Donor Hearts Research Articles

Orthotopic Heart Transplant with Concurrent Supracoronary Ascending Aortic Replacement

We report a case of successful orthotopic heart transplant with concurrent supracoronary ascending aortic replacement (SCAAR) using a vascular conduit. An orthotopic heart transplant was performed on a 29-year-old White man with idiopathic dilated cardiomyopathy and reduced ejection fraction (20%). During the revision of the donor heart, a wall defect was detected in the ascending part of the donor aorta that could not be corrected. It was decided to perform a SCAAR using a 22-mm polytetrafluoroethylene vascular conduit and double-patch sandwich technique with Teflon patches. Two months later postoperative computed topography scan demonstrated sufficient patency of the vascular conduit and aorta with an improvement in the general somatic and functional state of the patient, and normal systolic and diastolic function of the transplanted heart. Our clinical case is unique in the complexity of the procedure with potential high intraoperative and early postoperative risks as well as the fact that SCAAR was performed immediately after heart transplant. In this clinical case, reconstruction of the ascending aorta with a vascular conduit is a strategically correct solution in the event of aortic defects that cannot be corrected with a suture technique.

Cardiac donors with renal impairment: Usage and outcomes after heart transplant.

Utilization of hearts from donors with significant renal dysfunction and the impact of donor renal function on outcomes following heart transplant (HT) is unknown. We sought to investigate the trends, characteristics and outcomes associated with these donor hearts and the impact of donor renal function on survival and graft failure in adult HT recipients. We reviewed theScientific Registry of Transplant Recipients (SRTR) and summarized trends, characteristics and outcomes of hearts from adult donors by renal impairment. Single-organ HTs were evaluated and stratified by donors with estimated glomerular filtration rate (eGFRs) < and ≥30ml/min. We constructed Cox proportional hazards regression models to compare time-to-mortality over 30-day, 1-, 3-, and 5-year time-horizons between groups, and the association of donor eGFR group with graft failure. A total of 162,586 adults were evaluated for cardiac donation, of which, 22,780 (14%) had an eGFR≤30ml/min. Donors with an eGFR≤30ml/min increased over time, from 7.2% (358/4966) in 2000 to a high of 19.5% (2283/11,728) in 2020. Such donors were significantly more likely discarded (not offered (7.9%vs. 9.8%, p<.001) or accepted (62.6%vs. 72.2%, p<.001), and less likely to be transplanted (18.0 % vs. 29.5%; p<.001). Of 41,044 HT recipients, 3906 (9.5%) had hearts from such donors.Primary graft failure was similar between groups (OR 1.20, 95% CI .91-1.58; p=.1) while adjusted mortality was lower for recipients from donors with eGFR≤30ml/min. More than two-third of hearts from donors with renal dysfunction are discarded. Recipients from donors with renal dysfunction sustained lower mortality post HT during the study period. Increased evaluation and utilization of donors with renal dysfunction has the potential to expand the critically low donor pool.

Interaction between donor obesity and prolonged donor ischemic time in heart transplantation

BackgroundThe purpose of the study was to determine the impact of donor obesity on outcomes following heart transplantation in the setting of routine (<4 h) and prolonged (≥4 h) organ ischemic times. MethodsRetrospective review of the 2000–2020 United Network for Organ Sharing Database was performed to identify adult heart transplant recipients and donors. Nearest-neighbor propensity score matching by donor obesity was performed separately among routine and prolonged cohorts, with Kaplan-Meier survival estimates used to assess survival at 5 years following transplantation. ResultsA total of 43,304 heart transplant recipients were included in analysis, with 15,925 (36.8 %) receiving obese donor hearts. After propensity-score matching, 30-day mortality and 5-year survival following transplantation were not statistically different between recipients of obese and non-obese donor hearts when organ ischemic times were routine. In the setting of prolonged organ ischemic times, those receiving obese donor hearts experienced lower 30-day mortality (5.1 % vs 6.7 %, p = 0.04) and improved 5-year survival (74.9 % vs 71.2 %, p < 0.01) compared to non-obese donor hearts. ConclusionsRecipients of obese donor hearts experienced improved outcomes compared to those receiving non-obese donor hearts when organ ischemic times exceeded 4 h. These findings suggest that the detrimental impact of prolonged organ ischemic time may be attenuated by donor obesity.

