Pig-to-human heart xenotransplantation in two recently deceased human recipients
Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.
HHV-6 Myocarditis Progressing to Ventricular Standstill Requiring Cardiac Transplant
Human herpesvirus-6 (HHV-6) is an increasingly recognized cause of myocarditis. We present the case of a 46-year-old woman who presented with fulminant HHV-6 myocarditis requiring heart transplantation. (Level of Difficulty: Advanced.)
Commentary: United Network for Organ Sharing policies work, but progress only occurs at the speed of a snail: A need for expeditious adjustments [Editorial]
The Society of Thoracic Surgeons Intermacs 2022 Annual Report: Focus on 2018 Heart Transplant Allocation System
The thirteenth annual report from The Society of Thoracic Surgeons (STS) Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) highlights outcomes for 27,314 patients receiving continuous flow durable left ventricular assist devices (LVAD) over the last decade (2012-2021). In 2021, 2,464 primary LVADs were implanted, representing a 23.5% reduction in the annual volume compared to peak implantation in 2019 and an ongoing trend from the prior year. This decline is likely a reflection of the untoward effects of the COVID-19 pandemic and the change in the US heart transplant allocation system in 2018. The last several years have been characterized by a shift in device indication and type with 81.1% of patients now implanted as destination therapy and 92.7% receiving an LVAD with full magnetic levitation in 2021. However, despite an older, more ill population being increasingly supported pre-implant with temporary circulatory devices in the recent (2017-2021) vs prior (2012-2016) eras, the 1- and 5-year survival continues to improve at 83.0% and 51.9%, respectively. The adverse events profile has also improved, with significant reduction in stroke, gastrointestinal bleeding, and hospital readmissions. Finally, we examined the impact of the change in heart transplant allocation system in 2018 on LVAD candidacy, implant strategy, and outcomes. In the competing outcomes analysis, the proportion of transplant eligible patients receiving a transplant has declined from 56.5% to 46.0% at 3 years, while the proportion remaining alive with ongoing support has improved from 24.1% to 38.1% at 3 years, underscoring the durability of the currently available technology.
Donation after circulatory death heart transplantation using normothermic regional perfusion:The NYU Protocol
OBJECTIVE/UNASSIGNED:This study aimed to evaluate the impact of cardiopulmonary bypass for thoraco-abdominal normothermic regional perfusion on the metabolic milieu of donation after cardiac death organ donors before transplantation. METHODS/UNASSIGNED:Local donation after cardiac death donor offers are assessed for suitability and willingness to participate. Withdrawal of life-sustaining therapy is performed in the operating room. After declaration of circulatory death and a 5-minute observation period, the cardiac team performs a median sternotomy, ligation of the aortic arch vessels, and initiation of thoraco-abdominal normothermic regional perfusion via central cardiopulmonary bypass at 37 °C. Three sodium chloride zero balance ultrafiltration bags containing 50 mEq sodium bicarbonate and 0.5 g calcium carbonate are infused. Arterial blood gas measurements are obtained every 15 minutes after every zero balance ultrafiltration bag is infused, and blood is transfused as needed to maintain hemoglobin greater than 8 mg/dL. Cardiopulmonary bypass is weaned with concurrent hemodynamic and transesophageal echocardiogram evaluation of the donor heart. The remainder of the procurement, including the abdominal organs, proceeds in a similar controlled fashion as is performed for a standard donation after brain death donor. RESULTS/UNASSIGNED:.001) . On average, donation after cardiac death donors received transfusions of 2.3 ± 1.5 units of packed red blood cells. Of the 18 donors who underwent normothermic regional perfusion, all hearts were deemed suitable for recovery and successfully transplanted, a yield of 100%. Other organs successfully recovered and transplanted include kidneys (80.6% yield), livers (66.7% yield), and bilateral lungs (27.8% yield). CONCLUSIONS/UNASSIGNED:The use of cardiopulmonary bypass for thoraco-abdominal normothermic regional perfusion is a burgeoning option for improving the quality of organs from donation after cardiac death donors. Meticulous intraoperative management of donation after cardiac death donors with a specific focus on improving their metabolic milieu may lead to improved graft function in transplant recipients.
Long-term follow-up of acute and chronic rejection in heart transplant recipients from hepatitis C viremic (NAT+) donors
The long-term safety of heart transplants from hepatitis C viremic (NAT+) donors remains uncertain. We conducted a prospective study of all patients who underwent heart transplantation at our center from January 2018 through August 2020. Routine testing was performed to assess for donor-derived cell-free DNA, acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV). Allograft dysfunction and mortality were also monitored. Seventy-five NAT- recipients and 32 NAT+ recipients were enrolled in the study. All NAT+ recipients developed viremia detected by PCR, were treated with glecaprevir/pibrentasvir at the time of viremia detection, and cleared the virus by 59â€‰days post-transplant. Patients who underwent NAT testing starting on post-operative day 7 (NAT+ Group 1) had significantly higher viral loads and were viremic for a longer period compared with patients tested on post-operative day 1 (NAT+ Group 2). Through 3.5â€‰years of follow-up, there were no statistically significant differences in timing, severity, or frequency of ACR in NAT+ recipients compared with the NAT- cohort, nor were there differences in noninvasive measures of graft injury, incidence or severity of CAV, graft dysfunction, or mortality. There were five episodes of AMR, all in the NAT- group. There were no statistically significant differences between Group 1 and Group 2 NAT+ cohorts. Overall, these findings underscore the safety of heart transplantation from NAT+ donors.
Acute Myocarditis Associated With Desmosomal Gene Variants
BACKGROUND:The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown. OBJECTIVES/OBJECTIVE:The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV. METHODS:In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up. RESULTS:In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; PÂ < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM. CONCLUSIONS:Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk.
