Donor Hearts Research Articles

Cardioprotective effect of Interleukin-11 against warm ischemia-reperfusion injury in a rat heart donor model

Shortage of donor organs for heart transplantation is a worldwide problem. Donation after circulatory death (DCD) has been proposed to expand the donor pool. However, in contrast to the donation after brain death that undergoes immediate cold preservation, warm ischemia and subsequent reperfusion injury are inevitable in DCD. It has been reported that interleukin-11 (IL-11) mitigates ischemia-reperfusion injury in rodent models of myocardial infarction and donation after brain death heart transplantation. We hypothesized that IL-11 also offers benefit to warm ischemia in an experimental model of cardiac transplantation that resembles DCD. The hearts of naïve male Sprague Dawley rats (n = 15/group) were procured, subjected to 25-min warm ischemia, and reperfused for 60 min using Langendorff apparatus. IL-11 or saline was administered intravenously before the procurement, added to maintenance buffer, and infused via perfusion during reperfusion. IL-11 group exhibited significantly better cardiac function post-reperfusion. Severely damaged mitochondria was found in the electron microscopic analysis of control hearts whereas the mitochondrial structure was better preserved in the IL-11 treated hearts. Immunoblot analysis using neonatal rat cardiomyocytes revealed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation at Ser727 after IL-11 treatment, suggesting its role in mitochondrial protection. Consistent with expected activation of mitochondrial respiration by mitochondrial STAT3, immunohistochemical staining demonstrated a higher mitochondrial cytochrome c oxidase subunit 2 expression. In summary, IL-11 protects the heart from warm ischemia reperfusion injury by alleviating mitochondrial injury and could be a viable therapeutic option for DCD heart transplantation.

Increasing donor heart use in cardiac transplantation.

A shortage of donor hearts remains a critical problem in cardiac transplantation, resulting in longer recipient wait times and increased wait list mortality. The disparity between available donor hearts and patients with end-stage heart failure who need transplant is expected to grow. The donor heart pool can be increased by using organs from expanded criteria, Public Health Service increased risk, hepatitis C, and donation after circulatory death donors.

Hypothermic oxygenated perfusion (HOPE) safely and effectively extends acceptable donor heart preservation times: Results of the Australian and New Zealand trial

BackgroundCold static storage (CSS) preservation of donor hearts for periods longer than 4 hours increases the risk of primary graft dysfunction (PGD). The aim of the study was to determine if hypothermic oxygenated perfusion (HOPE) could safely prolong the preservation time of donor hearts. MethodsWe conducted a non-randomised, single arm, multi-center investigation of the effect of HOPE using the XVIVO Heart Preservation System on donor hearts with a projected preservation time of 6-8 hours on 30-day recipient survival and allograft function post-transplant. Each center completed 1 or 2 short preservation time followed by long preservation time cases. PGD was classified as occurring in the first 24 hours after transplantation or secondary (SGD) occurring at any time with a clearly defined cause. Trial survival was compared with a comparator group based on data from the International Society of Heart and Lung Transplantation Registry. ResultsWe performed heart transplants using 7 short and 29 long preservation time donor hearts placed on the HOPE system. The mean preservation time for the long preservation time cases was 414 minutes, the longest being 8 hours and 47 minutes. There was 100% survival at 30 days. One long preservation time recipient developed PGD, and 1 developed SGD. One short preservation time patient developed SGD. 30-day survival was superior to the ISHLT comparator group despite substantially longer preservation times in the trial patients. ConclusionsHOPE provides effective preservation out to preservation times of nearly 9 hours allowing retrieval from remote geographic locations.