Near-Wall Fluid Mechanics Of A Pulsatile Flow Through A Compliant Tube

The demand for heart transplantation far exceeds the supply. This shortage is mainly due to the high percentage of discarded hearts and the narrow time window of only six hours that the current standard preservation method, static cold storage (SCS), allows for completing the entire procedure from donor to recipient patient. An alternative method called ex-vivo heart perfusion (EVHP) maintains a human donor heart beating outside the body for the time preceding transplantation surgery. By keeping the donor heart beating in a quasi-physiological mode of operation and assessing its functions, the organ's health can be monitored so that, ultimately, the transplant time window can be extended to increase the geographic availability of donors. In order to improve and optimize the EVHP system, fundamental understanding of the system physics is needed. To achieve this, the present work aims to investigate the relationship between pulsatile flow and compliance, evaluating the near wall region of a compliant tube with a particular focus on the formation of the viscous boundary layer. Thus, an experimental setup was designed to replicate the flow loop of the EVHP system and an optical transparent compliant tube that mimics the functioning of the body's largest and most compliant artery, the aorta, was custom-made to allow optical access to the flow field matching the refractive index of the working fluid. A pulsatile waveform is generated using a computer-controlled mechanical diaphragm pump, also equipped with a tri-leaf exit valve to simulate the physiological working condition of the heart. In the present work, the flow field is assessed by first performing stereo particle image velocimetry (PIV) on the bulk flow to investigate the large-scale phenomena within a compliant tube and the results of these experiments will be further used as a guide to interrogate smaller near-wall regions of interest in the flow. The preliminary results show, in addition to the general characteristics of a pulsatile flow through a compliant tube, a potential complex fluid-structure relationship between the pulsatile flow and the moving wall of the tube has been observed. The presentation of this work will discuss the experimental setup and review the preliminary results presented here in addition to others findings that are still being analyzed, data processing is underway to do so.

Impact of Cardiopulmonary Resuscitation of Donors on Days Alive and Out of Hospital after Orthotopic Heart Transplantation.

Background: The number of patients waiting for heart transplantation (HTX) is increasing. Optimizing the use of all available donor hearts is crucial. While mortality seems not to be affected by donor cardiopulmonary resuscitation (CPR), the impact of donor CPR on days alive and out of hospital (DAOH) is unclear. Methods: This retrospective study included adults who underwent HTX at the University Hospital Duesseldorf, Germany from 2010–2020. Main exposure was donor-CPR. Secondary exposure was the length of CPR. The primary endpoint was DAOH at one year. Results: A total of 187 patients were screened and 171 patients remained for statistical analysis. One-year mortality was 18.7%. The median DAOH at one year was 295 days (interquartile range 206–322 days). Forty-two patients (24.6%) received donor-CPR hearts. The median length of CPR was 15 (9–21) minutes. There was no significant difference in DAOH between patients with donor-CPR hearts versus patients with no-CPR hearts (CPR: 291 days (211–318 days) vs. no-CPR: 295 days (215–324 days); p = 0.619). Multivariate linear regression revealed that there was no association between length of CPR and DAOH (unstandardized coefficients B: −0.06, standard error: 0.81, 95% CI −1.65–1.53, p = 0.943). Conclusions: Donor CPR status and length of CPR are not associated with reduced DAOH at one year after HTX.

Will previous palliative surgery for congenital heart disease be detrimental to subsequent pig heart xenotransplantation?

