Donor Hearts Research Articles

A Paradigm Shift in Heart Preservation: Improved Post-transplant Outcomes in Recipients of Donor Hearts Preserved with the SherpaPak System.

Traditional ice storage has been the historic standard for preserving donor's hearts. However, this approach provides variability in cooling, increasing risks of freezing injury. To date, no preservation technology has been reported to improve survival after transplantation. The Paragonix SherpaPak Cardiac Transport System (SCTS) is a controlled hypothermic technology clinically used since 2018. Real-world evidence on clinical benefits of SCTS compared to conventional ice cold storage (ICS) was evaluated. Between October 2015 and January 2022, 569 US adults receiving donor hearts preserved and transported either in SCTS (n = 255) or ICS (n = 314) were analyzed from the Global Utilization And Registry Database for Improved heArt preservatioN (GUARDIAN-Heart) registry. Propensity matching and a subgroup analysis of >240 minutes ischemic time were performed to evaluate comparative outcomes. Overall, the SCTS cohort had significantly lower rates of severe primary graft dysfunction (PGD) (p = 0.03). When propensity matched, SCTS had improving 1-year survival (p = 0.10), significantly lower rates of severe PGD (p = 0.011), and lower overall post-transplant MCS utilization (p = 0.098). For patients with ischemic times >4 hours, the SCTS cohort had reduced post-transplant MCS utilization (p = 0.01), reduced incidence of severe PGD (p = 0.005), and improved 30-day survival (p = 0.02). A multivariate analysis of independent risk factors revealed that compared to SCTS, use of ice results in a 3.4-fold greater chance of severe PGD (p = 0.014). Utilization of SCTS is associated with a trend toward increased post-transplant survival and significantly lower severe PGD and MCS utilization. These findings fundamentally challenge the decades-long status quo of transporting donor hearts using ice.

Short stature is a risk factor for heart transplant morbidity and mortality.

Short stature is associated with mortality after cardiac surgery and may increase size mismatch risk among transplant recipients. Yet, stature's impact on heart transplant outcomes is not well-characterized. The Scientific Registry of Transplant Recipients was queried for data on all adult heart transplants in the United States from 2000 to 2022. Recipients were stratified into five cohorts by sex-corrected stature. Morbidity was assessed with Kruskal-Wallis and chi-squared tests. Mortality was analyzed using Kaplan-Meier estimation. Risk factors for mortality were assessed with multivariable Cox regression. Among 43,420 transplant recipients, 5321 (12.2%) had short stature (females >4'11″ & ≤5'1″; males >5'4″ & ≤5'7″) and 765 (1.8%) had very short stature (females ≤4'11″; males ≤5'4″). Very short stature patients had higher waitlist status (1A and 1), more congenital heart disease, and received more oversized donor hearts than other cohorts (all p < 0.05). Very short stature patients had decreased 30-day, 1-, 5-, and 10-year survival (94.6%, 84.3%, 69.3% and 52.5%, respectively, all p < 0.001), but less acute rejection (p = 0.005) and comparable stroke rates (p = 0.107). On multivariable regression adjusting for congenital heart disease and oversized donor hearts, very short and short stature were associated with 10-year mortality (hazard ratios: 1.40 and 1.12, respectively, both p < 0.005). Short stature confers increased mortality risk for heart transplant recipients and merits inclusion in prognostic models.

Early national trends of lung allograft use during donation after circulatory death heart procurement in the United States