Impact of the coronavirus disease 2019 pandemic on drug overdoses in the United States and the effect on cardiac transplant volume and survival

ObjectivesDrug overdose (DO) deaths rose to unprecedented levels during the COVID-19 pandemic. This study examines the impact of COVID-19 on the availability of cardiac allografts from DO donors and the implications of DO donor use on recipient survival. MethodsHeart transplants reported to the United Network for Organ Sharing (UNOS) from January 2017-November 2019 (“pre-COVID”) and March 2020-June 2021 (“COVID pandemic”) were analyzed with respect to DO donor status. Outcomes were analyzed using Kaplan-Meier survival and Cox-regression to identify predictors of survival. Characteristics of discarded cardiac allografts were also compared by DO donor status. ResultsDuring the COVID-19 pandemic 27.2% of cardiac allografts were from DO donors versus 20.5% pre-COVID, a 32.7% increase (p<0.001). During the pandemic, DO donors were younger (84.7% vs. 76.3% <40 years, p<0.001), had higher cigarette use (16.1% vs. 10.8%, p<0.001), higher cocaine use (47.4% vs. 19.7%, p<0.001), and higher incidence of hepatitis C antibodies (26.8% vs. 6.1%, p<0.001) and RNA positivity (16.2% vs. 4.2%, p<0.001). While DO donors were less likely to require inotropic support (30.8% vs. 35.4%, p=0.008), they were more likely to have received cardiopulmonary resuscitation (CPR) (95.3% vs. 43.2%,p<0.001). Recipient survival was equivalent using Kaplan-Meier analysis (log-rank, p=0.33) and survival probability at 36 months was 85.6% (n. at risk=398) for DO donors versus 83.5% (n. at risk=1633) for all other donors. Cox-regression demonstrated that DO donor status did not predict mortality (HR 1.05; 95% CI 0.90-1.23, p=0.53). ConclusionsDuring the COVID-19 pandemic there was a 32.7% increase in heart transplants utilizing DO donor hearts, and DO became the most common mechanism of death for donors. The use of DO donor hearts did not have an impact on short-term recipient survival.

Monitoring left ventricular assist device parameters to detect flow- and power-impacting complications: a proof of concept.

The number of patients on left ventricular assist device (LVAD) support increases due to the growing number of patients with end-stage heart failure and the limited number of donor hearts. Despite improving survival rates, patients frequently suffer from adverse events such as cardiac arrhythmia and major bleeding. Telemonitoring is a potentially powerful tool to early detect deteriorations and may further improve outcome after LVAD implantation. Hence, we developed a personalized algorithm to remotely monitor HeartMate3 (HM3) pump parameters aiming to early detect unscheduled admissions due to cardiac arrhythmia or major bleeding. The source code of the algorithm is published in an open repository. The algorithm was optimized and tested retrospectively using HeartMate 3 (HM3) power and flow data of 120 patients, including 29 admissions due to cardiac arrhythmia and 14 admissions due to major bleeding. Using a true alarm window of 14 days prior to the admission date, the algorithm detected 59 and 79% of unscheduled admissions due to cardiac arrhythmia and major bleeding, respectively, with a false alarm rate of 2%. The proposed algorithm showed that the personalized algorithm is a viable approach to early identify cardiac arrhythmia and major bleeding by monitoring HM3 pump parameters. External validation is needed and integration with other clinical parameters could potentially improve the predictive value. In addition, the algorithm can be further enhanced using continuous data.

Donor/recipient ascending aortic diameter ratio as a novel potential metric for donor selection and improved clinical outcomes in heart transplantation: a propensity score-matched study.