IntroductionPig heart xenotransplantation might act as a bridge in infants with complex congenital heart disease (CHD) until a deceased human donor heart becomes available. Infants develop antibodies to wild-type (WT, i.e., genetically-unmodified) pig cells, but rarely to cells in which expression of the 3 known carbohydrate xenoantigens has been deleted by genetic engineering (triple-knockout [TKO] pigs). Our objective was to test sera from children who had undergone palliative surgery for complex CHD (and who potentially might need a pig heart transplant) to determine whether they had serum cytotoxic antibodies against TKO pig cells. MethodsSera were obtained from children with CHD undergoing Glenn or Fontan operation (n = 14) and healthy adults (n = 8, as controls). All of the children had complex CHD and had undergone some form of cardiac surgery. Seven had received human blood transfusions and 3 bovine pericardial patch grafts. IgM and IgG binding to WT and TKO pig red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry, and killing of PBMCs by a complement-dependent cytotoxicity assay. ResultsAlmost all children and adults demonstrated relatively high IgM/IgG binding to WT RBCs, but minimal binding to TKO RBCs (p < 0.0001 vs WT), although IgG binding was greater in children than adults (p < 0.01). All sera showed IgM/IgG binding to WT PBMCs, but this was much lower to TKO PBMCs (p < 0.0001 vs WT) and was greater in children than in adults (p < 0.05). Binding to both WT and TKO PBMCs was greater than to RBCs. Mean serum cytotoxicity to WT PBMCs was 90% in both children and adults, whereas to TKO PBMCs it was only 20% and < 5%, respectively. The sera from 6/14 (43%) children were cytotoxic to TKO PBMCs, but no adult sera were cytotoxic. ConclusionsAlthough no children had high levels of antibodies to TKO RBCs, 13/14 demonstrated antibodies to TKO PBMCs, in 6 of these showed mild cytotoxicity. As no adults had cytotoxic antibodies to TKO PBMCs, the higher incidence in children may possibly be associated with their exposure to previous cardiac surgery and biological products. However, the numbers were too small to determine the influence of such past exposures. Before considering pig heart xenotransplantation for children with CHD, testing for antibody binding may be warranted.

Challenges encountered in conducting donor-based research: Lessons learned from the Donor Heart Study

Solid organ transplantation continues to be constrained by a lack of suitable donor organs. Advances in donor management and evaluation are needed to address this shortage, but the performance of research studies in deceased donors is fraught with challenges. Here we discuss several of the major obstacles we faced in the conduct of the Donor Heart Study-a prospective, multi-site, observational study of donor management, evaluation, and acceptance for heart transplantation. These included recruitment and engagement of participating organ procurement organizations, ambiguities related to study oversight, obtaining authorization for donor research, logistical challenges encountered during donor management, sustaining study momentum, and challenges related to study data management. By highlighting these obstacles encountered, as well as the solutions implemented, we hope to stimulate further discussion and actions that will facilitate the design and execution of future donor research studies.

Durable Left Ventricular Assist Device as a Bridge to Heart Transplantation Under the New Donor Heart Allocation System.

The new donor heart allocation system prioritizes candidates supported by temporary devices. However, waitlist and posttransplant outcomes in candidates with durable left ventricular assist device (LVAD) remain to be elucidated. The United Network for Organ Sharing database was queried for adults listed from October 2015 to March 2020 for a single-organ, first-time heart transplant (HTx) with a durable LVAD. Waitlist removal within 1 year because of death or clinical deterioration and HTx was analyzed using competing risks regression. Candidates who underwent HTx within 1 year of listing were identified for examination of post-HTx survival using the Kaplan-Meier method and Cox proportional hazards models. Compared with candidates listed under the old system (n = 2,122), candidates listed under the new system (n = 1,562) were slightly younger ( p = 0.04) but had higher body mass index ( p < 0.01). Those listed under the new system were significantly less likely to experience waitlist removal because of death or clinical deterioration (subhazard ratio [HR] 0.68, 95% CI 0.52-0.90) but were also less likely to undergo HTx (sub-HR 0.91, 95% CI 0.83-0.998). Those who survived to HTx were more likely to experience death or need for re-HTx within 1 year of HTx under the new system (adjusted HR 1.50, 95% CI 1.11-2.03). Candidates with durable LVAD experience favorable waitlist outcomes under the new allocation system, although those who undergo HTx may be at increased mortality risk. Thus, candidates with a durable LVAD should be carefully selected for HTx listing under the new allocation system.

Modulation of Mitochondrial Respiration During Early Reperfusion Reduces Cardiac Injury in Donation After Circulatory Death Hearts.

