First-in-human beating-heart transplant.

Central MessageHere we report the first case of a beating heart transplant with uninterrupted coronary perfusion in a heart procured from a deceased after circulatory death donor using ex vivo heart perfusion with the Organ Care System. Here we report the first case of a beating heart transplant with uninterrupted coronary perfusion in a heart procured from a deceased after circulatory death donor using ex vivo heart perfusion with the Organ Care System. The use of donors who are deceased after circulatory death (DCD) for heart transplantation has the potential to expand the donor pool by 30% to 50%.1Dharmavaram N. Hess T. Jaeger H. Smith J. Hermsen J. Murray D. et al.National trends in heart donor usage rates: are we efficiently transplanting more hearts?.J Am Heart Assoc. 2021; 10e019655https://doi.org/10.1161/JAHA.120.019655Crossref PubMed Scopus (30) Google Scholar,2Jawitz O.K. Raman V. DeVore A.D. Mentz R.J. Patel C.B. Rogers J. et al.Increasing the United States heart transplant donor pool with donation after circulatory death.J Thorac Cardiovasc Surg. 2020; 159: e307https://doi.org/10.1016/J.JTCVS.2019.09.080Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Our institution has adopted a protocol for DCD that uses ex vivo heart perfusion (EVHP) with the TransMedics Organ Care System (OCS).3OCS for HCPs - Transmedics.https://www.transmedics.com/ocs-hcp/Date accessed: November 21, 2022Google Scholar Typically, the donor heart is exposed to 2 periods of warm ischemia and 2 periods of cold ischemia in DCD heart transplant, as opposed to 1 period of each in deceased after brain death (DBD) heart transplant. We have developed a strategy of performing DCD heart transplant without rearresting the heart, obliviating any additional ischemic time after procurement, wherein the donor heart is implanted while beating and perfused with warm blood. Here we report the first successful case of a beating heart transplant using ex vivo heart perfusion in a DCD donor heart. More details about the donor, recipient, procurement process, intraoperative transesophageal echocardiography (TEE), and postoperative course are provided in the Appendix 1. The patient provided informed consent for the publication of this material; Institutional Review Board approval was not required. Our donor was a 19-year-old male with blood type O who was admitted to the hospital after anoxic brain injury in the setting of epileptic neurologic disorder. He had no history of cardiac disease, had not undergone cardiopulmonary resuscitation, and had an echocardiogram demonstrating good biventricular function, an ejection fraction (EF) of 60%, and no valvular heart disease. An electrocardiogram showed normal sinus rhythm, and a chest computed tomography scan was unremarkable. Size matching, as determined by a predicted heart mass ratio of 1.01, and procurement distance were acceptable. The donor was deemed a suitable DCD donor, and we proceeded with procurement. At the donor hospital, the donor was terminally extubated, and the observation period began. Thirteen minutes passed from extubation to a systolic blood pressure (SBP) <50 mmHg. Within another 13 minutes, the donor was pronounced dead, and the chest was opened, a cross-clamp was applied, and antegrade cardioplegia was initiated. The heart was procured via a previously described method and placed on the OCS within 50 minutes. Once the donor organ arrived at the recipient operating room, our modified setup that allows for tandem OCS and cardiopulmonary bypass (CPB) was initiated (Figure 1 and Video 1). Antegrade perfusion with warm blood, now coming from the CPB circuit via a cardioplegia cannula pressurized at 300 mmHg for an estimated root pressure of 100 mmHg, was initiated in the donor heart, and a cross-clamp was placed just superior to the antegrade cannula to ensure direction of flow into the coronary arteries. The heart was then separated from the OCS machine and transferred sterilely to the operating table, ending OCS perfusion. The total time on OCS was 341 minutes. We performed the remainder of the heart transplantation procedure without any additional ischemia, as perfusion was now wholly provided by the CPB circuit with recipient warm blood while the heart was paced and beating. To facilitate sewing, we lowered the pacemaker rate to 60 bpm. As