Donor/recipient size matching is paramount in heart transplantation. Body weight, height, body mass index, body surface area, and predicted heart mass (PHM) ratios are generally used in size matching. Precise size matching is important to achieve better clinical outcomes. This study aims to determine the donor/recipient ascending aortic diameter (AAoD) ratio as a metric for donor selection and its effect on postoperative clinical outcomes in heart transplant patients. We retrospectively reviewed all consecutive patients who underwent heart transplantation from January 2015 to December 2018. A cutoff value of 0.8032 for the donor/recipient AAoD ratio (independent variable for the primary endpoint during unmatched cohort analysis) was determined for predicting in-hospital mortality. The patients were divided into two groups based on the cutoff value. Group A, AAoD < 0.8032 (n = 96), and Group B, AAoD > 0.8032 (n = 265). A propensity score-matched (PSM) study was performed to equalize the two groups comprising 77 patients each in terms of risk. A Cox regression model was developed to identify the independent preoperative variables affecting the primary end-point. The primary endpoint was all-cause in-hospital mortality. A total of 361 patients underwent heart transplantation during the given period. On the multivariate analysis, donor/recipient PHM ratio [HR 16.907, 95% confidence interval (CI) 1.535-186.246, P = 0.021], donor/recipient AAoD ratio < 0.8032 (HR 5.398, 95% CI 1.181-24.681, P = 0.030), and diabetes (HR 3.138, 95% CI 1.017-9.689, P = 0.047) were found to be independent predictors of in-hospital mortality. Group A had higher 3-year mortality than Group B (P = 0.022). The surgery time was longer and postoperative RBC, plasma, and platelets transfusion were higher in Group A (P < 0.05). Although not statistically significant the use of continuous renal replacement therapy (P = 0.054), and extracorporeal membrane oxygenation (P = 0.086), was realatively higher, and ventilation time (P = 0.079) was relatively longer in Group A. The donor/recipient AAoD ratio is a potential metric for patient matching and postoperative outcomes in heart transplantation. A donor/recipient AAoD ratio > 0.8032 could improve post-heart transplantation outcomes and donor heart utilization.

Need for cardiac implantable electronic devices and long-term follow-up in recipients of orthotopic heart transplants

BackgroundCardiac pacemaker implantation after orthotopic heart transplantation declined dramatically after development of the bicaval anastomosis technique. However, much less is known about the rate, indications, and predictors of device implantation procedures with the current surgical technique. ObjectiveThe purpose of this study was to evaluate the indications, patient characteristics, incidence, and survival related to cardiac implantable electronic device (CIED) implantation after heart transplantation. MethodsThis was a single-center study of 399 consecutive adult recipients of orthotopic heart transplants with bicaval anastomosis from 1991 to 2017. The primary end point was freedom from pacemaker or implantable cardioverter-defibrillator (ICD) implantation, and the secondary end point was all-cause mortality. ResultsAt the time of transplantation, the mean age of recipients was 50 ± 12 years and that of donors 31 ± 12 years. CIEDs were implanted in 8% of recipients (n = 31): 11 pacemakers (35%) for sinus node dysfunction, 17 (55%) for high-grade heart block, and 3 ICDs (10%) for the primary prevention of sudden cardiac death. Early CIED implantation (<30 days) was rare and absent for sinus node dysfunction. The risk for CIED implantation increased progressively during follow-up (0–30 years; median 11 years), with low-, moderate-, and high-risk periods between 0 and 10, between 10 and 20, and between 20 and 30 years, respectively. Recipients receiving CIEDs survived longer after transplantation (21 years vs 13 years; P < .01). Recipients receiving pacemakers for heart block were more likely to receive older donor hearts at the time of transplantation. ConclusionThe risk of pacemaker implantation increases progressively, while ICD implantation is rare. Donor age is the predominant risk factor for subsequent heart block. Early sinus node dysfunction requiring permanent pacing is rare.

Preserved 2-y Liver Transplant Outcomes Following Simultaneous Thoracoabdominal DCD Organ Procurement Despite Effects on Liver Utilization Rate.