Donation after circulatory death (DCD) donors are a potential source for heart transplantation. The DCD process has unavoidable ischemia and reperfusion (I/R) injury, primarily mediated through mitochondria, which limits routine utilization of hearts for transplantation. Amobarbital (AMO), a transient inhibitor of the electron transport chain, is known to decrease cardiac injury following ex vivo I/R. We studied whether AMO treatment during reperfusion can decrease injury in DCD hearts. Sprague Dawley rat hearts subjected to 25 minutes of in vivo ischemia (DCD hearts), or control beating donor hearts, were treated with AMO or vehicle for the first 5 minutes of reperfusion, followed by Krebs-Henseleit buffer reperfusion for 55 minutes (for mitochondrial isolation) or 85 minutes (for infarct size determination). Compared with vehicle, AMO treatment led to decreased infarct size (25.2% ± 1.5% vs. 31.5% ± 1.5%; P ≤ 0.05) and troponin I release (4.5 ± 0.05 ng/mL vs. 9.3 ± 0.24 ng/mL, P ≤ 0.05). AMO treatment decreased H 2 O 2 generation with glutamate as complex I substrate in both subsarcolemmal mitochondria (SSM) (37 ± 3.7 pmol·mg -1 ·min -1 vs. 56.9 ± 4.1 pmol·mg -1 ·min -1 ; P ≤ 0.05), and interfibrillar mitochondria (IFM) (31.8 ± 2.8 pmol·mg -1 ·min -1 vs. 46 ± 4.8 pmol·mg -1 ·min -1 ; P ≤ 0.05) and improved calcium retention capacity in SSM (360 ±17.2 nmol/mg vs. 277 ± 13 nmol/mg; P ≤ 0.05), and IFM (483 ± 20 nmol/mg vs. 377± 19 nmol/mg; P ≤ 0.05) compared with vehicle treatment. SSM and IFM retained more cytochrome c with AMO treatment compared with vehicle. In conclusion, brief inhibition of mitochondrial respiration during reperfusion using amobarbital is a promising approach to decrease injury in DCD hearts.

Aortic valve replacement using On-X valve in a child postorthotopic heart transplantation.

A 20-month-old girl presented with severe dilated cardiomyopathy and decompensated congestive cardiac failure. Despite escalating inotropic and mechanical ventilation support, she required placement on extracorporeal membrane oxygenation and transfer to the transplant centre in Newcastle, England. She was placed on biventricular assist device and then Berlin Heart but failed to show any recovery of ventricular function. She underwent orthotopic heart transplantation at 2 years of age. She developed bacterial endocarditis with Enterococcus faecalis resulting in severe aortic valve regurgitation requiring aortic valve replacement with a 19 mm On-X valve (Airtivion) 11 days after her transplant. Given the size of the donor heart, it was possible to implant a 19-mm valve in this 12 kg child with minimal risk of patient prosthesis mismatch. She was anticoagulated with warfarin (On-X valve INR 2-3 for first 3 months; INR 1.5-2.0 thereafter). Although she suffered several other post-operative complications, including malabsorption, nasojejunal feeding, liver dysfunction, vertebral fractures, renal impairment and renal calcification, and need for repeat opening of her tracheostomy site following her initial decannulation, her aortic valve function has remained stable.

Normothermic Regional Perfusion is an Emerging Cost-Effective Alternative in Donation After Circulatory Death (DCD) in Heart Transplantation.

In donation after circulatory death (DCD) organ transplantation, normothermic regional perfusion (NRP) restores oxygenated blood flow following cardiac arrest and reverses warm ischemia. Recently, NRP has also been used to help recover DCD hearts in addition to the abdominal organs. While DCD donation has increased the number of abdominal organs and lungs pool, it has not been able to increase the number of heart transplants, despite the fact that it has the potential to increase the number of heart transplants by 15-30%. Thoracoabdominal normothermic regional perfusion makes heart transplantation feasible and permits assessing heart function before an organ procurement without affecting the preservation of abdominal organs. NRP can be used in two ways for DCD donor heart transplants: normothermic regional perfusion followed by machine perfusion (NRP-MP) and normothermic regional perfusion followed by static cold storage (NRP-SCS). Normothermic regional perfusion is an emerging technology, a cost-effective alternative in donation after circulatory death (DCD), and will increase the pool of donors in heart transplantation.

Dynamic Metabolic Changes During Prolonged Ex Situ Heart Perfusion Are Associated With Myocardial Functional Decline.