is standard at our institution, we began with anastomosis of the left atrial cuff and then moved onto aortic anastomosis. Once the aortic anastomosis was complete, both the donor organ and recipient aortic cross-clamps were removed, with perfusion now being provided by the aortic cannula.4Shudo Y. Wang H. Woo Y.J. A modified technique for orthotopic heart transplantation to minimize warm ischaemic time.Eur J Cardio Thorac Surg. 2018; 53: 1089-1090https://doi.org/10.1093/EJCTS/EZX411Crossref PubMed Scopus (0) Google Scholar The total warm ischemia time was 13 minutes, and the total cold ischemia time was 50 minutes. The root cannula now served as a root vent. The remainder of the procedure was performed in standard fashion, involving pulmonary artery, then inferior vena cava, then superior vena cava anastomoses. On completion of the anastomoses and satisfaction with surgical hemostasis, we considered decannulation. TEE examination confirmed nonstenotic laminar flow of all anastomoses. Biventricular systolic function, preload, and panvalvular function were all confirmed to be normal. Background electro, mechanical, and vasoactive support during TEE interpretation included epicardial atrioventricular wire and isoproterenol (2 μg/minute) chemical pacing, intra-aortic balloon pumping at a ratio of 1:1, and the vasoactive agents inhaled nitric oxide at 20 ppm and epinephrine at 0.06 μg/kg/minute. Anticipatory coronary ischemic reperfusion injury was parried with a prophylactic nitroglycerin infusion at 0.2 μg/kg/minute, and we proceeded to wean from CPB, for a total reperfusion time of 72 minutes. We present the first beating heart transplant performed using a heart procured from a DCD donor facilitated by use of the OCS. In total, despite a nearly 3-hour travel time between donor hospital and recipient hospital, the only warm ischemic time was the 13 minutes from hemodynamic instability in the donor to cross-clamp application, and the only cold ischemic time was the 50 minutes from cross-clamp application in the donor to perfusion via the OCS. From then, the heart received uninterrupted perfusion with warm blood, including during implantation into the recipient. This was done by connecting the donor heart ex vivo to the CPB machine in tandem with the OCS and then discontinuing OCS perfusion. Doing so eliminated the need for additional cardioplegic arrest and additional ischemic time for the donor organ. A second cardioplegic arrest is normally required whenever the OCS is used, whether in the context of normothermic regional perfusion or extended donor criteria heart transplantation, so this strategy may be applicable beyond DCD donation.5Alomari M. Garg P. Yazji J.H. Wadiwala I.J. Alamouti-fard E. Hussain M.W.A. et al.Is the organ care system (OCS) still the first choice with emerging new strategies for donation after circulatory death (DCD) in heart transplant?.Cureus. 2022; 14e26281https://doi.org/10.7759/CUREUS.26281Crossref Google Scholar Further discussion is provided in the Appendix 1. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIzMzc0YjgzMGM3MjU3MThjYzM4MzgyMDcwOWY3YTZmMiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjk0OTMxMjc5fQ.FIcLTvlGH6noroK40gkmm3wbS9vyQr1MVcbkgUvv5iXigLsq2qht_uuZ_UKxX1FiAOVFQJp9BFcwwxjfvJB0x3lI5cvSgYgoRo6HpTKFl36r74wElf3fHEZgTXoPMQd99cYUUE5rPV9kGjBqaDiP9MEDIpN-GkSAJyKqLEesKM9KeG_jO-0qkYx8duPulKYAHUFhbgmzmOwE1NvWiB_bSBPxaHuWPtCyZ-IhBbDfUqtNCL_deuw0uoJyBYI5UMBdDULm6qeSVSgAFafN40mfEagg69i5IYj_Qqv9zpxCRzuX0YgFsE2yd4W4J_MCbB8yCvdog4iNqKi41d2m4U6NYQ Download .mp4 (21.18 MB) Help with .mp4 files Video 1Operative steps for beating heart DCD transplant. This operative video first shows the modifications made to the OCS system to allow for continuous coronary perfusion. We place new epicardial pacing wires, place cardiotomy suction catheters in the heart, and cannulate the root. Then we place a cross-clamp, initiate perfusion from the cardiopulmonary bypass machine, and separate the heart from OCS. The remainder of the video demonstrates our sewing technique while the heart is beating. Video available at: https://www.jtcvs.org/article/S2666-2507(23)00066-4/fulltext. Download .jpg (.44 MB) Help with files Video 1Operative steps for beating heart DCD transplant. This operative video first shows the modifications made to the OCS system to allow for continuous coronary perfusion. We