% (MMF) with the median time to a therapeutic level for EVL being 10 (tablet) & 11 (liquid) days. The coefficient of variation was lower for TAC, EVL, and LDTAC (36%, 47%, and 52% respectively) compared to MMF (103%). EVL levels were in target range 80% of times and the standard deviation of levels divided by therapeutic window was lowest for EVL. The authors concluded that EVL achieved stable target levels more frequently than MMF, LDTAC or TAC, likely due to decreased trough level variability and its wider therapeutic window.

Utility of Intravascular Ultrasound Early After Pediatric Heart Transplantation
Michael A. Kuhn, MD, Loma Linda University, Loma Linda, CA USA
The investigators examined the use of IVUS early (< 5 years) after pediatric HTX. They found 71 patients who had IVUS performed within 5 years of HTX. Patients were classified based on Stanford IVUS class (SIC) into SIC 1-2 and 3-4. Freedom from CAV and graft loss from CAV were lower in the SIC 3-4 group [CAV HR 2.7 (1.4-5.4), p=0.01 and graft loss from CAV HR 3.4 (1.3-8.9), p=0.005, respectively]. However, graft loss from all causes and patient survival were not different between the groups (p=NS) suggesting that early changes in IVUS were associated with the development of CAV and graft loss from CAV over time.

Clinical Practice Variation of Statin Use in Pediatric Heart Transplantation
Justin H. Berger, MD, PhD, Children’s Hospital of Philadelphia, Philadelphia, PA USA
Data regarding the benefit of statins in pediatric transplant patients is equivocal. The investigators sought to establish statin prescribing practices in a sample of U.S. pediatric HT recipients in the current era, hypothesizing that use of statins in pediatrics increases with age and has increased over time. They used the Marketscan database and identified 876 children who underwent HT between the ages of 2 and 19 and had ≥3 years of continuous coverage from 1 January 2013 through 30 June 2018.

A higher proportion of HT recipients received Medicaid than commercial insurance coverage (56% vs. 44%, p<0.001). Thirty-five percent (95% CI 32-38%) of HT recipients were on a statin, at an average age of 11.47 ± 4.6 years at the time of the first statin prescription with the earliest age of statin initiation being 2 years. Likelihood of statin prescription increased with age from 18% for those between 2-5 years of age to 47% in those over 13 years of age.