Ex situ heart perfusion (ESHP) was developed to preserve and evaluate donated hearts in a perfused beating state. However, myocardial function declines during ESHP, which limits the duration of perfusion and the potential to expand the donor pool. In this research, we combine a novel, minimally-invasive sampling approach with comparative global metabolite profiling to evaluate changes in the metabolomic patterns associated with declines in myocardial function during ESHP. Biocompatible solid-phase microextraction (SPME) microprobes serving as chemical biopsy were used to sample heart tissue and perfusate in a translational porcine ESHP model and a small cohort of clinical cases. In addition, six core-needle biopsies of the left ventricular wall were collected to compare the performance of our SPME sampling method against that of traditional tissue-collection. Our state-of-the-art metabolomics platform allowed us to identify a large number of significantly altered metabolites and lipid species that presented comparable profile of alterations to conventional biopsies. However, significant discrepancies in the pool of identified analytes using two sampling methods (SPME vs. biopsy) were also identified concerning mainly compounds susceptible to dynamic biotransformation and most likely being a result of low-invasive nature of SPME. Overall, our results revealed striking metabolic alterations during prolonged 8h-ESHP associated with uncontrolled inflammation not counterbalanced by resolution, endothelial injury, accelerated mitochondrial oxidative stress, the disruption of mitochondrial bioenergetics, and the accumulation of harmful lipid species. In conclusion, the combination of perfusion parameters and metabolomics can uncover various mechanisms of organ injury and recovery, which can help differentiate between donor hearts that are transplantable from those that should be discarded.

Is the Organ Care System (OCS) Still the First Choice With Emerging New Strategies for Donation After Circulatory Death (DCD) in Heart Transplant?

The scarcity of donor hearts continues to be a challenge in transplants for advanced heart failure patients. With an increasing number of patients on the waiting list for a heart transplant, the discrepancy in the number between donors and recipients is gradually increasing and poses a new challenge that plagues the healthcare systems when it comes to the heart. Several technologies have been developed to expand the donor pool in recent years. One such method is the organ care system (OCS). The standard method of organ preservation is the static cold storage (SCS) method which allows up to four hours of safe preservation of the heart. However, beyond four hours of cold ischemia, the incidence of primary graft dysfunction increases significantly. OCS keeps the heart perfused close to the physiological state beyond the four hours with superior results, which allows us to travel further and longer distances, leading to expansion in the donor pool. In this review, we discuss the OCS system, its advantages, and shortcomings.

Donor Utilization in the Recent Era: Effect of Sex, Drugs, and Increased Risk.

Background:Heart transplantation volumes have increased in recent years, yet less than a third of donors are typically accepted for transplantation. Whether donor sex, donor drug use, or perception of increased risk affects utilization for transplantation is unclear.Methods:The United Network for Organ Sharing database was queried for donors from January 1, 2007, to December 31, 2017. Donor toxicology was collected when available. Multivariate analysis was conducted to examine correlations with donor utilization.Results:Between January 1, 2007, and December 31, 2017, there were 87 816 heart donors aged ≥15 years. The mean age was 42.7±15.8 years, and 24 831 donors (28.3%) were utilized for heart transplantation. Subsequent analyses focused on donors between 15 and 39 years old.The strongest associations with donor acceptance were for male donor sex, blood type, hepatitis C antibody, donor age, left ventricular hypertrophy, and history of donor drug use. After removing hepatitis C, Public Health Service Increased Risk was identified as a strong negative predictor. Most positive drug toxicology results were associated with donor nonuse except for donors between 15 and 19 years of age. Exceptions included alcohol, marijuana, and cocaine. Opiates were associated with less utilization at all donor ages. The Public Health Service Increased Risk status was associated with significantly less utilization in all age groups except 15- to 19-year-old donors.Conclusions:While male donors were preferentially utilized, donors with drug use or those deemed Public Health Service Increased Risk were significantly less utilized for heart transplantation. Further consideration of such donors would be appropriate particularly as the demand for transplantation continues to increase.

Ischemic time and patient outcomes after the 2018 UNOS donor heart allocation system change.