Current techniques for donation after circulatory determination of death (DCD) heart procurement, through either direct procurement and machine perfusion or thoracoabdominal normothermic regional perfusion (NRP), have demonstrated excellent heart transplant outcomes. However, the impact of thoracoabdominal DCD (TA-DCD) heart procurement on liver allograft outcomes and utilization is poorly understood. One hundred sixty simultaneous heart and liver DCD donors were identified using the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between December 2019 and July 2021. Liver outcomes from TA-DCD donors were stratified by heart procurement technique and evaluated for organ utilization, graft survival, and patient survival. Results were compared with abdominal-only DCD (A-DCD; n = 1332) and donation after brain death (DBD; n = 12 891) liver transplants during the study interval. Kaplan-Meier methods with log-rank testing were used to evaluate patient and graft survival. One hundred thirty-three of 160 livers procured from TA-DCD donors proceeded to transplant. TA-DCD donors were younger (mean 28.26 y; P < 0.0001) with lower body mass index (mean 26.61; P < 0.0001) than A-DCD and DBD donors. TA-DCD livers had equivalent patient survival ( P = 0.893) and superior graft survival (P = 0.009) compared with A-DCD. TA-DCD livers had higher rates of organ discard for long warm ischemia time (37.0%) than A-DCD (20.5%) and DBD (0.5%; P < 0.0001), with direct procurement and machine perfusion procurements leading to a higher discard rate (18.5%) than NRP procurements (7.4%). Liver transplants after TA-DCD donation demonstrated equivalent patient outcomes and excellent graft outcomes. NRP procurements resulted in the lowest rate of organ discard after DCD donation and may represent an optimal strategy to maximize organ utilization.

Molecular Phenotyping and Mechanisms of Myocardial Fibrosis in Advanced Chronic Kidney Disease.

Myocardial fibrosis is a major life-limiting problem in chronic kidney disease (CKD). Despite this, the molecular phenotype and metabolism of collagen fibrillogenesis in fibrotic hearts of patients with advanced CKD have been largely unstudied. We analyzed explanted human left ventricular (LV) heart tissues in a 3-arm cross-sectional cohort study of deceased donor patients on hemodialysis (HD, n=18), hypertension with preserved renal function (HTN, n=8), and healthy controls (CON, n=17), ex vivo. RNA-seq and protein analysis was performed on human donor hearts and cardiac fibroblasts treated with mineral stressors (high phosphate and high calcium). Further mechanistic studies were performed using primary cardiac fibroblasts, in vitro treated with mineral stressors, pro-inflammatory and pro-fibrotic cytokines. Of the 43 donor participants, there was no difference in age (P>0.2), sex (P>0.8), or body mass index (P>0.1) between the groups. Hearts from the HD group had extensive fibrosis (P<0.01). All LV tissues expressed only the trimeric form of collagen type I. HD hearts expressed increased collagen type I (P<0.03), elevated collagen type I:III ratio (P<0.05), and decreased MMP1 (P<0.05) and MMP2 (P<0.05). RNA-seq revealed no significant differential gene expression of extracellular matrix proteins of interest in HD hearts, but there was significant upregulation of LH2, periostin, α-SMA, and TGF-β1 gene expression in mineral stressor-treated cardiac fibroblasts. Both mineral stressors (P<0.009) and cytokines (P<0.03) increased collagen type I:III ratio. Mineral stressors induced trimeric collagen type I, but cytokine treatment induced only dimeric collagen type I in cardiac fibroblasts. Mineral stressors downregulated fibronectin (P<0.03) and MMP2 zymogen (P<0.01) but did not significantly affect expression of periostin, MMP1, or cross-linking enzymes. TGF-β upregulated fibronectin (P<0.01) and periostin (P<0.02) only. Myocardial fibrosis in advanced CKD hearts is characterized by increased trimeric collagen type I and dysregulated collagen metabolism, and is differentially regulated by components of uremia.

Impact of prophylactic donor heart tricuspid valve annuloplasty on outcomes in heart transplantation

