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In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.

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.

Introduction:Current consensus holds that CPR must balance chest compressions and ventilation rate (VR), with a low VR being essential for venous return and cardiac output. AHA guidelines recommend a VR of 10 ventilations per minute (vpm) after advanced airway placement. We sought to examine VR adherence and its impact on end-tidal CO2(ETCO2) and ROSC >20 minutes.Methods:This is a retrospective analysis of data from AWARE II, a multicenter prospective observational study of adult in-hospital cardiac arrest (IHCA) outcomes at 14 US and UK sites. Inclusion criteria were: 1) adult patient in CA, 2) advanced airway already in place or placed during the CA, and 3) at least one minute of VR and ETCO2data available after removal of the last minute of CPR in subjects achieving ROSC (due to the rise of ETCO2just prior to ROSC).Results:A total of 563 subjects were enrolled in the parent study. Of these, 225 had ETCO2and VR tracings available, and 201 had sufficient data for inclusion. Mean age was 69.3 (range 18-100), patients were 63.7% male, and 16.4% had a shockable initial rhythm. A total of 116 subjects (57.7%) achieved ROSC, which was sustained in 76 (37.8%), leading to survival to hospital discharge with favorable neurological outcomes in 9 (4.5%). Mean VR was 16.3 vpm, with 171 (85.1%) subjects being ventilated in excess of guidelines; only 16 (8.0%) subjects received 8-10 vpm. Higher VR had a weak but significant association with increased mean ETCO2(linear R2= 0.11, p < 1x10-6) and sustained ROSC (OR 1.05; 95% CI: 1.01-1.11; p = 0.02). Patients with sustained ROSC had a significantly higher VR at 17.7 vpm than those without sustained ROSC at 15.6 vpm (p = 0.007). Patients receiving a VR close to AHA guidelines (6-12 vpm) had a significantly lower rate of sustained ROSC (26.1%, n = 46) than patients receiving >12 vpm (42.0%, n = 148) (OR 2.30; 95% CI: 1.08-4.89; p = 0.031 using a multivariate model including patient age, shockable initial rhythm, known cardiac disease, witnessed IHCA, and use of mechanical compressions).Conclusions:VR within AHA guidelines is rare during IHCA. However, ventilation in excess of current guidelines may increase rates of sustained ROSC, an essential predicate to survival. AHA guidelines on VR in CPR with an advanced airway may not yet be optimized.

Background:Cardiac arrest (CA) has an annual US incidence of >500,000 with survival rates ~10%. Although most studies focus on survival and neurological outcomes, understanding long-term psychological consequences is of equal importance. Some have reported negative psychological outcomes such as anxiety, depression, and PTSD; however, since survivors of other adverse life-threatening disorders, including cancer, report positive psychological growth, we sought to test the hypothesis that CA survival may also be associated with growth of positive psychological traits.Method:Invitations were sent to CA survivors through their local hospitals or national registries to participate in an online pilot cross sectional study. Overall, 47 agreed and were given a series of standardized questionnaires to assess the following positive personality traits: empathy, compassion, forgiveness, altruism, optimism, gratitude, positivity, spirituality, consideration for others’ needs, and happiness. Using a 5-point Likert scale, they then estimated the relative change in these traits since their CA event, where 1=significant decrease, 2=moderate decrease, 3=no change, 4 =moderate increase, and 5=significant increase.Results:Overall 42 of 47 (89%) reported a return to their daily functional activities. Personality trait ratings were analyzed using a sign test relative to a population median score of 3 (i.e. no change) for statistical analysis. Participants showed statistically significant differences in all the assessed personality traits: gratitude (median=4, p<0.0001), compassion (median=4, p= p<0.0001), altruism (median=4, p<0.0001), empathy (median=4, p<0.0001), spirituality(median=4, p<0.0001), consideration for others’ needs (median=4, p<0.0001), forgiveness(median=4, p<0.0005), optimism (median=4, p<0.001), positivity (median=4, p<0.005), and happiness(median=4, p<0.05).Conclusions:Long-term psychological sequelae of CA survivorship remains ill understood. However, some CA survivors may develop greater positive psychological traits following CA. Further studies are required to assess the relationship between CA and long-term positive changes and quality of life, as well as possible therapeutic interventions.