ObjectiveInnovative technology such as normothermic regional perfusion and the Organ Care System has expanded donation after circulatory death heart transplantation. We wanted to investigate the impact of donation after circulatory death heart procurement in concurrent lung donation and implantation at a national level. MethodsWe reviewed the United Network for Organ Sharing database for heart donation between December 2019 and March 2022. Donation after circulatory death donors were separated from donation after brain death donors and further categorized based on concomitant organ procurement of lung and heart, or heart only. ResultsA total of 8802 heart procurements consisted of 332 donation after circulatory death donors and 8470 donation after brain death donors. Concomitant lung procurement was lower among donation after circulatory death donors (19.3%) than in donation after brain death donors (38.0%, P < .001). The transplant rate of lungs in the setting of concomitant procurement is 13.6% in donation after circulatory death, whereas it is 38% in donation after brain death (P < .001). Of the 121 lungs from 64 donation after circulatory death donors, 22 lungs were retrieved but discarded (32.2%). Normothermic regional perfusion was performed in 37.3% of donation after circulatory death donors, and there was no difference in lung use between normothermic regional perfusion versus direct procurement and perfusion (20.2% and 18.8%). There was also no difference in 1-year survival between normothermic regional perfusion and direct procurement and perfusion. ConclusionsAlthough national use of donation after circulatory death hearts has increased, donation after circulatory death lungs has remained at a steady state. The implantation of lungs after concurrent procurement with the heart remains low, whereas transplantation of donation after circulatory death hearts is greater than 90%. The use of normothermic regional perfusion lungs has been controversial, and we report comparable 1-year outcomes to standard donation after circulatory death lungs. Further studies are warranted to investigate the underlying mechanisms of normothermic regional perfusion on lung function.

Cardiac transplantation in adult congenital heart disease: a narrative review.

As more children with congenital heart disease survive to adulthood, adult congenital heart disease (ACHD) prevalence will increase (currently ~1 million US patients). Heart failure (HF) accounts for 26-42% of ACHD deaths. The rate of ACHD heart transplantations (ACHD HTx) is also increasing. We describe the ACHD HTx recipient/candidate cohort, analyze ACHD HTx outcomes, identify ACHD HTx specific challenges, and discuss opportunities to better serve more patients with ACHD HF. PubMed literature search including articles published from 2010-2023. Reviewed 89 studies, 67 included. Our search focused on the challenges of ACHD HTx and potential solutions. ACHD HTx recipients are young [median age 35 years, interquartile range (IQR): 24-46 years]. 87-95% of ACHD HTx recipients had prior cardiac surgery. The most common underlying diagnoses include transposition of the great arteries (31%) and Fontan/Glenn circulation (28%). 63% of listed ACHD HTx candidates received a transplant within one year of listing. Post-transplant 1-year survival is 80%, 5-year survival 74%, and 10-year survival 59%. There are 4 unique ACHD HTx challenges: (I) difficulty in assessing pulmonary hypertension, resulting in some centers selecting oversized donor hearts. However, selecting oversized hearts does not improve post-operative mortality and could prolong waitlist time. (II) Increased immunologic sensitization, increasing rejection risk. Desensitization therapy has enabled sensitized HTx recipients to enjoy outcomes similar to non-sensitized recipients. (III) Procedural complexity with ~30% of cases requiring additional surgical reconstruction. Detailed multidisciplinary planning, extensive imaging, and transferring the patient into the operating room early can help manage the complexities and reduce organ ischemic time. (IV) Increased intraoperative bleeding due to patients' surgical histories and circulatory collaterals. Preoperative collateral coil embolization and select utilization of hypothermic circulatory arrest can help reduce bleeding. Additional Fontan specific challenges include extensive great artery repair, liver failure, plastic bronchitis, and protein loss enteropathy. Finally, given limited donor heart availability, mechanical circulatory support is a promising technology for patients with ACHD HF. The prevalence of ACHD HTx is slowly but steadily increasing. The operational complexity of ACHD HTx can be managed, and the majority of recipients have excellent outcomes (59% 10-year survival).

Donation after circulatory death improves probability of heart transplantation in waitlisted candidates and results in post-transplant outcomes similar to those achieved with brain-dead donors

ObjectiveTo quantitate the impact of heart donation after circulatory death (DCD) donor utilization on both waitlist and post-transplant outcomes in the United States. MethodsThe United Network for Organ Sharing database was queried to identify all adult waitlisted and transplanted candidates between October 18, 2018, and December 31, 2022. Waitlisted candidates were stratified according to whether they had been approved for donation after brain death (DBD) offers only or also approved for DCD offers. The cumulative incidence of transplantation was compared between the 2 cohorts. In a post-transplant analysis, 1-year post-transplant survival was compared between unmatched and propensity-score-matched cohorts of DBD and DCD recipients. ResultsA total of 14,803 candidates were waitlisted, including 12,287 approved for DBD donors only and 2516 approved for DCD donors. Overall, DCD approval was associated with an increased sub-hazard ratio (HR) for transplantation and a lower sub-HR for delisting owing to death/deterioration after risk adjustment. In a subgroup analysis, candidates with blood type B and status 4 designation received the greatest benefit from DCD approval. A total of 12,238 recipients underwent transplantation, 11,636 with DBD hearts and 602 with DCD hearts. Median waitlist times were significantly shorter for status 3 and status 4 recipients receiving DCD hearts. One-year post-transplant survival was comparable between unmatched and propensity score–matched cohorts of DBD and DCD recipients. ConclusionsThe use of DCD hearts confers a higher probability of transplantation and a lower incidence of death/deterioration while on the waitlist, particularly among certain subpopulations such as status 4 candidates. Importantly, the use of DCD donors results in similar post-transplant survival as DBD donors.