place new epicardial pacing wires, place cardiotomy suction catheters in the heart, and cannulate the root. Then we place a cross-clamp, initiate perfusion from the cardiopulmonary bypass machine, and separate the heart from OCS. The remainder of the video demonstrates our sewing technique while the heart is beating. Video available at: https://www.jtcvs.org/article/S2666-2507(23)00066-4/fulltext. Our recipient is a 57-year-old male with blood type O and a history of hyperlipidemia, hypertension, and well-controlled type 2 diabetes who was diagnosed in 2016 with nonischemic dilated cardiomyopathy. At the time, he felt uncharacteristically short of breath, prompting a visit to the emergency room where he was diagnosed with atrial fibrillation. Subsequent workup revealed a severely depressed EF of 30% without a clear etiology for systolic dysfunction. Coronary catheterization revealed nonobstructive coronary artery disease, and further history suggested a potential viral etiology to his cardiomyopathy. Despite goal-directed medical therapy, multiple endocardial ablations, and a thoracoscopic surgical ablation and left atrial appendage ligation, the patient’s EF and symptoms worsened. He experienced episodes of nonsustained ventricular tachycardia and eventual heart block, leading to initiation of cardiac resynchronization therapy plus defibrillator implantation. For the index hospitalization that led to heart transplantation, the patient presented to the emergency department with shortness of breath and fluid overload. Laboratory tests indicated acute kidney injury as well, and he also tested positive for influenza. His EF was <20%, and he was admitted to the coronary care unit for further management. After resolution of influenza, given the patient’s poor cardiac function, he had a femoral intra-aortic balloon pump placed and he was listed for heart transplant. Once a suitable DCD donor heart became available, we proceeded with transplantation. Our donor was a 19-year-old male with blood type O who was admitted to the hospital after anoxic brain injury in the setting of epileptic neurologic disorder. He had no history of cardiac disease, had not undergone cardiopulmonary resuscitation, and had an echocardiogram demonstrating good biventricular function, an EF of 60%, and no valvular heart disease. His electrocardiogram showed normal sinus rhythm, and a computed tomography scan of his chest was unremarkable. Size matching, determined by a predicted heart mass ratio of 1.01, and procurement distance were acceptable. The donor was deemed a suitable DCD donor, and we proceeded with procurement. At the donor hospital, the donor was terminally extubated, and the observation period began. Thirteen minutes passed from extubation to an SBP <50 mmHg. Within another 13 minutes, the donor was pronounced dead, and the chest was opened, a cross-clamp was applied, and antegrade cardioplegia was initiated. The heart was procured via a previously described methodE1Shudo Y. Hiesinger W. Oyer P.E. Woo Y.J. Operative technique and pitfalls in donor heart procurement.Asian Cardiovasc Thorac Ann. 2017; 25: 80-82https://doi.org/10.1177/0218492316678716Crossref PubMed Scopus (8) Google Scholar and placed on the OCS within 50 minutes. Figure E1 shows the OCS configuration. An aortic line perfuses the heart with donor blood at 34 °C. The superior vena cava and inferior vena cava are ligated, and the heart is vented via a left atriotomy. A drainage catheter from the pulmonary arterial measures coronary flow. Pacing wires are attached to the heart, and the heart is paced at 80 bpm throughout transport. Once satisfied with an initial lactate measurement and the visual appearance of cardiac function, the donor heart was transported to the recipient operating room, located approximately 3 hours from the donor hospital. In anticipation of donor organ arrival, we began the cardiectomy in the recipient. An intraoperative TEE examination was notable for severe biventricular systolic dysfunction and volume overload, globular chronic left ventricular (LV) geometric changes with associated moderate-severe central mitral regurgitation (Carpentier grade 1 and 3B), severe bilateral upper pulmonary vein S wave blunting, left atrial hypertension (>20 mmHg), no LV apical thrombus despite the presence of an apical false tendon, mild central tricuspid