BackgroundTricuspid regurgitation(TR) following heart transplantation could adversely affect clinical outcomes. In an effort to reduce the incidence of TR, prophylactic donor heart tricuspid valve annuloplasty has been performed during heart transplantation in our institution. We assessed early and long-term outcomes.MethodsBetween August 2011 and August 2021, 349 patients who underwent prophylactic tricuspid valve annuloplasty were included. Tricuspid valve annuloplasty was performed using the DeVega annuloplasty technique. The clinical outcomes of the interests included complete atrioventricular block requiring pacemaker implantation, the occurrence of significant TR(defined as moderate or greater), and survival. Long-term survival was compared in patients with and without significant TR using the Kaplan-Meier method. The Cox proportional hazards regression with time-dependent covariate analysis was used to see if significant TR affected the long-term survival.ResultsThere was one patient(0.3%) who required pacemaker implantation for complete atrioventricular block. No patients developed tricuspid valve stenosis that required intervention. Significant TR developed in 31 patients(8.9%) during the follow-up period. The survival rate of patients who developed significant TR was significantly lower than that of those who did not(log rank < 0.01). Significant TR was associated with the long-term mortality(HR2.92, 95%CI 1.47–5.82, p < 0.01).ConclusionsProphylactic donor heart tricuspid valve annuloplasty has the potential to reduce the occurrence of significant TR and can be performed safely. The significant TR that developed in patients with prophylactic annuloplasty negatively affected survival and was an independent predictor of long-term mortality.

Short-term outcomes after heart transplantation using donor hearts preserved with ex vivo perfusion

The standard Conventional Cold Storage (CCS) during heart transplantation procurement is associated with time-dependent ischemic injury to the graft, which is a significant independent risk factor for post-transplant early morbidity and mortality – especially when cold ischemic time exceeds four hours. Since 2018, Rigshospitalet (Copenhagen, Denmark) has been utilising ex vivo perfusion (Organ Care System, OCS) in selected cases. The objective of this study was to compare the short-term clinical outcomes of patients transplanted with OCS compared to CCS. Methods: This retrospective single-centre study was based on consecutive patients undergoing a heart transplant between January 2018 and April 2021. Patients were selected for the OCS group when the cold ischemic time was expected to exceed four hours. The primary outcome measure was six-month event-free survival. Results: In total, 48 patients were included in the study; nine were transplanted with an OCS heart. The two groups had no significant differences in baseline characteristics. Six-month event-free survival was 77.8% [95% CI: 54.9–100%] in the OCS group and 79.5% [95% CI: 67.8–93.2%] in the CCS group (p = 0.91). While the OCS group had a median out-of-body time that was 183 min longer (p < 0.0001), the cold ischemic time was reduced by 51 min (p = 0.007). Conclusion: In a Scandinavian setting, our data confirms that utilising OCS in heart procurement allows for a longer out-of-body time and a reduced cold ischemic time without negatively affecting safety or early post-transplant outcomes.

Better then ice! Utilization of Paragonix SherpaPak for human donor heart preservation – our experience

Better then ice! Utilization of Paragonix SherpaPak for human donor heart preservation – our experience

Outcomes of Heart Transplant Donation After Circulatory Death

BackgroundHeart transplantation using donation after circulatory death (DCD) allografts is increasingly common, expanding the donor pool and reducing transplant wait times. However, data remain limited on clinical outcomes. ObjectivesWe sought to compare 6-month and 1-year clinical outcomes between recipients of DCD hearts, most of them recovered with the use of normothermic regional perfusion (NRP), and recipients of donation after brain death (DBD) hearts. MethodsWe conducted a single-center retrospective observational study of all adult heart-only transplants from January 2020 to January 2023. Recipient and donor data were abstracted from medical records and the United Network for Organ Sharing registry, respectively. Survival analysis and Cox regression were used to compare the groups. ResultsDuring the study period, 385 adults (median age 57.4 years [IQR: 48.0-63.7 years]) underwent heart-only transplantation, including 122 (32%) from DCD donors, 83% of which were recovered with the use of NRP. DCD donors were younger and had fewer comorbidities than DBD donors. DCD recipients were less often hospitalized before transplantation and less likely to require pretransplantation temporary mechanical circulatory support compared with DBD recipients. There were no significant differences between groups in 1-year survival, incidence of severe primary graft dysfunction, treated rejection during the first year, or likelihood of cardiac allograft vasculopathy at 1 year after transplantation. ConclusionsIn the largest single-center comparison of DCD and DBD heart transplantations to date, outcomes among DCD recipients are noninferior to those of DBD recipients. This study adds to the published data supporting DCD donors as a safe means to expand the heart donor pool.