Left ventricular dysfunction in donor hearts is common and frequently reversible.

Left ventricular dysfunction in donor hearts is common and frequently reversible.

Erratum: Rat Model of Normothermic Ex-Situ Perfused Heterotopic Heart Transplantation.

Erratum: Rat Model of Normothermic Ex-Situ Perfused Heterotopic Heart Transplantation.

Combined triiodothyronine and preconditioning improves cardiac diastolic dysfunction in ex vivo rat hearts subjected to normothermic perfusion: a new method for donor heart preservation

Combined triiodothyronine and preconditioning improves cardiac diastolic dysfunction in ex vivo rat hearts subjected to normothermic perfusion: a new method for donor heart preservation

Use of Intravascular Ultrasound and Coronary Angiography to Measure the Prevalence of Myocardial Bridge in Heart Transplant Patients

Myocardial bridge (MB) detection rates vary across methods and most studies that have assessed MB include symptomatic patients. Intravascular ultrasound (IVUS) is a sensitive tool for MB detection and donor hearts may serve as a surrogate measure of asymptomatic patients. We used IVUS and coronary angiography to measure MB prevalence in heart transplant patients during routine follow-up invasive coronary assessments. This was a retrospective, single-center study of heart transplant patients who received follow-up coronary assessments at the University of Chicago Heart and Vascular Center between December 2014 and December 2021. A single experienced interventional cardiologist assessed incidental findings of MB in IVUS and coronary angiography. Detection rates were compared with meta-analysis-reported prevalence. Of 129 patients, IVUS-detected MB in 87 patients (67.4%), whereas coronary angiography detected 41 (31.8%). All MB found by coronary angiography were detected by IVUS. Some level of cardiac allograft vasculopathy was found in 92 patients (71.3%). Our IVUS-detected MB prevalence was greater than meta-analysis-reported pooled prevalence across all methods: autopsy, computed tomography angiography, and coronary angiography (67.4% [95% confidence interval [CI] 59.4 to 75.5] vs 42% [95% CI 30 to 55]; 22% [95% CI 18 to 25]; 6% [95% CI 5 to 8], p≤0.005). The difference between our observed IVUS-detected MB prevalence and meta-analysis autopsy reported MB prevalence was 1.25 (95% CI 1.11 to 1.40). In conclusion, the high prevalence of MB recorded in donor hearts emphasizes the need to further investigate the causes of chest pain in patients who are found to have MB.

Graft preservation in heart transplantation: current approaches.

Heart transplantation (HTx) represents the current best surgical treatment for patients affected by end-stage heart failure. However, with the improvement of medical and interventional therapies, the population of HTx candidates is increasingly old and at high-risk for mortality and complications. Moreover, the use of "extended donor criteria" to deal with the shortage of donors could increase the risk of worse outcomes after HTx. In this setting, the strategy of donor organ preservation could significantly affect HTx results. The most widely used technique for donor organ preservation is static cold storage in ice. New techniques that are clinically being used for donor heart preservation include static controlled hypothermia and machine perfusion (MP) systems. Controlled hypothermia allows for a monitored cold storage between 4°C and 8°C. This simple technique seems to better preserve the donor heart when compared to ice, probably avoiding tissue injury due to sub-zero °C temperatures. MP platforms are divided in normothermic and hypothermic, and continuously perfuse the donor heart, reducing ischemic time, a well-known independent risk factor for mortality after HTx. Also, normothermic MP permits to evaluate marginal donor grafts, and could represent a safe and effective technique to expand the available donor pool. However, despite the increasing number of donor hearts preserved with these new approaches, whether these techniques could be considered superior to traditional CS still represents a matter of debate. The aim of this review is to summarize and critically assess the available clinical data on donor heart preservation strategies employed for HTx.

Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder that can lead to heart failure and sudden cardiac death, characterized at the histological level by focal areas of myocyte disarray, hypertrophy and fibrosis, and only a few disease-targeted therapies exist. To identify the focal and spatially restricted alterations in the transcriptional pathways and reveal novel therapeutic targets, we performed a spatial transcriptomic analysis of the areas of focal myocyte disarray compared to areas of normal tissue using a commercially available platform (GeoMx, nanoString). We analyzed surgical myectomy tissue from four patients with HCM and the control interventricular septum tissue from two unused organ donor hearts that were free of cardiovascular disease. Histological sections were reviewed by an expert pathologist, and 72 focal areas with varying degrees of myocyte disarray (normal, mild, moderate, severe) were chosen for analysis. Areas of interest were interrogated with the Human Cancer Transcriptome Atlas designed to profile 1800 transcripts. Differential expression analysis revealed significant changes in gene expression between HCM and the control tissue, and functional enrichment analysis indicated that these genes were primarily involved in interferon production and mitochondrial energetics. Within the HCM tissue, differentially expressed genes between areas of normal and severe disarray were enriched for genes related to mitochondrial energetics and the extracellular matrix in severe disarray. An analysis of the gene expression of the ligand-receptor pair revealed that the HCM tissue exhibited downregulation of platelet-derived growth factor (PDGF), NOTCH, junctional adhesion molecule, and CD46 signaling while showing upregulation of fibronectin, CD99, cadherin, and amyloid precursor protein signaling. A deconvolution analysis utilizing the matched single nuclei RNA-sequencing (snRNA-seq) data to determine cell type composition in areas of interest revealed significant differences in fibroblast and vascular cell composition in areas of severe disarray when compared to normal areas in HCM samples. Cell composition in the normal areas of the control tissue was also divergent from the normal areas in HCM samples, which was consistent with the differential expression results. Overall, our data identify novel and potential disease-modifying targets for therapy in HCM.

A murine groin site cardiac transplantation model-applicable tool for studying roles of peripheral lymph nodes in transplantation.

The murine heterotopic cardiac transplantation model has been widely used to study antigen-specific immune responses or new immunosuppressive agents, which have a strong correlation with peripheral lymph nodes. Thus, a new organ transplantation model that is applicable to related studies is needed. Here, we describe a groin-site murine heart transplantation model using a cuff technique, in which the donor aorta and pulmonary artery are anastomosed to the truncated femoral vessels of the recipient. The mean survival time (MST) of the grafts in BALB/c-to-C57BL/6 allo-transplant group was 7.2 ± 0.3 days, and 1.9 ± 0.2 days in BALB/c-to-Sprague-Dawley (SD) rat xeno-transplant group. H&E results show that donor hearts from both groups demonstrate typical pathological features at the endpoint. Evans Blue tracing revealed that the popliteal lymph nodes of the grafted side hindlimb are larger than those of the contralateral side. Moreover, IHC staining for CD3, CD20 shows that the germinal center and cortex region of the grafted side of popliteal lymph nodes is apparently increased than that of the contralateral side. To sum up, this model may serve as an ideal model to study the role of peripheral lymph nodes in organ transplant rejection. In addition, extra-peritoneal grafting makes a step forward in animal welfare under the 3Rs' principle (Replacement, Reduction, Refinement).

Effect of Hematocrit and Elevated Beat Rate on the 12cc Penn State Pediatric Ventricular Assist Device.