regurgitation, right atrial hypertension (coronary sinus 1.3 cm), and no pleural fluid collections. We performed a median sternotomy and went on CPB with an aortic cannula and venous cannulas in the superior and inferior vena cava. An LV vent was placed in the right superior pulmonary vein. The left atrial appendage ligation clip was carefully dissected out with no issues. Postoperatively, the patient was transferred uneventfully to the intensive care unit, where he was extubated on postoperative day 0 to high-flow nasal cannula on stable doses of dobutamine, epinephrine, isoproterenol, and norepinephrine. His postoperative course was routine, with appropriate diuresis after initial resuscitation and weaning of inotropy, with discontinuation of the balloon pump on postoperative day 5. His cardiac function remained excellent throughout. On postoperative day 8, he experienced fever and a rising white blood cell count, with elevated pressor requirements and imaging suggestive of pneumonia. He was treated with broad-spectrum antibiotics and recovered uneventfully, transferring to the floor on postoperative day 13 on intermittent hemodialysis for his preexisting kidney injury. On the floor, his urine output and creatinine improved to the point of no longer needing dialysis, and he was discharged without issue. At 90 days post-transplantation, the patient reported significant symptom improvement and a full return to activities of daily living without assistance, with no clinical signs of allograft rejection. Our protocol for DCD heart transplant involves allowing for up to 60 minutes total from terminal extubation of the donor to declaration of death and a maximum of 30 minutes from an SBP <50 mmHg to declaration of death for functional warm ischemia time to proceed with procurement. In addition to the warm and cold ischemic times to which the heart is exposed during procurement, when the donor organ is ready for implantation, it is rearrested by flushing cold cardioplegia solution and placed on ice, initiating another period of cold ischemia, and then is taken off ice during implantation, prompting another period of warm ischemia. The strategy that we describe herein avoided that second cardioplegic arrest and its necessary warm and cold ischemia times. Doing so might limit additional ischemia-reperfusion injury to the donor organ. Ischemia-reperfusion injury likely has a major role in immediate graft dysfunction and long-term chronic graft rejection by causing oxidative damage to cardiomyocytes and prompting the release of damage-associated molecular patterns that prime the immune system for chronic allograft vasculopathy.E3Dashkevich A. Raissadati A. Syrjälä S.O. Zarkada G. Keränen M.A. Tuuminen R. et al.Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts.Am J Transplant. 2016; 16: 1160-1172https://doi.org/10.1111/AJT.13564Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, E4Lee J.C. Christie J.D. Primary graft dysfunction.Proc Am Thorac Soc. 2009; 6: 39-46https://doi.org/10.1513/PATS.200808-082GOCrossref PubMed Scopus (0) Google Scholar, E5Silvis M.J.M. Kaffka genaamd Dengler S.E. Odille C.A. Mishra M. van der Kaaij N.P. Doevendans P.A. et al.Damage-associated molecular patterns in myocardial infarction and heart transplantation: the road to translational success.Front Immunol. 2020; 11: 1https://doi.org/10.3389/FIMMU.2020.599511Crossref PubMed Google Scholar Using this beating heart technique for DCD donors makes the total ischemia comparable to and potentially even less than that with the current gold standard of DBD heart donation, which may translate into fewer immune-mediated complications.E6Osaki S. Ishino K. Kotani Y. Honjo O. Suezawa T. Kanki K. et al.Resuscitation of non-beating donor hearts using continuous myocardial perfusion: the importance of controlled initial reperfusion.Ann Thorac Surg. 2006; 81: 2167-2171https://doi.org/10.1016/J.ATHORACSUR.2006.01.066Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, E7White C.W. Ali A. Hasanally D. Xiang B. Li Y. Mundt P. et al.A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death.J Heart Lung Transplant. 