The allocation system for heart donors in the United States changed on October 18, 2018. The typical distance from donor hospitals to recipient hospitals has increased as has the ischemic time. We investigated patient outcomes with the new allocation system and the differential effects of ischemic time under both the old and new allocation schemas. The United Network for Organ Sharing Registry (UNOS) was queried for data regarding heart transplants occurring from October 1, 1987 to March 1, 2021. In total, 62,301 adult heart transplants were examined. Survival outcomes at 30 days and 1 year and ischemic times were compared via adjusted logistic and Cox models (overall survival and time until post-transplant rejection). Mean ischemic time was slightly increased in the new system (3.43 h vs. 3.03 h, p < .001). Survival differences between old versus new systems were not observed in adjusted models (p = .818). However, there was evidence to suggest longer ischemic times are more detrimental to long-term survival under the new system (hazard ratio [HR] = 1.15 per hour increase; p = .001) versus the old system (HR = 1.08 per hour increase; p < .001), although this relationship did not reach statistical significance (p = .150). Although travel distances have significantly increased under the new allocation system, survival outcomes remain largely unchanged. Ischemic time is an influential factor in recipient survival that should be limited during organ transport. Further studies on the impact of travel distances and ischemic time under the new allocation system are needed.

Reduction of Adverse Events With Phosphodiesterase 5 Inhibitors Post LVAD Implantation: Is It Time for a Randomized Trial?

The improved survival of patients with advanced heart failure after left ventricular assist device (LVAD) implantation together with the scarcity of donor hearts has significantly increased the population of LVAD-supported patients. However, despite the improvement in LVAD technology and the advent of third-generation continuous flow LVADs, complications such as those related to hemocompatibility and stroke rates remain ongoing clinical challenges. Thus, improvement in LVAD technology should be coupled with innovative medical management to further reduce adverse events. We have previously shown a strong association between post LVAD implant phosphodiesterase-5 inhibitors (PDE-5i) use and fewer thrombotic events, as well as improved survival in 2 observational studies. We caution, nevertheless, the use of PDE-5i based on these observations and encourage clinicians to support enrollment in a randomized control trial. A randomized control trial will determine the efficacy and safety of PDE-5i use after implantation in patients with a centrifugal flow LVAD.

The ongoing quest for the first total artificial heart as destination therapy.

Many patients with end-stage heart disease die because of the scarcity of donor hearts. A total artificial heart (TAH), an implantable machine that replaces the heart, has so far been successfully used in over 1,700 patients as a temporary life-saving technology for bridging to heart transplantation. However, after more than six decades of research on TAHs, a TAH that is suitable for destination therapy is not yet available. High complication rates, bulky devices, poor durability, poor biocompatibility and low patient quality of life are some of the major drawbacks of current TAH devices that must be addressed before TAHs can be used as a destination therapy. Quickly emerging innovations in battery technology, wireless energy transmission, biocompatible materials and soft robotics are providing a promising opportunity for TAH development and might help to solve the drawbacks of current TAHs. In this Review, we describe the milestones in the history of TAH research and reflect on lessons learned during TAH development. We summarize the differences in the working mechanisms of these devices, discuss the next generation of TAHs and highlight emerging technologies that will promote TAH development in the coming decade. Finally, we present current challenges and future perspectives for the field.

The Effect of Spiral Inducing Chamber to Left Ventricular Assist Device Outflow Cannula

The rise of heart failure in the setting of shortage heart donor had brought to the emergence of development of left ventricular assist device (LVAD). However, patients are still encountering severe complications such as stroke and device thrombosis due to the hemodynamic changes. This study aimed to compare the hemodynamic characteristic between the standard and spiral LVAD outflow cannula. Two different anastomosis sites (2cm and 3cm) from sino-tubular junction are used and a spiral inducing chamber is attached to the cannula to promote spiral flow. The result showed that spiral LVAD cannula exhibit a lower output velocity with 37% percentage difference and lower region of low WSS value.

MERGING ADVANCE TECHNOLOGY TO IMPROVE OUTCOMES IN HEART TRANSPLANTATION - A CASE REPORT

One of the signicant obstacles to donor heart utilization is that increasingly prolonged cold ischemic times are associated with worsened short- and long-term outcomes. As a result, most transplant centers aim to limit cold ischemic times to less than four hours. The TransMedics Organ Care System (OCS) (Trans Medics, Andover MA) is a portable ex vivo perfusion system designed to store a donor heart in a beating, metabolically active state, until it reaches the recipient, thereby allowing extended time outside the body while minimizing the effects of cold storage. We present a case of a heart transplant recipient supported with the Impella 5.5 as a bridge to transplantation who received a donation after circulatory death (DCD) heart supported by OCS. To our knowledge, this is the rst report of such a case.

IFI16-STING-NF-κB signaling controls exogenous mitochondrion-induced endothelial activation

Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. The stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here, we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/effector memory T cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. The exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T cell-mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.