Congenital heart disease affects approximately 40,000 infants annually in the United States with 25% requiring invasive treatment. Due to limited number of donor hearts and treatment options available for children, pediatric ventricular assist devices (PVADs) are used as a bridge to transplant. The 12cc pneumatic Penn State PVAD is optimized to prevent platelet adhesion and thrombus formation at patient nominal conditions; however, children demonstrate variable blood hematocrit and elevated heart rates. Therefore, with pediatric patients exhibiting greater variability, particle image velocimetry is used to evaluate the PVAD with three non-Newtonian hematocrit blood analogs (20%, 40%, and 60%) and at two beat rates (75 and 120 bpm) to understand the device's performance. The flow fields demonstrate a strong inlet jet that transitions to a solid body rotation during diastole. During systole, the rotation dissipates and reorganizes into an outlet jet. This flow field is consistent across all hematocrits and beat rates but at a higher velocity magnitude during 120 bpm. There are also minor differences in flow field timing and surface washing due to hematocrit. Therefore, despite patient differences in hematocrit or required pumping output, thorough surface washing can be achieved in the PVAD by altering operating conditions, thus reducing platelet adhesion potential.

Abstract P2060: Gja1-20k Expression Increases With Left Ventricular Mechanical Unloading In Patients With Arrhythmogenic Cardiomyopathy And Advanced Heart Failure

GJA1-20k, the internally translated isoform of the gap junction protein Connexin-43 (Cx43) is required for trafficking of the full length Cx43 to the membrane. We recently found that GJA1-20k expression is reduced in patients and mice with arrhythmogenic cardiomyopathy (ACM), and that gene therapy-mediated introduction of GJA1-20k in a mouse model of ACM rescues Cx43 trafficking to the intercalated disc and reduces arrhythmia burden, indicating that loss of GJA1-20k contributes to arrhythmogenesis in ACM. Here, we examined cardiac muscle from patients with a confirmed diagnosis of ACM for GJA1-20k expression before and after left ventricular assist device (LVAD) support. The goal of this study was to determine if left ventricular (LV) unloading benefits endogenous expression of this critical trafficking protein. Cardiac tissue was collected from consecutive, prospectively enrolled patients undergoing LVAD implantation or heart transplantation in hospitals comprising the Utah Cardiac Recovery program and donor patients from hospitals throughout the Intermountain West. Samples were prepared for analysis using a standard lysis buffer and analyzed via Western Blotting using antibodies to GAPDH and Cx43-CT. Consistent with prior findings, cardiac muscle samples from patients with ACM had decreased GJA1-20k expression relative to muscle from healthy donor hearts not allocated for transplantation. However, tissue obtained from the same ACM patients post LVAD support (at the time of heart transplantation) revealed a large and significant increase in GJA1-20k expression compared to the pre LVAD timepoint (1 +/- 0.5 vs 10.2+/- 1, p=0.0013, n=3 ACM pre/post). In contrast to patients with ACM, patients with non-ischemic cardiomyopathy (NICM) that underwent LVAD implantation had no significant change in GJA1-20k expression after LV unloading (1+/- 0.5 vs 1.4+/- 0.7, p= 0.424, n=4 NICM pre/post). These data indicate that LV mechanical unloading increases GJA1-20k expression in hearts of patients with known ACM. Further work will focus on how mechanical unloading regulates GJA1-20k expression and whether mechanical unloading is sufficient to recover Cx43 trafficking and limit arrhythmias in ACM.

Abstract P2003: Cardiomyocyte Polyploidy: Friend Or Foe?

Developmental polyploidization (whole genome duplication) of cardiomyocytes is well conserved across mammals, birds and Drosophila . However, it is unclear whether precise control of cardiomyocyte polyploidy is essential. We found that there is a chamber-specific asymmetry to cardiomyocyte polyploidy in the Drosophila cardiac organ which is regulated by differential sensitivity of Insulin signaling. Higher ploidy cardiomyocytes correspond to the heart chamber, while lower ploidy cardiomyocytes correspond to the aorta chamber. Using immunofluorescence staining (IF), optical coherence tomography (OCT) and live imaging, we found that reducing chamber-specific ploidy affects cardiac function and reduces the velocity of circulating hemocytes, which indicates systemic heart failure. Intriguingly using human donor heart samples, we found that chamber specific asymmetry in cardiomyocyte ploidy and insulin sensitivity is similar to Drosophila . Our findings suggest that precise control of ploidy levels for cardiac organ sculpting is conserved across species. Polyploidization may have negative effects on cardiomyocyte regeneration, but our results suggest that region-specific control of ploidy levels is important for organ development and functionally.