Personalized Numerical Cardiovascular Model with Weight Growth for Evaluating Pediatric Left Ventricular Assist Devices: Derivation from an Experimental Mock Circulatory Loop.

Pediatric patients with heart failure have limited treatment options because of a shortage of donor hearts and compatible left ventricular assist devices (LVADs). To address this issue, our group is developing an implantable pediatric LVAD for patients weighing 5-20kg, capable of accommodating different physiological hemodynamic conditions as patients grow. To evaluate LVAD prototypes across a wide range of conditions, we developed a numerical cardiovascular model, using data from a mock circulatory loop (MCL) and patient-specific elastance functions. The numerical MCL was validated against experimental MCL results, showing good agreement, with differences ranging from 0 to 11%. The numerical model was also tested under left heart failure conditions and showed a worst-case difference of 16%. In an MCL study with a pediatric LVAD, a pediatric dataset was obtained from the experimental MCL and used to tune the numerical MCL. Then, the numerical model simulated LVAD flow by using an HQ curve obtained from the LVAD's impeller. When the numerical MCL was validated against the experimental MCL, hemodynamic differences ranged between 0 and 9%. These findings suggest that the numerical model can replicate various physiological conditions and impeller designs, indicating its potential as a tool for developing and optimizing pediatric LVADs.

Non-inferior outcomes in lower urgency patients transplanted with extended criteria donor hearts

Recent work has suggested that outcomes among heart transplant patients listed at the lower-urgency (United Network for Organ Sharing Status 4 or 6) status may not be significantly impacted by donor comorbidities. The purpose of this study was to investigate outcomes of extended criteria donors (ECD) in lower vs. higher urgency patients undergoing heart transplantation. The United Network for Organ Sharing (UNOS) database was queried for all adult patients undergoing heart transplantation from 10/18/2018 through 12/31/2021. Patients were stratified by degree of urgency (higher urgency: UNOS 1 or 2 vs. lower urgency: UNOS 4 or 6) and receipt of ECD hearts, as defined by donor hearts failing to meet established acceptable use criteria. Outcomes were compared using propensity score matched cohorts. Among 9,160 patients included, 2,320 (25.4%) were low urgency. ECD hearts were used in 35.5% of HU patients and 39.2% of LU patients. While ECD hearts had an impact on survival among high-urgency patients (p<0.01), there was no difference in 1- and 2-year survival (p>0.05) found among low urgency patients receiving ECD vs. standard hearts. Neither ECDs nor individual ECD criteria were independently associated with mortality in low urgency patients (p>0.05). Post-transplant outcomes among low urgency patients are not adversely affected by receipt of ECD vs. standard hearts. Expanding the available donor pool by optimizing use of ECDs in this population may increase transplant frequency, decrease waitlist morbidity, and improve postoperative outcomes for the transplant community at large.

Outcomes of tricuspid valve regurgitation after heart transplantation; a single center retrospective cohort study

BackgroundTricuspid valve regurgitation (TR) of the donor's heart is a common problem that can develop immediately after cardiac transplantation. There is still little data about its impact on clinical outcomes. We aimed to evaluate the short-term and 1-year effects of significant TR after heart transplantation. We retrospectively analyzed 120 patients who underwent elective orthotopic heart transplantation between 2011 and 2022. According to the postoperative TR, the patients were divided into insignificant (n= 106) and significant (n= 14) TR groups.ResultsPatients with significant TR were younger [median age: 38 (Q1- Q3: 36- 39) vs. 49 (35- 55) years, p=0.037] and had a higher prevalence of nonischemic cardiomyopathy (85.71% vs. 42.45%, p=0.003) and donor female gender (35.7% vs. 19.8%,p=0.021). The patients with significant TR had a longer ICU stay [19 (14-27) vs. 11 (9-14) days, p=0.001], more frequent acute kidney injury (57.14% vs. 32.08%, p=0.023), and continuous renal replacement therapy (14.3% vs. 5.66%, p=0.031), with higher 30-day mortality (7.14% vs. 1.9%, p=0.046) and 1-year mortality (14.3% vs. 2.8%, p=0.022) compared to patients with insignificant TR. The degree of TR significantly decreased during the follow-up [β: -0.18 (95% CI: -0.25 to -0.10); p<0.001]. All patients with TR were managed medically without surgical interventions. Logistic multivariable regression revealed that nonischemic heart disease (OR: 3.41,95% CI: 1.31-41.2, p=0.024) and female donor (OR:1.56, 95%CI: 1.13-25.3, p=0.013) independently predicted significant postoperative TR.ConclusionsSignificant TR was associated with early mortality and morbidities with prolonged hospitalization. The degree of TR significantly decreased during the first year after transplantation.