2013; 32: 734-743https://doi.org/10.1016/J.HEALUN.2013.04.016Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar An additional potential benefit of our strategy is the short reperfusion time on CPB, limiting exposure to CPB, which, especially in patients with kidney injury, can lead to worsened kidney function, increased risk of death, and a global inflammatory response that disrupts endothelium and contributes to postoperative global tissue edema.E8Robich M. Ryzhov S. Kacer D. Palmeri M. Peterson S.M. Quinn R.D. et al.Prolonged cardiopulmonary bypass is associated with endothelial glycocalyx degradation.J Surg Res. 2020; 251: 287-295https://doi.org/10.1016/J.JSS.2020.02.011Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, E9Madhavan S. Chan S.P. Tan W.C. Eng J. Li B. Luo H.-D. et al.Cardiopulmonary bypass time: every minute counts.J Cardiovasc Surg. 2018; 59: 274-281https://doi.org/10.23736/S0021-9509.17.09864-0Crossref PubMed Scopus (60) Google Scholar, E10Kumar A.B. Suneja M. Cardiopulmonary bypass–associated acute kidney injury.Anesthesiology. 2011; 114: 964-970https://doi.org/10.1097/ALN.0B013E318210F86ACrossref PubMed Scopus (0) Google Scholar Other strategies involved in DCD heart transplantation include normothermic regional perfusion (NRP). This involves the same standoff period of extubation of the donor to declaration of circulatory death, followed by the use of CPB to initiate normothermic perfusion while the donor heart is still within the donor. The head vessels are ligated or occluded to prevent perfusion of the brain, and once a period of reperfusion is complete, the heart is weaned off CPB and undergoes cardioplegic arrest and cold storage until implantation, which is carried out in the usual fashion. Given the complicated ethical considerations regarding NRP, as outlined by the 2021 American College of Physicians position statement on NRP,E11American College of Physicians Ethics, determination of death, and organ transplantation in Normothermic Regional Perfusion (NRP) with Controlled Donation after Circulatory Determination of Death (cDCD): American College of Physicians statement of concern.https://www.acponline.org/acp_policy/policies/ethics_determination_of_death_and_organ_transplantation_in_nrp_2021.pdfDate: 2021Date accessed: January 25, 2023Google Scholar our institution has adopted an ex vivo heart perfusion approach to DCD donation. Some are concerned that NRP may violate the dead donor rule, wherein donors must not be “made dead” for the purpose of procuring organs for transplantation.E11American College of Physicians Ethics, determination of death, and organ transplantation in Normothermic Regional Perfusion (NRP) with Controlled Donation after Circulatory Determination of Death (cDCD): American College of Physicians statement of concern.https://www.acponline.org/acp_policy/policies/ethics_determination_of_death_and_organ_transplantation_in_nrp_2021.pdfDate: 2021Date accessed: January 25, 2023Google Scholar In any case, our beating heart ex vivo heart perfusion approach still mitigates the necessary warm ischemic time associated with NRP during implantation of the donor organ. Notably, NRP was used to perform a similar beating heart transplant in a brain dead donor in China.E12Yin S. Rong J. Chen Y. Cao L. Liu Y. Mo S. et al.Transplantation of a beating heart: a first in man.Lancet Reg Health West Pac. 2022; 23: 1-8https://doi.org/10.1016/j.lanwpc.2022.100449Abstract Full Text Full Text PDF Scopus (4) Google Scholar Since the donor was declared brain dead, there was no standoff period, and the donor heart could be assessed in usual fashion. Once donor allograft function was determined to be suitable, the heart was cannulated for CPB and explanted while on CPB using a similar clamp method as ours. Then it was sewn in while maintaining continuous perfusion from a CPB circuit. Our approach differs significantly in that it offers a strategy to mitigate the additional ischemic periods associated with DCD donation. As the use of DCD hearts continues to expand, we feel it is important to consider ways to improve our procurement and implantation strategies so that DCD heart transplant can become a comparable gold standard procedure to DBD heart transplant. Our methodology described in this report may serve as a template for minimizing the ischemic-reperfusion injury necessitated by DCD ex vivo heart perfusion heart transplant while potentially minimizing the time on CPB. Beating heart transplant with uninterrupted coronary perfusion from DCD donors is technically feasible and led to an excellent outcome in our recipient.