Elevated cardiac hemoglobin expression is associated with a pro-oxidative and inflammatory environment in primary mitral regurgitation

BackgroundPrimary mitral regurgitation (PMR) is associated with oxidative and inflammatory myocardial damage. We reported greater exosome hemoglobin (Hb) in pericardial fluid (PCF) versus plasma, suggesting a cardiac source of Hb. ObjectiveTest the hypothesis that Hb is produced in the PMR heart and is associated with increased inflammation. Methods and resultsHb gene expression for subunits alpha (HBA) and beta (HBB) was assessed in right atria (RA), left atria (LA) and left ventricular (LV) tissue from donor hearts (n = 10) and PMR patient biopsies at surgery (n = 11). PMR patients (n = 22) had PCF and blood collected for macrophage markers, pro-inflammatory cytokines, and matrix metalloproteinases (MMPs). In-situ hybridization for HBA mRNA and immunohistochemistry for Hb-alpha (Hbα) and Hb-beta (Hbβ) protein was performed on PMR tissue. ResultsHBA and HBB genes are significantly increased (>4-fold) in RA, LA, and LV in PMR vs. normal hearts. In PMR tissue, HBA mRNA is expressed in both LV cardiomyocytes and interstitial cells by in-situ hybridization; however, Hbα and Hbβ protein is only expressed in interstitial cells by immunohistochemistry. PCF oxyHb is significantly increased over plasma along with low ratios (<1.0) of haptoglobin:oxyHb and hemopexin:heme supporting a highly oxidative environment. Macrophage chemotactic protein-1, tumor necrosis factor-α, interleukin-6, and MMPs are significantly higher in PCF vs. plasma. ConclusionThere is increased Hb production in the PMR heart coupled with the inflammatory state of the heart, suggests a myocardial vulnerability of further Hb delivery and/or production during cardiac surgery that could adversely affect LV functional recovery.

Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

Synchronous Donor Heart and Lung Procurement Does Not Impair Outcomes After Heart Transplant.

Donor hearts frequently originate from donors whose lungs are also recovered for transplant. Synchronous heart and lung procurement is more complex than procurement ofthe heart alone, and the effects on outcomes are debated. This study examines the effect of synchronous procurement on outcomes in heart transplant recipients. This single-center study included patients who received a heart transplant from September 2010 to June 2022. Main outcomes were overall mortality and mortality at 30 days, 3 months, 1 year, and 3 years and morbidity within the first year. We analyzed overall mortality using KaplanMeier survival analysis. Logistic regression was used for the remaining outcomes, adjusting for covariates. P < .05 was considered significant. Our study included 253 heart transplant recipients (72.3% male, mean age 55.0 years), of which 184 patients (72.7%) received hearts from donors of heart and lung, and 69 (27.3%) received hearts from donors of only hearts. Heart-and-lung donors were younger than heart-only donors (43.2 vs 47.2 years; P = .017). Transplant recipient baseline characteristics were not different between the 2 groups. Receipt of hearts from heart-and-lung donors was not associated with higher overall mortality (P = .33) or mortality at 3 months (P = .199), 1 year (P = .348), or 3 years (P = .375), and even showed better 30-day survival than receipt of hearts from heart-only donors (p=0.035). Recipients of hearts from heart-and-lung donors did not have higher rates of postoperative mechanical circulatory support, resternotomy, or pacemaker implantation within the first year. Our study confirms that synchronous heart and lung procurement for transplant is not associated with worse outcomes in heart transplant recipients and that hearts originating from heart-andlung donors may even be associated with improved outcomes.

Dilemmas concerning heart procurement in controlled donation after circulatory death.

With an expanding population at risk for heart failure and the resulting increase in patients admitted to the waiting list for heart transplantation, the demand of viable organs exceeds the supply of suitable donor hearts. Use of hearts after circulatory death has reduced this deficit. Two primary techniques for heart procurement in circulatory death donors have been described: direct procurement and perfusion and thoraco-abdominal normothermic regional perfusion. While the former has been accepted as an option for heart procurement in circulatory death donors, the latter technique has raised some ethical questions in relation to the dead donor rule. In this paper we discuss the current dilemmas regarding these heart procurement protocols in circulatory death donors.

Donor circadian clock influences the long-term survival of heart transplantation by immunoregulation.

Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection. In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group. Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.