Early experience with donation after circulatory death heart transplantation using normothermic regional perfusion in the United States
OBJECTIVE:This pilot study sought to evaluate the feasibility of our donation after circulatory death (DCD) heart transplantation protocol using cardiopulmonary bypass (CPB) for normothermic regional reperfusion (NRP). METHODS:Suitable local DCD candidates were transferred to our institution. Life support was withdrawn in the operating room (OR). On declaration of circulatory death, sternotomy was performed, and the aortic arch vessels were ligated. CPB was initiated with left ventricular venting. The heart was reperfused, with correction of any metabolic abnormalities. CPB was weaned, and cardiac function was assessed at 30-minute intervals. If accepted, the heart was procured with cold preservation and transplanted into recipients in a nearby OR. RESULTS:Between January 2020 and January 2021, a total of 8 DCD heart transplants were performed: 6 isolated hearts, 1 heart-lung, and 1 combined heart and kidney. All donor hearts were successfully resuscitated and weaned from CPB without inotropic support. Average lactate and potassium levels decreased from 9.39Â Â±Â 1.47Â mmol/L to 7.20Â Â±Â 0.13Â mmol/L and 7.49Â Â±Â 1.32Â mmol/L to 4.36Â Â±Â 0.67Â mmol/L, respectively. Post-transplantation, the heart-lung transplant recipient required venoarterial extracorporeal membrane oxygenation for primary lung graft dysfunction but was decannulated on postoperative day 3 and recovered uneventfully. All other recipients required minimal inotropic support without mechanical circulatory support. Survival was 100% with a median follow-up of 304Â days (interquartile range, 105-371Â days). CONCLUSIONS:DCD heart transplantation outcomes have been excellent. Our DCD protocol is adoptable for more widespread use and will increase donor heart availability in the United States.
Pre-transplant immune cell function assay as a predictor of early cardiac allograft rejection
INTRODUCTION/BACKGROUND:ImmuKnow, an immune cell function assay that quantifies overall immune system activity can assist in post-transplant immunosuppression adjustment. However, the utility of pre-transplant ImmuKnow results representing a patient's baseline immune system activity is unknown. This study sought to assess if pre-transplant ImmuKnow results are predictive of rejection at the time of first biopsy in our cardiac transplant population. METHODS:This is a single center, retrospective observational study of consecutive patients from January 1, 2018 to October 1, 2020 who underwent orthotopic cardiac transplantation at NYU Langone Health. Patients were excluded if a pre-transplant ImmuKnow assay was not performed. ImmuKnow results were categorized according to clinical interpretation ranges (low, moderate, and high activity), and patients were divided into two groups: a low activity group versus a combined moderate-high activity group. Pre-transplant clinical characteristics, induction immunosuppression use, early postoperative tacrolimus levels, and first endomyocardial biopsy results were collected for all patients. Rates of clinically significant early rejection (defined as rejectionÂ â‰¥Â 1R/1B) were compared between pre-transplant ImmuKnow groups. RESULTS:Of 110 patients who underwent cardiac transplant, 81 had pre-transplant ImmuKnow results. The low ImmuKnow activity group was comprised of 15 patients, and 66 patients were in the combined moderate-high group. Baseline characteristics were similar between groups. Early rejection occurred in 0 (0%) patients with low pre-transplant ImmuKnow levels. Among the moderate- high pre-transplant ImmuKnow group, 16 (24.2%) patients experienced early rejection (PÂ =Â .033). The mean ImmuKnow level in the non-rejection group was the 364.9Â ng/ml of ATP compared to 499.3Â ng/ml of ATP for those with rejection (PÂ =Â .020). CONCLUSION/CONCLUSIONS:Patients with low pre-transplant ImmuKnow levels had lower risk of early rejection when compared with patients with moderate or high levels. Our study suggests a possible utility in performing pre-transplant ImmuKnow to identify patients at-risk for early rejection who may benefit from intensified upfront immunosuppression as well as to recognize those where slower calcineurin inhibitor initiation may be appropriate.
Missed Opportunities in Identifying Cardiomyopathy Aetiology Prior to Advanced Heart Failure Therapy
BACKGROUND:Specific aetiologies of cardiomyopathy can significantly impact treatment options as well as appropriateness and prioritisation for advanced heart failure therapies such as ventricular assist device (VAD) or orthotopic heart transplantation (OHT). We reviewed the tissue diagnoses of patients who underwent advanced therapies for heart failure (HF) to identify diagnostic discrepancies. METHODS:This study presents a retrospective cohort of the aetiology of cardiomyopathy in 118 patients receiving either durable VAD or OHT. Discrepancies between the preoperative aetiological diagnosis of cardiomyopathy with the pathological diagnosis were recorded. Echocardiographic and haemodynamic data were reviewed to examine differences in patients with differing aetiological diagnoses. RESULTS:Twelve (12) of 118 (12/118) (10.2%) had a pathological diagnosis that was discordant with pre-surgical diagnosis. The most common missed diagnoses were infiltrative cardiomyopathy (5) and hypertrophic cardiomyopathy (3). Patients with misidentified aetiology of cardiomyopathy had smaller left ventricular (LV) dimensions on echocardiography than patients with dilated cardiomyopathy (5.8Â±0.9 vs 6.7Â±1.1 respectively p=0.01). CONCLUSIONS:Most HF patients undergoing VAD and OHT had a correct diagnosis for their heart failure prior to treatment, but a missed diagnosis at time of intervention (VAD or OHT) was not uncommon. Smaller LV dimension on echocardiogram in a patient with a non-ischaemic cardiomyopathy warrants further workup for a more specific aetiology.