No Evidence for Oversizing Hearts and Donor Size Impact on 1-Year Survival in Heart Failure Patients With Left Ventricular Assist Device

The predicted heart mass (PHM) ratio has recently emerged as a better metric for donor-to-recipient size-matching than weight ratios. It is unknown whether this applies to transplant candidates on left ventricular assist device (LVAD) support. Our study examines if PHM ratio is optimal for size-matching specifically in the LVAD patient population. Patients with LVAD who received a heart transplant from January 1997 to December 2020 in the Scientific Registry of Transplant Recipients database were studied. We compared 5 size-matching metrics, including donor-recipient ratios of weight, height, body mass index, body surface area, and PHM. Single and multivariable Cox proportional hazards models for 1-year mortality were calculated. Our sample consisted of 11,891 patients. In our multivariate analysis, we found that patients in the undersized group with PHM ratios <0.83 had a hazard ratio for 1-year mortality of 1.34 (95% confidence interval 1.08 to 1.65, p=0.007) suggestive of increased mortality with the use of undersized donors. There was no statistical difference in mortality between the matched (PHM ratio 0.83 to 1.2) and oversized group (PHM ratio ≥1.2). In heart transplant recipients on LVAD support, the PHM ratio provides better risk stratification than other metrics. Use of undersized donor hearts with PHM ratio <0.83 confers higher 1-year mortality. Using oversized donor hearts for transplantation in recipients on LVAD support has no benefit.

Adequacy of Size Matching With Predicted Heart Mass Ratio in Diverse Types of Cardiomyopathies

Predicted heart mass ratio (PHMr) has been proposed as an optimal size metric in the selection of a donor heart for transplant; however, it is not known if the same size matching criteria pertains uniformly to all types of cardiomyopathies. Heart transplant recipients in the United Network for Organ Sharing registry database were categorized into 6 groups based on the type of cardiomyopathy, dilated, coronary artery disease, hypertrophic, restrictive, valvular and adult congenital heart disease. Patients in each group of etiology were stratified based on the PHMr into 5 groups: severely undersized <0.86, moderately undersized 0.86 to 0.94, matched 0.95 to 1.04, moderately oversized 1.05 to 1.24, and severely oversized >1.25. The survival and cause of death of patients in each etiology group were reviewed. The United Network for Organ Sharing registry database from January 1987 to July 2021 included 53,573 patients who received a heart transplant. Compared with patients with size matched hearts, recipients with dilated (hazard ratio 1.17, p=0.001) and valvular (hazard ratio 1.79, p=0.032) cardiomyopathy who had an undersized heart with PHMr <0.86 had decreased survival. In addition, the survival of patients with hypertrophic or restrictive cardiomyopathy and adult congenital heart disease was not affected by size matching based on the PHMr (0.601 and 0.079, respectively, p=0.873). In conclusion, our analysis suggests that the size matching criteria based on PHMr may not be uniform to all patients across various etiologies of cardiomyopathy. Therefore, the data can be used to increase the acceptance rate of donor hearts, particularly, for patients with hypertrophic, restrictive cardiomyopathy and congenital heart disease in which size matching is less significant for survival outcome.

Novel ceRNA network construction associated with programmed cell death in acute rejection of heart allograft in mice.

T cell-mediated acute rejection(AR) after heart transplantation(HT) ultimately results in graft failure and is a common indication for secondary transplantation. It's a serious threat to heart transplant recipients. This study aimed to explore the novel lncRNA-miRNA-mRNA networks that contributed to AR in a mouse heart transplantation model. The donor heart from Babl/C mice was transplanted to C57BL/6 mice with heterotopic implantation to the abdominal cavity. The control group was syngeneic heart transplantation with the same kind of mice donor. The whole-transcriptome sequencing was performed to obtain differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and lncRNAs (DElncRNAs) in mouse heart allograft. The biological functions of ceRNA networks was analyzed by GO and KEGG enrichment. Differentially expressed ceRNA involved in programmed cell death were further verified with qRT-PCR testing. Lots of DEmRNAs, DEmiRNAs and DElncRNAs were identified in acute rejection and control after heart transplantation, including up-regulated 4754 DEmRNAs, 1634 DElncRNAs, 182 DEmiRNAs, and down-regulated 4365 DEmRNAs, 1761 DElncRNAs, 132 DEmiRNAs. Based on the ceRNA theory, lncRNA-miRNA-mRNA regulatory networks were constructed in allograft acute rejection response. The functional enrichment analysis indicate that the down-regulated mRNAs are mainly involved in cardiac muscle cell contraction, potassium channel activity, etc. and the up-regulated mRNAs are mainly involved in T cell differentiation and mononuclear cell migration, etc. The KEGG pathway enrichment analysis showed that the down-regulated DEmRNAs were mainly enriched in adrenergic signaling, axon guidance, calcium signaling pathway, etc. The up-regulated DEmRNAs were enriched in the adhesion function, chemokine signaling pathway, apoptosis, etc. Four lncRNA-mediated ceRNA regulatory pathways, Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox, 1700071M16Rik/miR-145a-3p/Themis2, were finally validated. In addition, increased expression of PVT1, 1700071M16Rik, Tox and Themis2 may be considered as potential diagnostic gene biomarkers in AR. We speculated that Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox and 1700071M16Rik/miR-145a-3p/Themis2 interaction pairs may serve as potential biomarkers in AR after HT.

Utilization of hepatitis C virus infected donors in heart transplant recipients with elevated MELD-XI score.

The advent of direct-acting antivirals has helped to increase the safe utilization of organs from hepatitis C virus positive (HCV+) donors. However, the outcomes of heart transplantation (HT) using an HCV+ donor are unclear in recipients with underlying liver disease represented by an elevated model for end-stage liver disease excluding international normalized ratio (MELD-XI). The United Network of Organ Sharing database was queried from Jan 2016 to Dec 2021. Post-transplant outcomes stratified by recipient MELD-XI score (low<10.37, medium, 10.38-13.39, and high>13.4) was compared between patients with HT from HCV+ (N=792) and patients with HT from HCV-negative donors (N=15,266). The median MELD-XI score was comparable (HCV+, 12.1, vs. HCV-negative, 11.8, p=.37). In the HCV+ group, donors were older (33vs. 31 years, p<.001). Ischemic time of donor hearts (3.48vs. 3.28h, p<.001) and travel distance (250vs. 157 miles, p<.001) were longer in HCV+ group. In the Kaplan Meier analysis with a median follow-up of 750 days, survival was comparable between the two groups (2-year survival, MELD-XI Low: HCV+, 92.4±3.6% vs. HCV-negative, 91.1±.8%, p=.83, Medium: HCV+ 89.2±4.3% vs. HCV-negative, 88.2±1.0%, p=.68, and High: HCV+, 84.9±4.5% vs. HCV-negative, 84.6±1.1%, p=.75) In multivariate Cox hazard models, HCV donors were not associated with mortality in each MELD-XI subgroup (Low: adjusted hazard ratio (aHR), 1.02, p=.94; Medium: aHR, .95, p=.81; and High: aHR, .93, p=.68). Utilization of HCV+ hearts was not associated with an increased risk of adverse outcomes in recipients with an elevated MELD- XI score.